CURS ENGLEZA Boli Infectioase

INFECTIOUS DISEASES
COURSE
2013
Authors:
ef Lucrri Dr. Brndua ilea
ef Lucrri Dr. Carmen Chiriac
ef Lucrri Dr. Iringo Kezdi
ef Lucrri Dr. Anca Georgescu
ef Lucrri Dr. Cristina Grbovan
Asistent Univ. Dr. Andrea Incze
Asistent Univ. Dr. Nina incu
Contents
Preface
Introduction
Chapter 1
Antibacterial Treatment
Chapter 2
Scarlet fever
Erysipelas
Measles
Rubella
Varicella-zoster virus infections. Varicella (Chickenpox)
Herpes zoster (Shingles)
Mumps
Whooping cough
Epstein-Barr virus (infectious mononucleosis)
Diphtheria
Influenza
Viral respiratory infections
Parainfluenza virus infections
Human respiratory syncitial virus infections
Human metapneumovirus infections
Coronavirus infections
44
49
53
56
60
64
67
71
75
79
82
89
93
94
95
96
Chapter 3
Central nervous system infections
Encephalitis
99
125
Chapter 4
Leptospirosis
Rabies
Lyme borreliosis
Anthrax
Tetanus
132
135
139
149
153
Chapter 5
Enterovirus infections
Poliomyelitis
Acute infectious diarrheal diseases
Salmonellosis and typhoid fever
Shigellosis
Cholera
Botulism
158
163
169
178
186
190
195
Chapter 6
Acute viral hepatitis
198
Chapter 7
Sepsis
215
Chapter 8
Infection with the human immunodeficiency virus HIV (HIV)
232
Preface
Despite decades of dramatic progress in their treatment and prevention, infectious diseases
remain a major cause of death and debility and are responsible for worsening the living
conditions of many millions of people around the word.Our goal in publishing this book is to
offer convenient source to the medical students about the basic knowledgein infectiousdisease.
The physicians caring patients for infectious disease must cope with new challenges in diagnosis,
treatment and prevention. Infections frequently challenge the physicians diagnostic skill and
must be considered in the differential diagnoses of syndromes affecting every organ system.
The incidence of different kind of infections is an ever-changing pattern, which is one reason
why the study of infectious diseases is so interesting.We want to convince our students that in 21
century without basic knowledge about infectious diseases nobody can practice medicine
We hope that this book will prove valuable to medical students and young doctors in medical
training, in the day to day management of patients with infectious disease.
The authors
INTRODUCTION
Basic considerations
A century of advance in medicine and public health (better sanitation, clean food and
water supplies, good housing, personal hygiene, vaccines and drugs) has markedly controlled
some diseases and attenuated the risk of most infectious diseases. Because of this, the
epidemiology of infectious disease has changed.In the resource-poor developing countries
infectious diseases continue to cause significant morbidity and mortality.
In this days,there are a numerous emerging and reemerging infectious diseases.
In the last few years a lot of factors were identified as forces to contribute to diseases
emergence and reemergence, such as:
Climate change, global warming, could extend the geographical range of infections
(malaria)
Increased number of older persons, immunocompromised hosts leading to severe,
opportunistic infections
Transplant and cancer patients treated with cytotoxic drugs, become a feertile field for
formerly unusual pathogenic bacteria, fungus, viruses etc.
Environmental degradation could result in inadequate suppliesof safe food and water
Economic development (industrialization, urbanization, irrigation) changes human
demographics, behaviors
In developing and developed countries poverty and malnutrition, migrating people, wars
may bring high rates of diseases (like tuberculosis) into cities.
Genetic modification could, in theory, result in new human pathogens,
We must be prepared for the unpredictable and unexpected: bioterrorism and other
deliberate releases of biological agents
The picture of infectious diseases, at the beginning of the 21st century can be summarized as
follows.
Some infectious diseases start to disappaer: smallpox has been completely eradicated
(WHO 08.05.1980) although there is a potential threat of its deliberate release. Mosquito
control has removed malaria from Romania. Poliomyelitis is close to global eradication.
There are a few infections which have virtually disappeared as endemic diseases: cholera,
typhus, diphtheria.
Some Infections have become much less common or less virulent: scarlet fever, measles,
mumps, rubella, whooping cough, tetanus, Haemophilus influenzae type b diseases,
There are infections whose incidence has remained unchanged: respiratory infections,
chickenpox (except in countries practising universal childhood varicella vaccination) and
herpes zoster, gastroenteritis, infections of the nervous system, urinary infections etc.
There are infections whose incidence has increased: sexually transmitted infections,
infections in immunocompromised, dibilitated and intensive care unit patients,
methicilin-resistant Staphylococcus aureus (MRSA) infection,Clostridium difficile
infection, infections in intravenous drug users.
There are new infection problems like
a, Infections associated with the increasing travel to tropical countries: malaria, enteric
fever, ameobiasis, helminthiasis, exotic viral infections, travellers diarrhoea
b, Infections associated to newly identified agents: Human immunodeficiency virus
(HIV) infection, variant Creutzfeldt-Jakob disease, multidrug resistance in pneumococci,
4
salmonellae, tuberculosis and staphylococci, severe acute respiratory distress syndrome

(SARS).
Infectious diseases will always exist, continuing advances in dignostics, surveillance,
therapeutics, vaccines are very important in prevention and control.
Transmission of infection
Infection spreads by one of the following methods:
I.
Airborne
Airborne transmittal occurs when infectious agents traveltrough the air on small water or dust
particlesoften for great distances.
Diseases spread by airborne routes include:
Exanthemata: measles, rubella, chickenpox, scarlet fever.
Mouth and throat infections: diphteria, tonsilitis, mumps, herpes stomatitis.
Respiratory tract infections: whooping cough, influenza and other respiratory virus
infections, pulmonary tuberculosis.
General: meningococcal and staphylococal infection.
II.
Intestinal
Diseases spread by the intestinal route include typhoid and paratyphoid, salmonellosis,
dysentery, cholera, gastroenteritis, poliomyelitis and other enterovirus infections, and viral
hepatitis A and E.In another group of ingestion diseases, transmission is direct from
contaminated food. This group includes brucellosis, Q fever, salmonellosis, trichinellosis and
other helminth infections.
III.
Direct contact
Infection may be transmitted directly by local skin contact. This mostly involves cutaneous
infections and includes impetigo and scabies.
IV.
Venereal route
Infection may be transmitted by sexual contact, including sypihilis, gonorrhoea,

lymphogranuloma venereum and herpes genitalis infection, HIV and hepatitis B infection.
V.
Insect or animal bite
Infections transmitted by bites include malaria, leishmaniasis, trypanosomiasis, typhus, rabies,

Lyme disease and simian herpesvirus infection.
VI.
Blood-borne
Some infections are commonly transmitted via infected blood or blood products, e.g. hepatitis B,
HIV, hepatitis C.
These do not cover all the complex routes by which disease spreads.
Other diseases may spread by two or more alternative routes. For example, tuberculosis
commonly spreads by airborne infection, but may spreadvia milk by ingestion or even by direct
skin contact.
Pathogenesis of infections
Infectious diseasaes occurs when a pathogenic organism causes signs and sympthoms of
inflammation or organic dysfunction. An infecting agent can be from endogenous ( those
residing on mucosal surfaces or resting latent in various tissues) or exogenous source
5
(transmitted to host from source by direct or indirect contact). The infectious agent first
colonizes at the site of entry (the portal of entry). The most frequent portal of entry of
pathogenic bacteria are: respiratory, gastrointestinal, genital, urinary tracts. The appearence of
disease is supported when the infecting dose is sufficiently large and adherence to epithelium or
other tissue is possible. There are a few adherence factors like: surface hydrophobicity and net
surface charge (the more hydrophobic the bacterial cell surface, the greater the adherence to the
cell surface); specific surface molecules: pili (eg. E coli), fimbriae ( group A Streptococci):
lipoteichoic acid and M protein found on the fimbriae. They multiply and spread directly
through tissues or via the lymphatic system to the blood stream. Alternarively, the proliferative
phase may not result in invasive disease, but instead continue and cause prolonged excretion of
infectious organism-carrier state.
The fitness of a pathogen can be defined as its ability to multiply within a host,
disseminate from that host, translocate to a new host, colonize the new host, and cause infection.
This can be distinguished from the virulence from a pathogen, which refers to the severity of
clinical illness resulting from infection.The specific virulence factors allow pathogens to invade
tissue in a predictable way, they give the ability to evade the hosts immune system by the
production of enzymes: coagulase, beta-lactamases, streptokinases, etc. Outside the factors that
promote colonization, proliferation, and tissue invasion, other important virulence factors include
the capacity to form toxins (toxigenicity). The toxins are secreted proteins (exotoxins) or
structural portionst of the microorganisms (endotoxins).
Host responses to the release of this substances, by fever, chills, local inflamation,
leukocytosis, protein catabolism, serum acute phase reaction, etc. The pathogenesis of infectious
diseases is a complex interplay of microbial action and host reaction. Disease is a complex
phenomenon resulting from tissue invasion and destruction, toxin elaboration and host response.
Diagnosis of infectious diseases
The basic goals of diagnosis in infectious diseases are
-to determin which organ system is affected
-to determin which agent is responsabile
The methods used for the diagnosis of infectious diseases are as follows:
-Careful history, extensive review of occupational, travel, sexual and social informations
-Complete physical examination
-Laboratory tests: for direct and indirect detection of causative agent
direct detection with microscopy; microscopic examinations of body fluids, exudates,

tissues
detection of microbial antigens (particle agglutination tests, enzyme linked
immunosorbent assays, DNA probes, etc)
culture techniques and susceptibility testing
immunologic methods, serologic tests
others:biopsy, skin tests
Treatment of infectious diseases

The rational use of antiinfectiousagents (antibacterial, antiviral, antifungal, antihelmintic etc)
depends on:
I.
Drugs parameters
a, the drugs mechanism of action

6
-spectrum of activity
-pharmacokinetics
-pharmacodynamics
-toxicities
-interactions
b, mechanism underlying infectious agents resistance
c, strategies used by clinicians to prevent, limit resistance
II.
Patient-associated parameters:
-infection site
-other drugs being taken,
-allergies,
-immune status
-excretory status
Writing a prescription for infectious disease practical advices
To treat a patient with infectious disease is much more than prescribing a drug. To approach a
rational treatment, you must cover the folloing aspects:
-Where you want to treat the patient: at home or in hospital?
-Do the patiet need isolation or not?
-Do the patient need a total rest?
-What about his diet?
The chosen drugs must be efficient on
-causative agent (the ethiological treatment: antibacterial, antiviral, antifungal. etc)
-pathophysiology
-symptoms
Before writing a prescription for infectious disease........
It is a truism that any drug that can produce therapeutic benefit can also cause
unexpected, adverse effects (related to dose, to time-course, to patient susceptibility, to other
drugs interactions). Ask yourself if the patient has an infectious diseaseor not? Will the
treatment prevent the disease or not?
State the dose-write out in full
State the route of administration
State the frecvency of administration dosage interval
Give special instructions if necessary
Think about Carmeli s score if you use antibacterial or antifungal treatment
CHAPTER 1
ANTIBACTERIAL TREATMENT
Iringo Kezdi
The number of antimicrobial agents increased year by year because of resistance of new
and old pathogens to the previously used antibiotics.
Antimicrobial treatment is started empirically in most of the cases, because at the time
therapy is initiated, usually, the knowlidge of the infecting microorganism is not available.The
selection of antimicrobial drugs is based on antibacterial activity,susceptibility of infecting
microorganism, efficacy, toxicity, host factors, genetic factors, site of infection, drug
interactions, cost, etc.
These chapter deals with important informations concerning the antimicrobial drugs.
ANTIMICROBIAL DRUG CLASSES
1. -LACTAM ANTIBIOTICS
2. ERYTHROMYCIN GROUP (MACROLIDES)
3. TETRACYCLINE GROUP
4. CHLORAMPHENICOL
5. AMINOGLYCOSIDES
6. POLYMYXINES
7. ANTITUBERCULOUS DRUGS
8. RIFAMYCINS
9. SULFONAMIDES
10. BACITRACIN, MUPIROCIN
11. LINCOSAMIDES
12. METRONIDAZOLE AND TINIDAZOLE
13. GLYCOPEPTIDES
14. STREPTOGRAMINS
15. OXAZOLIDINEDIONES
16. DAPTOMYCIN/LIPOPEPTIDE
17. LIPOGLYCOPEPTIDE/TELAVANCIN
18. QUINOLONES
19. PENTAMIDINE AND ATOVAQUONE
20. URINARY ANTISEPTICS
1.-LACTAM ANTIBIOTICS
Those antibacterial drugs which share a commonchemical nucleus that contains a -lactam
ringare named -lactam antibiotics. These antibiotics areas follows:
I.monobactams
Aztreonam
II.dibactams:
1penicillins (penams)
1.1narrow spectrum
1.1.1- lactamase sensitive
natural penicillin: Phenoxymethylpenicillin (V)-oral
natural penicillin: Benzylpenicillin (G)Benzathine
benzylpenicillin, Procaine benzylpenicillin-parenteral
1.1.2- lactamase resistant
Cloxacillin, (Dicloxacillin, Flucloxacillin),
Oxacillin,
Meticillin,
Nafcillin
1.2extended spectrum penicillins
1.2.1 aminopenicillins:
Amoxicillin,
Ampicillin,
1.2.2.carboxypenicillins:
Carbenicillin(Carindacillin),
Ticarcillin,
Temocillin
1.2.3 ureidopenicillins:
Azlocillin,
Piperacillin,
Mezlocillin
1.2.4other:
Mecillinam(Pivmecillinam),
Sulbenicillin
2cephalosporins
Cefazolin, Cefacetrile, Cefalexin, Cefaloglycin, Cefalonium, Cefaloridine,
1stgeneration Cefalotin, Cefapirin, Cefatrizine, Cefazedone, Cefazaflur, Cefradine,
Cefroxadine, Ceftezole
9
Cefaclor, Cefamandole, Cefminox, Cefonicid, Ceforanide, Cefotiam,

2nd Cefprozil, Cefbuperazone, Cefuroxime, Cefuzonam
generation Cephamycin (Cefoxitin, Cefotetan, Cefmetazole),
Carbacephem (Loracarbef)
Cefixime, Ceftriaxone, Antipseudomonal(Ceftazidime, Cefoperazone),
Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefmenoxime
3rd
Cefodizime, Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime,
generation
Cefsulodin, Cefteram, Ceftibuten, Ceftiolene, Ceftizoxime
Oxacephem: Flomoxef, Latamoxef
4th
Cefepime, Cefozopran, Cefpirome, Cefquinome
generation
5th
Ceftobiprole, Ceftaroline, Fosamil
generation
3carbapenems
Biapenem,
Ertapenem,
antipseudomonal : Doripenem, Imipenem, Meropenem
Panipenem
III.tribactams
Antimicrobial Action
-binding of the drug to receptors, penicillin-binding proteins, blockage of transpeptidation,
inhibitionof peptidoglycan synthesis
Only organisms actively synthesizing peptidoglycan (in the process of multiplication) are
susceptible to beta-lactam antibiotics. Nonmultiplying organisms or those lacking cell walls are
not susceptible.
Microbial resistance to penicillins is caused by four factors:
1 Production of beta-lactamases, eg, by staphylococci, gonococci, Haemophilus species, and
coliform organisms, including extended-spectrum beta-lactamaseproducing bacteria;
2 Lack of penicillin-binding proteins or decreased affinity of penicillin-binding protein for betalactam antibiotic receptors (eg, resistant pneumococci, methicillin-resistant staphylococci,
enterococci) or impermeability of cell envelope;
3 Failure of activation of autolytic enzymes in the cell wall"tolerance," eg, in staphylococci,
group B streptococci;
4 Cell wall-deficient (L) forms or mycoplasmas, which do not synthesize peptidoglycans.
I. Monobactams
Monobactams, so named due their monocyclic beta-lactam ring.The sole marketed monobactam
10
is Aztreonam, resistant to many beta-lactamases.

Aztreonam is active against gram-negative organisms including: Pseudomonas, E
coli,Klebsiella, Proteus Pseudomonasspp,unpredictable against Acinetobacter, Enterobacter,
Citrobacterspp
Clinical use: severe gram negative infections with susceptibil germs
Has no activity against gram-positive organisms or anaerobes.
It can be used in patients with IgE-mediated penicillin allergy.
Dose: 1 g/day, i.v. in gram negative cocci and bacilli infections
II Dibactames
1.Narrow spectrum penicillins
lactamase sensitive
The natural penicillins
-penicillin G for parenteral administration (aqueous crystalline or benzathin penicillin G)
- penicillin V, phenoxymethyl penicillin fororal administration
They are most active against gram-positive organisms and are susceptible to hydrolysis by betalactamases.
Table 1. Antimicrobial spectrum and therapeutical indications of natural penicillins
ANTIMICROBIAL ACTIVITY
CLINICAL USES
1. streprococcus
group
including
anaerobic streptococci
2. susceptible
and
moderately
susceptible pneumococci
3. nonbeta-lactamase-producing
staphylococci
4. meningococci
5. Treponema
pallidumand
other
spirochetes
6. Propionibacterium acnesand other
gram-positive anaerobic bacilli
7. non-difficile clostridia
8. actinomyces
streptococcal pharyngitis and cellulitis

scarlet fever
pneumonia,
meningitis,
sepsis,
endocarditis
diphtheria
anthrax
syphillis
leptospirosis
Lyme disease
actinomycosis
Most infections due to susceptible organisms respond to aqueous penicillin G in daily doses of
12 million units administered intravenously every 46 hours. For life-threatening infections
(meningitis, endocarditis), increased doses (34 million units intravenously every 4 hours) are
required.
11
Pharmacokinetics
-wide extracellular distribution after parenteral administration
-lower levels in the eye, prostate, and central nervous system (however, with inflammation of the
meninges and with appropriate dosing, adequate levels in cerebrospinal fluid)
-benzathine penicillin release extended amount of penicillin, continuous blood and tissue levels
are achieved, allowing the treatment of syphilis.
-penicillin V is the oral penicillin of choice because of its superior bioavailability.
Penicillin is primarily renally eliminated by glomerular filtration and active tubular secretion.
-lactamase resistant penicillins
Antistaphylococcal Penicillins
Oxacillin, cloxacillin, dicloxacillin, and nafcillin are resistant to degradation by beta-lactamases
produced by staphylococci. They are less active than natural penicillins against
nonstaphylococcal gram-positive bacteria. The primary route of clearance of the above agents is
nonrenalthus, no dosage adjustment is needed in chronic kidney disease.
Methicilline is no longer approved in practice due to its nephrotoxicity
Extended-Spectrum Penicillins
The extended-spectrum group of penicillins includes the
Aminopenicillins: ampicillin, amoxicillin
Table 2. Antimicrobial spectrum and therapeutical indications of aminopenicillins
CLINICAL USES
-strains of Proteus mirabilis,
Amoxicillinis
infections
-Listeria,
-nonbeta-lactamase-producing
Haemophilus influenza
strains
given
orally
for
minor
of - acute sinusitis
- acute otitis media
-penicillin-susceptible pneumococcus
- and prophylaxis for endocarditis
-Enterococcus faecalis ampicillin-resistant E Ampicillin is administered intravenously for

faecalis has emerged
-pneumonia,
-meningitis,
-bacteremia, sepsis
-endocarditis.
Ampicillincan be given orally or parenterally.
Amoxicillin is preferable to ampicillin in the oral treatment of infection because of its improved
oral bioavailability and less frequent dosage frequency.
12
Ureidopenicillins(available even in combination with the beta-lactamase inhibitor tazobactam).

These drugs are susceptible to destruction by staphylococcal (and other) beta-lactamases,their
spectrum of activity is similar to the natural penicillins against gram-positive bacteria; however,
these agents offer modest aerobic gram-negative coverage as well.
Table 3. Antimicrobial spectrum and therapeutical indications of ureidopenicillins
CLINICAL USES
-Pseudomonas aeruginosa
Severe infections with sensitive germs
-Klebsiella.
Plurimicrobial infections: biliary, digestive,

genitourinary tract
-E faecalis
-pneumococci.
-Bacteroides fragilis
-Proteus
-Enterobacter spp
-Serratia marcescens
-Enterobacter cloacae
-Citrobacter
Piperacillin(in combination with tazobactam) is given intravenously and increased doses (200
300 mg/kg/d) are required for treatment of infections due to P aeruginosa.
Penicillins Combined with Beta-Lactamase Inhibitors
The addition of beta-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam) prevents
inactivation of the parent penicillin by some, but not all, bacterial beta-lactamases.
Table 4 Marketed products include
Name
penicillin
Augmentin
amoxicillin
Unasyn
ampicillin
Timentin
ticarcillin
Zosyn
piperacillin
beta-lactamase
inhibitor
route
of
administration
250 mg, clavulanic acid

500 mg,
875 mg,
1g
sulbactam
3g
3g
clavulanate
125 mg
orally
0.5 g
1g
100 mg
intravenously
3g
4g
0.375 g
0.5 g
intravenously
tazobactam
intravenously
Table . Antimicrobial spectrum and therapeutical indications of penicillins combined with

beta lactamase inhibitors
13
Drug combination
generally
inactivate
beta-lactamases infections with sensitive germs
produced by Staphylococcus
aureus, H influenzae, Moraxella
catarrhalis, B fragilis
Timentin,
Zosyn
Unasyn, -ampicillin-susceptible
enterococci
P aeruginosa,
Serratia,
Klebsiella
Augmentin
CLINICAL USES
infections with sensitive germs

polymicrobial infections such
as peritonitis from a ruptured
viscus, osteomyelitis in a
diabetic patient, or traumatic
osteomyelitis.
Staphylococcus
aureus,
H acute bacterial rhinosinusitis
influenzae, Moraxella catarrhalis, infections
resulting
from
B fragilis
animal and human bites
refractory cases of otitis media
The beta-lactamase inhibitors are variably and unpredictably effective against beta-lactamases
produced by certain aerobic gram-negative bacilli, such as Enterobacter
Toxicity and adverse events
All penicillins
-allergic reactions, ranging from anaphylaxis and bronchospasm, to macular papular rash
-diarrhea (higher incidence after amoxicillin-clavulanate use)
-liver toxicity (higher incidence after oxacillin use)
-inhibition of platelet aggregation after use of high doses of penicillins, particularlypiperacillin
with tazobactam)
-in excessive doses, particularly with decreased renal function, all penicillins have been
associated with seizures.
CEPHALOSPORINS
The cephalosporins, consist of a beta-lactam ring attached to a dihydrothiazoline ring.
Substitutions of chemical groups result in varying pharmacologic properties and antimicrobial
activities. Cross reactions between penicillins and cephalosporins are related to similarities in the
molecular structure of side chains.
The mechanism of action of cephalosporins is analogous to that of the penicillins:
1 binding to specific penicillin-binding proteins,
2 inhibition of cell wall synthesis,
3 activation of autolytic enzymes in the cell wall.
Resistance to cephalosporins may be due to
-poor permeability of the drug into bacteria,
14
-lack of penicillin-binding proteins,

-degradation by beta-lactamases.
Cephalosporins have been divided into five major groups or "generations" based on their
antibacterial activity:
Table . Antimicrobial spectrum and therapeutical indications of Cephalosporins
GENERATION
ANTIMICROBIAL
ACTIVITY
CLINICAL USES
First-generation
-aerobic
gram-positive
organismsStreptococcus
including
viridans
streptococci,
group
A
hemolytic
streptococcistreptococcus
pneumoniae,
(except
Enterococcus),
meti-Sstaphylococcus
Respiratory infections
Urinary infections
Skin infections,
tissue infections
soft
Prophylaxis of infection
of most clean surgical
procedures
some community-acquired
gram-negative organisms P
mirabilis, Escherichia coli,
Klebsiellaspecies
Second-generation
gram-negative bacteria
Otitis, sinusitis,
indole-positive Proteus and

Klebsiella(including
firstgeneration cephalosporinresistant
strains),
M
catarrhalis,
Neisseriaspecies,
H
influenzae, E.coli,
Tonsillitis ( if failure
with penicillin G, or
reccurences)
mixed
anaerobic
infections,
eg,
peritonitis
and
diverticulitis
some are active against are superior to firstgram-negative anaerobes;

generation agents for
prophylaxis of infection
following
elective
colorectal surgery or
hysterectomy.
Third-generation
Enhanced activity versus

aerobic
Gram
negative
bacteria: E.coli, Shigella,
Proteus, Salmonella
Severe Infections:
Meningitis
Sepsis
Broncho-Pneumoniae
inconsistant activity versus: Nosocomial Infections
Serratia,
Acinetobacter, Surgery
Enterobacter
antibioprophylaxis
15
Modest activity against Febrile

neutropenic
anaerobes
(only
for patient (Ceftazidime)
ceftizoxime)
Gonorrhea, chancroid,
Antipseudomonal
active: and more serious forms
ceftazidime
of
Lyme
diseaseLess active than 1st g. Ceftriaxon
cephalosporins versus Gram
positive
cocci,
gramnegative bacteria
Fourth-generation
are more stable

plasmid-mediated
lactamase
against Severe Infections:

beta- Sepsis
Febrile
neutropenic
has little or no beta- patient Cefepime
lactamase-inducing capacity Broncho-Pneumoniae
that results in improved Nosocomial Infections
coverage
against Surgery
Enterobacter
and antibioprophylaxis
Citrobacter species
Fifth-generation
S Severe Infections:
Skin,
soft
tissues
gram-negative
spectrum infections
activity as third-generation Sepsis
Broncho-Pneumoniae
agents.
Nosocomial Infections
methicillin-resistant
aureus
In meningitis in older patients, third-generation cephalosporins should be combined with

ampicillin or trimethoprim-sulfamethoxazole until L monocytogeneshas been excluded.
Not all cephalosporins fit neatly into this grouping, and there are exceptions to the general
characterization of the drugs in the individual classes.
They are inactive against enterococci, methicillin-resistant staphylococci, B fragilis. Activity
against H influenzaeis poor, and penicillin-resistant streptococci (both intermediately and highly
resistant) are resistant to first-generation cephalosporins.
Pharmacokinetics and dministration
The 1st Generation
ORAL
Cephalexin, cephradine, and cefadroxilare generally well absorbed. Cefadroxil, because of its
longer half-life, can be given twice daily instead of four times daily.
INTRAVENOUS
Cefazolinis preferred because its longer half-life allows for less frequent dosing. In kidney
disease, it requires dosage adjustment.
First-generation cephalosporins do not adequately penetrate into cerebrospinal fluid they cannot
16
be used in the treatment of meningitis.

The second-generation
Second-generation cephalosporins are a heterogeneous group with marked individual differences
in activity and pharmacokinetics. In general, they are active against gram-negative organisms
inhibited by first-generation cephalosporins, however, with additional aerobic gram-negative
activity.Against gram-positive organisms, second-generation agents are generally less active
than the first-generation cephalosporins (cefuroxime is an exception). Second-generation agents
have no activity against P aeruginosa.
Pharmacokinetics and administration
ORAL
Only cefaclor, cefuroxime axetil, and cefprozil can be given orally.
INTRAVENOUS AND INTRAMUSCULAR
Drugs with shorter half-lives (cefoxitin) require more frequent dosing than drugs with longer
half-lives (eg, cefuroxime). Dosage adjustment is required with kidney disease.
Third-, Fourth- and Fifth-Generation Cephalosporins
Antimicrobial Activity
Most of these drugs are active against staphylococci (not methicillin-resistant strains) but less so
than first-generation cephalosporins.
While inactive against enterococci, most third- and fourth-generation cephalosporins inhibit
most streptococci (ceftazidime is an exception to this rule).
Ceftriaxone and cefotaximeoffer the most reliable antipneumococcal coverage.
Ceftazidime is unique among all third-generation agents because it is active against P
aeruginosa.Acinetobacter, Citrobacter, Enterobacter, and nonaeruginosa strains of
Pseudomonasare variably sensitive to third-generation cephalosporins,
Listeria is uniformly resistant.
Activity against B fragilisis variable.
In contrast to the third-generation agents, cefepimethe only currently available fourthgeneration cephalosporinis more active against Enterobacter and Citrobacter, and has grampositive activity similar to that of ceftriaxone.
Cefpodoxime proxetil, cefdinir, cefixime, and ceftibuten(the only oral agents in this group) are
more active than cefuroxime axetilagainst gram-negative pathogens. However, none of these oral
agents are equal to the parenteral third-generation cephalosporins against these pathogens.
All third- and fourth-generation cephalosporins are uniformly active against Streptococcus
pyogenes (group A Streptococcus).
This class drugs are ineffective against enterococci and Listeria monocytogenes.
The one available fifth-generation cephalosporin, ceftaroline, is unique in that it represents the
only beta-lactam with in vitro activity against methicillin-resistant S aureus.The gram-negative
spectrum of activity approximates that of ceftriaxone, thus it is inactive against P aeruginosa,
Acinetobacter spp, and B fragilis.
Pharmacokinetics and Administration
The intravenous third- and fourth-generation agents distribute into extracellular fluid and reach
levels in the cerebrospinal fluid exceeding those needed to inhibit susceptible pathogens. At the
17
present time, the cerebrospinal fluid penetration of ceftaroline is unknown and the drug has not
been studied in the treatment of meningitis.
The half-lives of these drugs are variable, resulting in differing dosage needs Ceftriaxoneis
eliminated primarily by biliary excretion, and no dosage adjustment is required in kidney
disease. The other drugs are eliminated primarily by the kidney and thus require dosage
adjustment in kidney disease.
Adverse Effects of Cephalosporins
Allergy, including anaphylaxis, fever, skin rashes, nephritis, hemolytic anemia. The frequency of
cross-allergy between cephalosporins and penicillins approximates 510%.
Toxicity
Ceftriaxone has been associated with a dose-dependent biliary sludging syndrome and
cholelithiasis due to precipitation of drug when its solubility in bile is exceeded.
Cefepimemay be associated with neurotoxicity, particularly with large doses and concomitant
kidney disease.
CARBAPENEMS
This class of drugs is structurally related to beta-lactam antibiotics.
Tabel Antimicrobial spectrum and therapeutical indications of carbapenems
Drug
CLINICAL USES
Imipenem
most
gram-negative
rods
including P aeruginosa grampositive
organisms
and
anaerobes, with the exception of
Burkholderia
cepacia,
Stenotrophomonas maltophilia, E
faecium, and methicillin-resistant
S aureus and Staphylococcus
epidermidis
like imipenem plus extendedspectrum
beta-lactamaseproducing
E
coli
and
Klebsiellaspp
Respiratory infections
Urinary infections
like imipenem plus extendedspectrum

beta-lactamaseproducing
E
coli
and
Klebsiellaspp
aerobic
gram-positive
and
anaerobic organisms is inactive
against
Pseudomonas,Acinetobacter
intra-abdominal
infections
peritonitis and pelvic infections and
pyelonephritis
Meropenem
Doripenem
Ertapenem
18
Skin
infections,
infections
soft
tissue
Prophylaxis of infection of most

clean surgical procedures
Febrile neutropenic patient
Serious hospital-acquired infections,
meningitis
Febrile neutropenic patient
Polymicrobial infections such as
peritonitis and pelvic infections.
Severe infections with susceptibile

germs
Imipenem. Dosage adjustment is required in renal insufficiency.

Meropenem and doripenem are less likely to cause seizures than imipenem.
The usual dose for meropenem is 12 g intravenously every 8 hours. Dosage adjustment in renal
insufficiency is required.
Ertapenem can be administered once daily. The usual dose is 1 g intravenously every 24 hours
and adjustments are needed for renal insufficiency.
The most common adverse effects of carbapenems are diarrhea, reactions at the infusion site, and
skin rashes. Seizures, nausea, and vomiting are more commonly observed with imipenem.
Patients allergic to penicillins may be allergic to imipenem and meropenemas well.
ERYTHROMYCIN GROUP (MACROLIDES)
The macrolides are characterized by a macrocyclic lactone ring with various sugars attached.
Erythromycins inhibit protein synthesis by binding to the 50S subunit of bacterial ribosomes.
While they are generally bacteriostatic, they can sometimes be bactericidal for certain organisms.
Similar to penicillin, the rate of macrolide-resistant S pneumoniae has increased (2535%), and
increased regional resistance in group A streptococci has been reported. Erythromycin-resistant
pneumococci are resistant to azithromycin and clarithromycinas well
Table 21. Antimicrobial spectrum and indications of macrolides
Antimicrobial activity
Clinical use
Legionella,
Bronchitis
Mycoplasma,
Pneumonia with Legionella
Ureaplasma,
Atypical pneumonia
Corynebacterium (including diphtheria),
Skin infections
Campylobacter
Rhodococcus species
Enteral infections (Yersinia, Campylobacter,

Cryptosporidium)
Bartonella species
Genital infections
ChlamydiaandChlamydophila(including
ocular and respiratory infections) organisms.
Toxoplasmosis (pregnancy)
Bacillary angiomatosis, hepatic peliosis
They are useful alternatives in the treatment Infections in stomatology

of streptococcal and pneumococcal disease in
patients with serious penicillin allergy, such
as anaphylaxis.
Methicillin- Sensitive Staphylococcus
Moraxella catarrhalis, Bordetella pertussis
Erysipelotrix, Campylobacter, Treponema
Mycoplasma, Chlamydia, Rickettsia
19
GN cocci,
Toxoplasma
gondii
(SPYRAMICINE,
ROXITHRO, CLARITHROMYCINE)
Atypical Mycobacteria
Bartonella
SINERGISTINS:
-
Methicillin- resistant Staphylococcus

Penicillin- restistant Pneumococcus
GP anaerobes

Erythromycins are excreted primarily nonrenally; no adjustment is therefore required in renal
insufficiency.
Azithromycinis available for oral and intravenous use; the latter is particularly useful in the
treatment of Legionnaire disease.
Adverse Effects
Nausea, vomiting, and diarrhea may occur after oral or intravenous intake.
Erythromycinsparticularly the estolatecan produce acute cholestatic hepatitis (fever, jaundice,
impaired liver function), probably as a hypersensitivity reaction. Hepatitis recurs if the drug is
readministered.
Fidaxomycin
Fidaxomycin is a nonabsorbed macrolide approved for the treatment of Clostridium
difficileinfection.
At a dose of 200 mg twice daily for 10 days, fidaxomycin is equal to vancomycinin the treatment
of this disease.
An advantage of fidaxomycin compared to oral vancomycin is that the macrolide is associated
with fewer recurrences as measured by 25 days after treatment conclusion.
While the drug offers an important advance in the treatment of C difficile infection, its
considerable acquisition cost is a barrier to its use in most patients with this disease. The most
common adverse events reported in clinical trials include nausea and vomiting.
Azalides
Table 21. Antimicrobial spectrum and indications of azalides
Clinical uses
H influenzae(azithromycin > clarithromycin > treatment of streptococcal pharyngitis,

erythromycin).
uncomplicated skin infections,
Chlamydia trachomatis,
acute bacterial exacerbations of chronic
Ureaplasma urealyticum,
bronchitis, acute sinusitis
Haemophilus ducreyi.
Azithromycinis used as single-dose therapy (1

g) for: chlamydial genital infections,
20
Atypical
mycobacteria
(Mycobacterium chancroid,nongonococcal urethritis in men
avium-intracellulare,
Mycobacterium and incubating syphilis, treating trachoma,
chelonei,
Mycobacterium
fortuitum, severe cholera
Mycobacterium marinum),
Weekly 1200-mg doses of azithromycin are
Toxoplasma gondii,
effective in preventing Mycobacterium
Campylobacter jejuni,
aviumcomplex infections in HIV-positive
patients, and doses of 500 mg daily are useful
Helicobacter pylori,
in M aviumcomplex pulmonary infections in
Borrelia burgdorferi.
nonHIV-positive patients.
azithromycin (500 mg weekly) is as effective
as benzathine penicillin in preventing
streptococcal infections
Clarithromycinhas been used for the therapy
of
-M avium complex infections, usually in
combination with other drugs (eg,rifabutin
and ethambutol), and can be given daily (500
mg twice daily) or three times weekly (1000
mg) as intermittent therapy.
oral clarithromycin (500 mg twice daily for 6
months), in combination with other agents
inM aviumcomplex infections
Clarithromycin in combination regimens for
the therapy of H pylori infections.
Macrolides are inactive on Fusobacterium necrophorum,the etiologic agent in Lemierre

syndrome.
Azithromycin and clarithromycinconcentrate intracellularly and in tissues, have a long terminal
half-life, with high tissue concentrations that persist for days.
Outpatient oral treatment with azithromycin is with once-daily dosing for a total of 5 days (500
mg)
Adverse Effects
Adverse effects of azithromycin and clarithromycin are similar to those of erythromycin, but
upper gastrointestinal upset, the major side effect, occurs less often. Hepatic enzymeelevations
and reversible cochlear toxicity have been reported. Macrolides prolong QT in patients at risk
(patients receiving concomitant agents known to prolong QT, history of prolonged QT).
21
KETOLIDES
Telithromycin, the one available ketolide, is similar in structure to macrolides but has a broader
spectrum of activity. The dose is 800 mg/d orally, and no adjustment is needed for kidney
disease or liver insufficiency. Upon telithromycin's approval, upper gastrointestinal toxicity,
hepatotoxicity and visual disturbances were the most commonly observed adverse events.
Table 21. Antimicrobial spectrum and indications ketolides
Clinical uses
Gram- positive cocci, including: macrolides- There is no clear indication for this agent.
resistant Streptococcus pyogenes, S. aureus,
S. pneumoniae
Gram- negative pathogens: H. influenzae,
Moraxella catarralis, Legionella pneumophila,
Mycoplasma
pneumoniae,
Chlamydia
pneumoniae
TETRACYCLINE GROUP
The tetracyclines are a group of drugs with common basic chemical structures, antimicrobial
activity, and pharmacologic properties.These agentsare inhibitors of protein synthesis, they are
bacteriostatic for many gram-positive and gram-negative bacteria
Table 18. Antimicrobial activity and indications of tetracyclines
DRUG
DOSE-ADULT
DOSE-CHILD
1st Generation
They are strongly inhibitory for

the growth of mycoplasmas,
rickettsiae, chlamydiae, ehrlichia
Vibrio organisms,
spirochetes,
some protozoa (eg, amebas).
Bronchopulmonary
infections,acne,Brucellosis,
Tularemia (in combination
with streptomycin),
TETRACYCLINE
OXYTETRACYCLINE
ROLITETRACYCLINE
3rd Generation
Tetracyclines also have some

activity against pneumococcus
spp., some vancomycin-resistant
enterococci, staphylococus even
methicillin-resistant strains.
Cholerae, genital infections

with
Chlamydia,
endocervicitis,
urethritis,
proctitis,
granuloma
inguinale epididymitis pelvic
inflammatory disease.
DOXICYCLINE
H influenzae
-psittacosis, -Lyme disease
nd
2 Generation
LYMECYCLINE
METACYCLINE
-relapsing
fever,
actinomycosis, -nocardiosis,
MINOCYCLINE
-infections
marinum
caused
by
-malaria, malariaprophylaxis
(including multidrug-resistant
P falciparum).
22
- amebiasis, (in combination

with other drugs)
-recurrent ulcers due to H
pylori.
doxycycline
should
be
considered as a potential
empiric therapy for mild to
moderate
outpatient
pneumonia.

Oral bioavailability varies depending on the drug.
Absorption is impaired by dairy products, doses of tetracyclines should be staggered at least 2
hours before or after receipt of multivalent cations.
Oral bioavailability is moderate with tetracycline and highest with doxycycline and minocycline
(95% or more). Lipid solubility of minocycline and doxycycline accounts for their penetration
into the cerebrospinal fluid, prostate, tears, and saliva.Tetracyclines are primarily metabolized in
the liver and excreted in bile. Doxycyclinerequires no dosage adjustment in kidney disease; in
contrast, other tetracyclines should be avoided or given in reduced dosage.
Doxycycline,minocycline are formulated even for parenteral administration in doses similar to
the oral ones.
Adverse Effects
Allergy, gastrointestinal side effectslike:diarrhea, nausea, and anorexia, impaired hepatic
function Tetracycline administration, particularly doxycycline and minocycline, should be
avoided at bedtime due to the risk of esophageal erosion.
Bones and teeth
Tetracyclines are bound to calcium deposited in growing bones and teeth, causing fluorescence,
discoloration, enamel dysplasia, deformity, or growth inhibition. Therefore, tetracyclines should
not be given to pregnant women, nursing women, or children under 8 years of age.
GLYCYLCYCLINES
Tigecycline, a tetracyclinederivative, is available as a parenteral antibacterial for the treatment of
nosocomial infection.
Table . Antimicrobial spectrum and indications of Tigecycline
Clinical uses
-gram-positive bacteria: methicillin-resistant -complicated

staphylococci, vancomycin-resistant enterococci,
infection
skin
and
-multidrug resistant aerobic gram-negative -intra-abdominal infections

bacilli:Acinetobacter, Enterobacter, Citrobacter E
coli Klebsiella anaerobes B fragilis gram-positive
anaerobes
23
soft-tissue
A loading dose of 100 mg is administered intravenously with maintenance at 50 mg every 12

hours.
Tigecycline has similar adverse events as the tetracyclines; upper gastrointestinal side effects are
particularly common.
CHLORAMPHENICOL
Chloramphenicolbinds to the 50S subunit of ribosomes and inhibits protein synthesis.
Table . Antimicrobial spectrum and indications of cloramphenicol
Clinical uses
S. aureus, S. epidermidis, S. pneumoniae, Chloramphenicolis an alternative to more

Peptococcus- Peptosreptococcus
standard therapy for
1 meningococcal, H influenzae, or
N. gonorrhoeae, Pasteurella multocida, H. pneumococcal infections of the central
nervous system;
influenza, Brucella spp, Bordetella pertussis
2 anaerobic or mixed infections in the central
GP bacilli:
nervous system, eg, brain abscess; subdural
Cprynebacterium
diphtheriae,
Listeria empiema
monocytogenes,
Clostridium
spp,
Prpionibacterium acnes, Actinomyces israelli, 3 alternative to tetracyclines in rickettsial
infections, especially in pregnant women, in
Actinobacillus actinomycetemcomitans
whom tetracycline is contraindicated.
GN bacilli:
4.Typhoid fever
E.coli, S.typhi and Proteus mirabilis (the
other Enterobacteriaceae have verying
sensitivities)
GN cocci and coccobacilli:
Chlamydia, Mycoplasma, Rickettsies

It is used minimally because of its toxicity and the availability of alternative agents.
Chloramphenicolis widely distributed in tissues, including the eye and cerebrospinal fluid.
Chloramphenicol is metabolized in the liver, and < 10% is excreted unchanged in the urine.
Thus, no dosage adjustment is needed in kidney disease. Patients with liver disease may
accumulate the drug, and levels should be monitored.
Adverse Effects
Chloramphenicolin excess of 50 mg/kg/d regularly causes reversible disturbances in red cell
maturation within 12 weeks. In contrast, it is also associated with an irreversible aplastic
anemia in 1:40,0001:25,000 courses of chloramphenicol treatment.
24
AMINOGLYCOSIDES
Aminoglycosides are a group of bactericidal drugs sharing chemical, antimicrobial,
pharmacologic, and toxic characteristics.
All these agents inhibit protein synthesis in bacteria by inhibiting the function of the 30S subunit
of the bacterial ribosome.
Resistance is based on
1 a deficiency of the ribosomal receptor (chromosomal mutant);
2 the enzymatic destruction of the drug (plasmid-mediated transmissible resistance of clinical
importance) by acetylation, phosphorylation, or adenylylation;
3 a lack of permeability to the drug molecule or failure of active transport across cell
membranes.
Resistance can be chromosomal (eg, streptococci are relatively impermeable
aminoglycosides) or plasmid-mediated (eg, in gram-negative enteric bacteria).
to
Anaerobic bacteria are resistant to aminoglycosides because transport across the cell membrane
is an oxygen-dependent energy-requiring process.
Amynoglycosides are not effective against anaerobes, pneumococcus, treponemes!
Absorption, distribution, metabolism, and excretion
Aminoglycosides are not absorbed from the gastrointestinal tract. They diffuse poorly into the
eye, prostate, bile, central nervous system, and spinal fluid after parenteral injection.
The serum half-life is 23 hours in patients with normal kidney function. Excretion is almost
entirely by glomerular filtration.
Adverse effects
All aminoglycosides can cause
-ototoxicity can be irreversible and is cumulative, presenting as hearing loss, or vestibular
damage, manifested by vertigo and ataxia.
-nephrotoxicity is usually reversible
-neurotoxicity appearsin very high doses, usually associated with irrigation of an inflamed
peritoneum, producing a curare-like effect with neuromuscular blockade that results in
respiratory paralysis.
Because of their considerable toxicity and the availability of less toxic agents, aminoglycosides
have been used less often in recent years.
Table 18. Antimicrobial activity and indications of aminoglycosides
DRUG
1st Generation
Streptomycin
Clinical uses
plague and tularemia;
enterococci,
penicillin-resistant
viridans streptococci, S aureus
endocarditis, S aureus and S
epidermidis,
francisella
tuleransis,
brucella,
25
-endocarditis caused by E
faecalisor
viridans
streptococci
(use
in
conjunction with penicillin or
vancomycin)
mycobacterium tuberculosis
-active tuberculosis when

other less toxic drugs cannot
be used;
-acute
brucellosis
combination
tetracycline).
Neomycin, Kanamycin
.
Paromomycin,
These
aminoglycosides
are
closely related, with similar
activity and complete crossresistance. Systemic use has been
abandoned because of ototoxicity
and nephrotoxicity
(in
with
Neomycin, often combined

with
bacitracinand
polymyxin, is a component of
several topical ointments and
creams.
closely related to neomycin and asymptomatic

intestinal
kanamycin, is poorly absorbed amebiasis to treat
after oral administration
-giardiasis in pregnancy in
doses of 2530 mg/kg/d in
three divided doses for 7
days.
-cryptosporidiosis
in
HIV/AIDS, the dosage is 500
mg orally three or four times
daily
2nd Generation
Gentamicin
Tobramycin
The addition of gentamicinto cell -serious infections caused by

wall active agents, such as gram-negative bacteria
penicillin
or
vancomycinis -endocarditis
associated
with
increased
bactericidal
activity
against
viridans streptococci, E faecalis
Tobramycin is like gentamicinin by aerosol (300 mg twice
antibacterial activity
daily) to patients with cystic
It is more active than gentamicin fibrosis
against P aeruginosa
3rd Generation
Amikacin
It is active against many severe

gram
gentamicin-resistant strains:
infections
semisynthetic derivative Proteus,

of kanamycin.
Enterobacter,
negative
mycobacterial infections
Serratia organisms
M avium complex
M fortuitum are inhibited.
26
Netilmicin
less ototoxic and less nephrotoxic severe

infections
than the other aminoglycosides
susceptible germs
with
POLYMYXINS
Basic polypeptides,the polymyxins (colistin and polymyxin B) are bactericidal for certain gramnegative aerobic rods, including Pseudomonas.Systemic use of these agents has been limited
bypoor distribution into tissues, substantial toxicity (nephrotoxicity and neurotoxicity),
It is used in infections caused by multidrug-resistant gram-negative organisms that are sensitive
only to the polymyxins.
Colistin has been used with succes in the treatment of pan-resistant Acinetobacter baumanii and
P aeruginosa.
Dosage adjustments are required with decreased renal function.
ANTITUBERCULOUS DRUGS
Mycobacterium spp are intracellular, have long periods of metabolic inactivity, and tend to
develop resistance to any one drug. Therefore, combined drug therapy is used to delay the
emergence of this resistance. First-line drugs, increasingly used together in all tuberculosis, are
isoniazid,
ethambutol,
rifampin,
pyrazinamide.
Alternative drugs in tuberculosis treatment
In cases of drug resistance (clinical or laboratory) to first-line drugs we can use:
Capreomycin- injectable agent given intramuscularly
Clofazimine - active in vitro against M avium complex and Mycobacterium tuberculosis, given
orally
Cycloserine,a bacteriostatic agent, orally
Ethionamide, like cycloserine, is bacteriostatic and is given orally
The fluoroquinolonesofloxacin, levofloxacin, ciprofloxacin, and moxifloxacinare active in vitro
against M tuberculosis, they have been demonstrated to be efficacious in treating tuberculosis in
patients unable to take isoniazid, rifampin, and pyrazinamide.
Linezolid is effective in achieving culture conversion in patients with treatment-refractory,
highly resistant pulmonary tuberculosis.
RIFAMYCINS
Rifampinused as a primary antituberculous agent, is used as an adjunct in the treatment of S
aureus infections.Is associated with rapid emergence of resistance when is used as monotherapy.
When is used in combinationwith primary antistaphylococcal agents, rifampin improves
outcomes in the treatment of infected prosthetic hardware.
Rifaximin, is a derivative of rifamycin, is nonabsorbable, reaches very high levels in the stool. It
27
is approved for use in nonpregnant women and for persons aged 12 years and older to treat
Rifapentine, a long-acting rifamycin, in combination with isoniazid, can be administered onceweekly for 12 weeks in the treatment of latent tuberculosis.
Table . Antimicrobial spectrum and indications of rifaximin
Clinical uses
aerobic and anaerobic gram-positive and noninvasive traveler's diarrhea (200 mg three
gram-negative organisms.
times daily for 3 days)
- prophylaxis of traveler's diarrhea (200 mg/d)
-recurrent disease with C difficile
-irritable bowel syndrome in certain patients.
-therapy of hepatic encephalopathy (400 mg
twice daily).
SULFONAMIDES
Sulfonamides are structural analogs of p-aminobenzoic acid (PABA) and compete with PABA to
block its conversion to dihydrofolic acid. Organisms that utilize PABA in the synthesis of folates
and pyrimidines are inhibited. Sulfonamides alone are rarely used in the treatment of bacterial
infection. In combination with other drugs, are useful in the treatment of toxoplasmosis and
pneumocystosis.
Trimethoprim and pyrimethamineare compounds that inhibit the conversion of dihydrofolic acid
to tetrahydrofolic acid by blocking the enzymedihydrofolate reductase.
Table . Antimicrobial spectrum of sulfonamides
DRUG
SULFADIAZINE
Gram positive organisms (S.aureus, S.pneumoniae,

S.pyogenes, Enterococcus, fecalis, Corynebacterium
diphtheriae, Listeria monocytogenes, Bacillus antracis)
SULFISOXAZOLE
SULFAMETOXAZOLE
SULFADOXINE
Gram negative organisms (E.coli, Klebsiella, Salmonella,

Serratia, Shigella, H. influenza, N. meningitidis)
Other: Chlamydia trachomatis, Nocardia asteroids
These two agents are generally used in combination with other drugs (usually sulfonamides) to
prevent or treat a number of bacterial and parasitic infections.
Table . Antimicrobial spectrum oftrimethoprim(one part) plus sulfamethoxazole (five parts)
Clinical uses
E coli, Klebsiella, Enterobacter, urinary tract infections, -acute prostatitis,

Salmonella,Shigella,Serratia,
-chronic prostatitis, -parasitic infections:
28
Providencia, S maltophilia, B
cepacia(formerly
Pseudomonas
cepacia),
and
Burkholderia
pseudomallei, Nocardi S aureus
(including methicillin-resistant S
aureus) and about 50% of S
epidermidis isolates, M catarrhalis, H
influenzae,
H
ducreyi,
L
monocytogenes.
prophylaxis (160 mg trimethoprim/day daily)and

treatment (15 mg/kg/d of trimethoprim/day 21 days)
of Pneumocystis pneumonia,
Cyclospora infection
Isospora belliinfection.
- meningitis caused by gram-negative rods
Sulfonamides are the drugs of choice for Nocardia
infections and leprosy
It is inactive against anaerobes and enterococci;

Trimethoprim-sulfamethoxazole is well absorbed from the gastrointestinal tract and widely
distributed in tissues and fluids, including cerebrospinal fluid, achieving similar serum levels
with either intravenous or oral administration. Dosage adjustment is required for renal
insufficiency (creatinine clearance 50 mL/min).
Adverse Effects
-a minor rash or gastrointestinal disturbance, occur in 1015% of non-HIV/AIDS patients
-rash, fever, neutropenia, and thrombocytopenia, often severe enough to require discontinuation
of therapy,occur in up to 50% of patients with HIV/AIDS
-systemic side effects: fever, skin rashes, urticaria; nausea, vomiting, or diarrhea; stomatitis,
conjunctivitis, arthritis, aseptic meningitis, exfoliative dermatitis; bone marrow depression,
thrombocytopenia, hemolytic anemia or aplastic anemia, granulocytopenia, leukemoid reactions;
hepatitis, polyarteritis nodosa, vasculitis, Stevens-Johnson syndrome; reversible hyperkalemia;
BACITRACIN
This polypeptide has a selective activity against gram-positive bacteria. Its use has been limited
to topical application usually in combination with polymyxin or neomycin because of severe
nephrotoxicity associated with systemic administration.
MUPIROCIN
Mupirocinis a naturally occurring antibiotic produced by Pseudomonas fluorescens,active
against:
-gram-positive cocci, including methicillin-sensitive and methicillin-resistant S aureus
-streptococci (but not enterococci).
Used topically, to the anterior nares twice daily for 5 days it is effective in eliminating
staphylococcal nasal carriage. The IDSA recommends the use of mupirocin with chlorhexidine
preferentially over oral antibacterials for methicillin-resistant S aureusdecolonization.
LINCOSAMIDES
CLINDAMYCIN AND LINCOMYCINE
Table . Antimicrobial spectrum of lincosamides and indications
Clinical uses
gram-positive organisms: S pneumoniae, prophylaxis against endocarditis following dental

viridans
streptococci,
group
A procedures in patients allergic to amoxicillin.
29
streptococci, and S aureus, though -as alternative to metronidazolefor the therapy of

resistance has been described in all of bacterial vaginosis.
these organisms.
- to treat aspiration pneumonia,
-anaerobes: Prevotella, Clostridium, - to treat pelvic and abdominal infections,
Peptococcus,
Peptostreptococcus,
to
treat
Pneumocystis pneumonia
(in
Fusobacterium
combination with primaquine)
- to treat staphylococcal osteomyelitis.
While useful in brain abscess, clindamycin is
ineffective in meningitis.
It is widely distributed in tissues but not in cerebrospinal fluid. Excretion is primarily nonrenal
While useful in brain abscess, clindamycin is ineffective in meningitis.
Common side effects are diarrhoea, nausea, skin rashes, antibiotic-associated C difficilecolitis
Metronidazole and tinidazole
Metronidazole is an antiprotozoaldrug(used to treat) active also against some bacteria.
Table . Antimicrobial spectrum and indications of metronidazol
Clinical uses
amebia, giardiasis, Trichomonas amebiasis

and
giardiasis
vaginalis
by Trichomonas vaginalis
Vaginitis
caused
anaerobic gram-negative bacilli Anaerobic infections, active against virtually allB fragilis
(Bacteroides,
Prevotella, isolates.
Fusobacterium),
C difficilecolitis, is less expensive and equally as
Clostridium
efficacious as oral vancomycin
Brain abscess, in combination with penicillin or a thirdgeneration cephalosporin.
H pyloriinfections in combination with clarithromycin plus
omeprazole
After oral administration is well absorbed and is widely distributed in tissues. It penetrates well
into the cerebrospinal fluid, yielding levels similar to those in serum. The drug is metabolized in
the liver, and dosage reduction is required in severe hepatic insufficiency or biliary dysfunction.
Tinidazoleis identical in spectrum of activity to metronidazole.
GLYCOPEPTIDES
VANCOMYCIN AND TEICOPLANIN
Bactericidal for most gram-positive organisms, particularly staphylococci and streptococci;
bacteriostatic for most enterococci (vancomycin-resistant strains of enterococci, particularly E
faecium have emerged)
VANCOMYCIN
30
Vancomycin is not absorbed from the gastrointestinal tract and thus useful orally only for the
treatment of antibiotic-associated enterocolitis. For systemic effect, the drug must be
administered intravenously (30 mg/kg/d in two or three divided doses).
The excretion is via the kidneys. In end-stage kidney disease, the half-life may extend to 8 days.
Indications for parenteral vancomycininclude the following:
1 Severe staphylococcal infections in penicillin-allergic patients; for methicillin-resistant S
aureus and S epidermidisinfections and for serious infections (pneumonia, meningitis) due to
resistant S pneumoniae.
2 Severe enterococcal infections in the penicillin-allergic patient or if the enterococcus is
penicillin-resistant.
3 Other gram-positive infections in penicillin-allergic patients, eg, viridans streptococcal
endocarditis.
4 Surgical prophylaxis in penicillin-allergic patients.
5 For gram-positive infections due to organisms that
Corynebacterium jeikeium.
are multidrug-resistant, ie.
6 Endocarditis prophylaxis in the penicillin-allergic patient.

7.Antibiotic-associated enterocolitis
Rapid infusion or high doses (1 g or more) may induce diffuse hyperemia ("red man syndrome")
and can be avoided by extending infusions over 12 hours.
The drug is potentially ototoxic, nephrotoxic.
STREPTOGRAMINS
Synercid,the one approved streptogramin, is a combination of two synthetic derivatives of
pristinamycinquinupristin and dalfopristinin a 30:70 ratio that is administered
intravenously. Inhibits protein synthesis by binding to bacterial ribosomes. It is bactericidal.
It is used in the therapy of gram-positive infections, particularly:
-methicillin-resistant S aureus,
-S epidermidis
-enterococci, including vancomycin-resistant E faecium.
The recommended dose is 7.5 mg/kg/dose intravenously every 8 hours.
In addition to phlebitis with peripheral administration, the major adverse effect is arthralgias and
myalgias, which resolve with discontinuation of the drug.
It is primarily cleared via the liver.
With the availability oflinezolidanddaptomycin, the indications for this agent are extremely
limited.
OXAZOLIDINEDIONES
Oxazolidinediones represent a class of antibacterials of whichthe one available is Linezolida
bacteriostaticagent. The oral bioavailability of linezolid is complete, with serum levels
approaching those observed with intravenous administration.
The drug is eliminated by liver 70%+ renal 30%.
Bone marrow suppression, particularly the platelet and white blood cell lines represent the
31
primary toxicity. Other adverse effects include neuropathy and mitochondrial toxicity with longterm use.
Table . Antimicrobial spectrum and indications of linezolid
Clinical uses
Methicillin resistant S. aureus (MRSA)

S. epidermidis
Community
pneumonia
Penicillin resistant pneumococci (PRP)
Skin infections
Vancomycin resistant enterococci (VRE)
Other infections with gram positive resistant

germs
and
hospital-
acquired
Vanco- intermediate strains (VISA)

Mycobacteria
DAPTOMYCIN
Daptomycinis a bactericidal lipopeptide with a spectrum of activity similar to that of linezolidor
quinupristin-dalfopristin.
Table . Antimicrobial spectrum and indications of daptomycin
Clinical uses
methicillin-resistant staphylococci
skin and soft tissue infection
vancomycin-resistant enterococci;
treatment of bacteremia
right-sided endocarditis
Daptomycin is only available as a parenteral drug with once-daily dosing.

Dosage adjustment is necessary in the presence of kidney disease.
Adverse event associated with daptomycin is a reversible, myopathy. Daptomycin cannot be
used in the treatment of respiratory tract infection because pulmonary surfactantbinds
daptomycin, resulting in minimal free drug concentrations in pulmonary secretions.
TELAVANCIN
Telavancinis the first approved lipoglycopeptide. It is usedonly for the treatment of skin and
soft-tissue infections due to resistant gram-positive bacterial pathogens in once-daily dosing.
The most commonly observed adverse events are taste disturbance, nausea, headache, reversible
kidney injury.
QUINOLONES
Table 24. Classification and antimicrobial spectra of fluoroquinolones
BIOLOGIC
CLASSIFICATION
FLUOROQUINOLONES
Group I. Limited spectrum
OF MICROBIOLOGIC CLASSIFICATION
Enterobacteriaceae
Nalidixic acid
32
Flumequine
Oxolinique acid
Piromedique acid
Pipemidique acid
Cinoxacine
Group II. Large spectrum
Enterobacteriaceae and: H. influenza
Pefloxacin
Neisseria spp.
Enoxacin
Coagulase negative staphylococcus
Norfloxacin
intracellular pathogens
Ciprofloxacin
Mycoplasma spp
Fleroxacin
P. aeruginosa
Lomefloxacin
Acinetobacter spp.
Ofloxacin
Vibrio cholera
M. tuberculosis
M. leprae
Group III. Extended spectrum
Group II. Spectra
Temafloxacin
Tosufloxacin
S. pneumonia
Moxifloxacin
Streptococcus spp
Grepafloxacin
+/-
Clinafloxacin
Anaerobes
Gemifloxacin
Trovafloxacin
Levofloxacin
Gatifloxacin
Sitafloxacin
The synthetic analogs of nalidixic acid are the quinolones, with a broad spectrum of activity by
inhibition of bacterial DNA synthesis as result of blocking the enzymeDNA gyrase.
The earlier quinolones nalidixic acid, oxolinic acid, cinoxacin,were used only as urinary antiseptics.
The fluoroquinolonederivatives (ciprofloxacin, levofloxacin, gemifloxacin, and moxifloxacin) have
more potent antibacterial activity, achieve clinically useful levels in blood and tissues, and have low
toxicity.
Table . Antimicrobial spectrum and indications of fluoroquinolones
33
Clinical uses
gram-negative bacteria , Enterobacteriaceae
acute and chronic bacterial prostatitis.
Haemophilus,Neisseria,
Brucella,
Moraxella, -sexually
transmitted
diseases
C
trachomatiscervicitis, urethritis, and proctitisShigella, ofloxacin.
Legionella,
Salmonella,
Campylobacter, Yersinia, Vibrio,Aeromonas -nongonococcal
urealyticum.
E coli but resistant strains emerged
P aeruginosalevofloxacin
only
urethritis
caused
by
ciprofloxacinand -pelvic inflammatory disease

-epididymitis- levofloxacin
2. M tuberculosis moxifloxacin,
-complicated skin and soft tissue infections
M fortuitum,Mycobacterium kansasii.
-osteomyelitis caused by gram-negative

3. gram-positive activityincluding against organisms.
streptococci, pneumococci and S aureus and -malignant otitis externa
S epidermidis,including some methicillin traveler's diarrhea
resistant strains -gemifloxacin, levofloxacin,
domestically acquired acute diarrhea.
moxifloxacin.
Fluoroquinolones are effective for prophylaxis:
anaerobic pathogens- moxifloxacin
-against gram-negative
neutropenic patient,
infections
-to eradicate meningococci

nasopharynx of carriers
in
from
the
the
"respiratory
fluoroquinolones"are
gemifloxacin, levofloxacin, and moxifloxacin
are reserved forr the treatment of refractory
infections or high-risk patients, including those
with comorbidities or with recent receipt of
beta-lactam antibacterials.
T pallidum and Nocardiaare resistant to all fluoroquinolones.

After oral administration, the fluoroquinolones are well-absorbed and widely distributed in body
fluids and tissues and are concentrated intracellularly. Optimal oral bioavailability is achieved if
fluoroquinolones are taken 1 hour before or 2 hours after meals.
Most are eliminated via mixed renal and nonrenal pathways. As a result, only modest accumulation
takes place in the presence of kidney disease. Exceptions are ofloxacin and levofloxacin, which are
primarily dependent upon the kidney for elimination.
Adverse Effects
They have a lot of advers effects as follovs:nausea, vomiting, and diarrhea, occasionally, headache,
dizziness, seizures, insomnia, impaired liver function, and skin rashes have been observed as well as
more serious reactions such as acute kidney injury, hypoglycemia (especially withgatifloxacin, which
34
has been removed from the US market), and anaphylaxis.

Fluoroquinolones as a class prolong the QT interval;
Tendinitis and tendon rupture have been reported with quinolone agents. risk factors are well known
and include concomitant corticosteroid use and age > 60 years. The FDA has approved a black box
warning for tendinopathy. Patients experiencing musculoskeletal symptoms while receiving
fluoroquinolones should discontinue therapy.
PENTAMIDINE AND ATOVAQUONE
Pentamidine and atovaquone are antiprotozoalagents that are primarily used to treat
Pneumocystispneumonia.
Atovaquone inhibits mitochondrial electron transport and probably alsofolatemetabolism. Major
adverse effects include rash, nausea, vomiting, diarrhea, fever, and abnormal liver function tests.
The use of atovaquone is limited to patients with mild to moderate Pneumocystis infections who
have not responded to, or cannot tolerate other therapies.
URINARY ANTISEPTICS
These drugs exert antimicrobial activity in the urine but have little or no systemic antibacterial
effect. Their usefulness is limited to therapy and prevention of urinary tract infections.
Table Antimicrobial activity and indications of urinary antiseptics
Drug
Clinical uses
Nitrofurantoin
gram-positive
urinary therapy or prophylaxis of
pathogens E faecalis and cystitis in patients with
Staphylococcus
normal kidney function
saprophyticus,
gram-negative
urinary
pathogens E coli,Citrobacter
Fosfomycin
E coli, including extended- uncomplicated urinary tract

spectrum
beta-lactamase infection
producing isolates,
-E faecalis, and other gramnegative aerobic urinary
pathogens
Nitrofurantoin cannot be used to treat pyelonephritis or prostatitis.

Fosfomycin should not be used for systemic infection.
ANTIFUNGAL DRUGS
Empiric antifungal therapy is instituted only for febrile neutropenic and other high-risk patients.
Tabel Antifungal activity and indications of antifungal drugs
Antifungal drugs
Antifungal activity
Clincal uses
Lipid-based amphotericin B
Aspergillus,
systemic mycotic infections,

infections
caused
by
35
Histoplasma,
Aspergillus and Mucor.
Cryptococcus,
-cryptococcal
meningitiscombined treatment with
flucytosine
Coccidioides,
Candida,
-systemic candidiasis.
Blastomyces,
Sporothrix
Nystatin
wide spectrum
oral candidiasis
Infections of skin
Flucytosine
Candida,
candiduria
Cryptococcus
Combined use of flucytosine

and
amphotericin
B
cryptococcal
meningitis
systemic candidiasis
Natamycin
Fusarium, Acremonium, and keratitis

(plus
others
measures)
Terbinafine
Candida, Aspergillus
Clotrimazole,
cutaneous
candida
Fluconazole
Cryptococcus, Blastomyces oropharyngeal candidiasis,infections. Candida albicans, candidal esophagitis.,-vaginal

C tropicalis, C parapsilosus
candidiasis; candidemia in
both
neutropenic
and
nonneutropenic patients.
surgical
in combination with other

antifungals severe infections
Terbinafine
is
available
topically as well as oral
administration,Is god to use
for fingernail and toenail
infections,.
dermatophytes, oral candidiasis. vaginal

candidiasis,cutaneous
dermatophytosis
-cryptococcal meningitis in
patients with HIV/AIDS
-coccidioidal meningitis
-cutaneous leishmaniasis due
to Leishmania major
is
effective
prophylaxis
against
superficial
and
invasive fungal infections in
36
bone marrow and

transplant recipients
liver
Itraconazole
Histoplasma
capsulatum,
Blastomyces
dermatitidis,
Cryptococcus
neoformans,
Sporotrichum schenkii, and
various
dermatophytes
Aspergillus species
Voriconazol
Candida
and
molds, documented and suspected
Aspergillus,
Fusarium, fungal infections in febrile
Pseudallescheria,and others
neutropenic patients,
sporotrichosis, dermatophytic
infections (including those of
the nails, onychomycosis),
and oral and esophageal
candidiasis.
nonmeningeal
coccidioidomycosis,
and
skeletal disease.
disseminated aspergillosis
drug of choice in Fusarium
and Scedosporiuminfections
Ketoconazol
Posaconazol
Candida
and
molds, prophylaxis of neutropenia
Aspergillus,
Fusarium,
Pseudallescheria
plus
zygomycete
Echinocandins
Candida,
including drugs of choice in the
nonalbicans
species, treatment of infections due to
Aspergillus species.
C glabrata and C krusei.
candidemia
candidiasis
and
invasive
Pseudallescheria boydiiand Fusariumare often resistant to amphotericin B.

Lipid-based amphotericin B is less nephrotoxic than conventional amphotericin B.
The intravenous administration of amphotericin B often produces chills, fever, vomiting, and
headache.
Nystatin has a wide spectrum of antifungal activity but is used almost exclusively to treat
superficial candidal infections.
It is too toxic for systemic administration, and the drug is not absorbed from mucous membranes
or the gastrointestinal tract.
Flucytosine
Flucytosine inhibits some strains of Candida, Cryptococcus,and other fungi. With oral
administration we can achive therapeutic levels in serum, urine, and cerebrospinal fluid. When
used as monotherapy, development of resistance is common; thus, flucytosine is not used as a
single drug therapy except in candiduria. In kidney disease, flucytosine may accumulate to toxic
levels, and dosage adjustment is needed. Toxic effects include bone marrow depression,
abnormal liver function, and nausea.
37
Natamycin
Natamycinis a polyene antifungal drug effective against many different fungi in vitro. The
toxicity after topical application appears to be low.
Terbinafine
Terbinafine, an allylamine, inhibits fungal cell membrane function by blocking ergosterol
synthesis.Most adverse effects are minor (diarrhea, dyspepsia) or transient (taste disturbance).
Rare cases of severe hepatic injury have occurred.
Antifungal Imidazoles and Triazoles
These antifungal drugs (Clotrimazole,Fluconazole, inhibit synthesis of ergosterol, resulting in
inhibition of membrane-associated enzymeactivity, cell wall growth, and replication.
Fluconazole, a bis-triazole with activity similar to that of ketoconazole, is water-soluble and can
be given both orally and intravenously. It penetrates well into the cerebrospinal fluid and eye.
Fluconazole is well absorbed after oral administration (> 90% bioavailability), and serum levels
approach those seen after administering the same dose intravenously. While generally well
tolerated, fluconazole is associated with dose-dependent nausea and vomiting. Altered liver
function tests (alanine aminotransferase, aspartate aminotransferase ) and hepatitis have been
reported.
Itraconazoleis an oral triazole with variable bioavailability. The drug is metabolized by the
liver, and no dosage adjustment is needed in kidney disease.
Adverse effects are; anorexia, nausea, vomiting, and abdominal pain occurring most commonly.
Skin rash has been reported in up to 8% of patients. Hepatitis and hypokalemia occur
uncommonly.
Voriconazoleis a triazole antifungal, oral administration leads to predictable absorption.
The primary toxicity associated with voriconazole is infusion-related, transient visual
disturbances, particularly during the first week of therapy. In addition, voriconazole is associated
with photosensitivity reactions.
Posaconazoleis an antifungal derivative of itraconazole. Posaconazole is superior to
fluconazoleas prophylaxis of neutropenia. The drug is only available as an oral formulation,.
Posaconazole should always be administered with food to ensure adequate oral bioavailability;
the drug is primarily eliminated via nonrenal mechanisms. Posaconazole has primarily upper
gastrointestinal adverse events and occasional liver function test abnormalities. posaconazole is
an inhibitor of cytochrome P450.
Ketoconazole, the first orally bioavailable azole, previously was used in the treatment of a
variety of fungal infections. However, the improved spectrum of activity, reduced toxicity, and
superior pharmacokinetics of newer azoles have reduced ketoconazole to a secondary role.
Echinocandins
The echinocandins (anidulafungin, caspofungin, micafungin) act by inhibiting fungal cell wall
synthesis.Their long pharmacologic half-life confers the advantage of once-daily dosing. No
change in dose is necessary in patients with kidney disease; however, moderate to severe hepatic
disease necessitates a reduction in dosage for caspofungin.
ANTIVIRAL CHEMOTHERAPY
The Antiviral Agents start to develop in the last few years, still we have not so much experience
with them like with antibacterial drugs.
38
We classified this drugs as follows:

Antiviral drugs active against respiratory infections
Antiviral drugs active against herpesvirus infections
Antiviral drugs active against hepatitis viruses
Antiviral drugs active against retroviruses-HIV (discussed in chapter....)
Antiviral drugs active against respiratory infections
Several compounds can influence viral replication and the development of viral disease.
Antivirals for influenza viruses
Table spectrum of activity, route of administration, indications of antivirals against respiratory
infections
Antivirals
Rout
of Active against
administration
Clinical uses
Amantadine
oral
influenza A virus
prophylaxis
and
therapy of influenza A
infection
Rimantadine
oral
influenza A virus
prophylaxis
and
therapy of influenza A
infection
aerosol
influenza A and B
prophilactic
treatment
susceptibile
infections
Adamantanes
Neuraminidase inhibitors
Zanamivir
influenza A H1N1
parenteral
Oseltamivir
oral
critically ill patients

influenza A and B
influenza A H1N1
Peramivir
Parenteral
A H1N1 influenza virus
aerosol
Respiratory
virus (RSV)
availableinvestigationally
Ribavirin
and
of
virus
prophilactic
treatment
susceptibile
infections
and
of
virus
Critically ill patients

with influenza
syncycial RSV infection infants

Parainfluenza
infection
virus
Influenza
A,
B
infection
older
children, adults severe
39
acute
respiratory
syndrome
oral or I.V
Lassa virus
Lassa fever
I.V
Hantaan virus
Hemorhhagic fever
Neuraminidase inhibitors
Zanamivir inhalers are difficult to use for some patients, especially those with asthma and
chronic obstructive pulmonary disease, in whom bronchospasm has been reported. Both drugs
are administered twice daily (oseltamavir, 75 mg orally; zanamivir 10 mg inhalation)
Gastrointestinal adverse events are the most commonly observed side effects with oseltamivir. In
addition, while cause and effect are not well-established, neuropsychiatric disorders, including
suicidal ideation, have been associated with oseltamivir.
Antivirals against herpesviruses
Table spectrum of activity, route of administration, indications of antivirals against
herpesviruses
Drug
Route
of Activ against
administration
Clinical uses
Acyclovir
oral
herpes simplex
intravenous
virus varicella-zoster virus
mucocutaneous herpes
simplex, varicella,
Citomegalovirus
herpes zoster
herpes encephalitis
prophylaxis
against
recurrent
mucocutaneous
and
visceral herpes viruses
infections in transplant
recipients
herpes simplex
topical
Famciclovir
Valacyclovir
Foscarnet
oral
oral
intravenous
herpes simplex,
mucocutaneous
orallesions
varicella
acute herpes zoster

recurrent genital herpes
herpes simplex,
herpes zoster
varicella
acute and reccurent

genital herpes
CMV
prevention of CMV
infection
in
transplanted patient
CMV, herpes
varicella-zoster,
40
simplex, CMV retinitis in HIV

HIV,
HHV6,
ganciclovir- HHV6
resistant CMV
immunossupressed
acyclovir-resistant herpes patients
in
simplex varicella-zoster
Cidofovir
intravenous
all human herpesviruses, CMV retinitis

HHV6,
HHV8,
polyomaviruses,
papillomaviruses,
adenoviruses, poxviruses
(variola, vaccinia)
CMV, herpes simplex
virus, and herpes zoster
virus that are resistant
toganciclovir or acyclovir
Ganciclovir
intravenous
CMV
CMV
retinitis,
esophagogastrointestinal
infections,
hepatitis,
pneumonitis, wasting
illness
in
imunosupressed
patients
prophilaxis of CMV
disease in transplant
recipients
Acyclovir
The absolute oral bioavailability of acycloviris 1030%. Dosage reduction in kidney disease is
required. Since hemodialysis reduces serum levels significantly, the daily dose should be given
after hemodialysis.Acycloviris relatively nontoxic. Resistance has been described, usually in
immunosuppressed patients who have received multiple courses of therapy.
Valacyclovir
Valacyclovir is a prodrug of acyclovirthat has significantly increased oral bioavailability when
compared with acyclovir. After absorption, it is converted to acyclovir and serum levels are three
to five times higher than those achieved with acyclovir.
Foscarnet
Foscarnetis a pyrophosphate analog that inhibits viral DNA polymerase of human
herpesviruses, and the reverse transcriptase of HIV. The drug is much less well tolerated than
acyclovir and ganciclovirand more difficult to administer. Dose adjustments are required for
even minimal impairment in kidney function.Foscarnetcan cause severe phlebitis, hypocalcemia
peripheral neuropathy, seizures and arrhythmias, hypomagnesemia, and hypophosphatemia,
nausea and vomiting
41
Cidofovir
The drug has a prolonged pharmacokinetic intracellular half-life, allowing for administration
every 12 weeks. Cidofovir is associated with a high incidence of nephrotoxicity, sometimes
severe Ocular toxicity, including uveitis and iritis.
Ganciclovir
This is an analog of acyclovirwith similar antiviral activity, including activity against CMV. The
major adverse effect is neutropenia, which is reversible but may require the concomitant use of
colony stimulating factors. Thrombocytopenia, nausea, rash, and phlebitis occur less commonly.
Antiviral drugs active against hepatitis viruses
Tabel Nr Antiviral drugs active against hepatitis viruses, spectrum route of
action,indications
Drug
Route
administration
Lamivudine(3TC)
oral
of Active against
Clinical uses
hepatitis B virus
HIV infection
HIV
Chronic
infection
HBV
prevention
HBV
associated with liver
transplantation
Adefovir
oral
hepatitis B virus
lamivudine-resistant
HBV
Chronic
infection
HBV
HIV
Herpes simplex
CMV
Tenofovir
oral
HBV, HIV
Entecavir
oral
HBV susceptible and Chronic B hepatitis

resistant
to
lamivudine
Telbivudine
oral
HBV susceptible and Chronic B hepatitis

resistant
to
lamivudine
Boceprevir
oral
HCV genotype 1
42
HIV-HBV
coinfection
only in combination
with peginterferon or
oral
ribavirin,
Chronic C genotype 1
hepatitis
Telaprevir
oral
HCV genotype 1
Human interferons
only in combination
with peginterferon or
oral
ribavirin,
Chronic C genotype 1
hepatitis
therapy of chronic
hepatitis
due
to
hepatitis B, C, and D
Lamivudine.
While lamivudine is useful, development of resistance is common with long-term therapy.
Adefovir
high doses have been associated with substantial nephrotoxicity, this complication is rare with
the lower doses (10 mg/d) used to treat hepatitis B.
Tenofovir
The antiretroviral is at least as effective as adefovir and is particularly useful in the treatment of
HIV- and hepatitis Bcoinfected patients.
Similar to adefovir, the primary toxicity associated with tenofovir is nephrotoxicity.
Entecavir
Adverse events are similar to those of other hepatitis B agents and include severe, acute
exacerbation of hepatitis B after discontinuation as well as headache, abdominal pain, diarrhea,
fatigue, and dizziness.
Telbivudine
The most recently approved agent, telbivudine is administered once daily,patients with moderate
or severe kidney disease require dosage adjustment. The adverse effect profile is comparable to
that observed with other nucleoside analogs.
Boceprevir andTelaprevir
The serine protease inhibitors boceprevir and telaprevirrepresent a remarkable advancement in
the treatment of hepatitis C. They are associated with substantial toxicity and adverse events,
drug interactions. Approximately half of patients receiving boceprevir experience anemia,
necessitating erythropoietinadministration. In addition to anemia, dysgeusia, neutropenia, and
thrombocytopenia are common with the use of boceprevir.
Telaprevir is associated with substantial pruritus and other rash, observed in over 50% of
patients.
Human interferons
These agents have antiviral, antitumor, and immunoregulatory properties.
Adverse effects are common and include bone marrow suppression,an influenza-like illness with
fever, chills, nausea, vomiting, headache, arthralgia, myalgias.Considering the poor tolerability
of interferon, only a minority of patients infected with hepatitis C are actually candidates for
therapy.
43
CHAPTER 2
Scarlet fever
Anca Georgescu
Scarlet fever is an acute infectious, endemic-epidemic disease, caused by the infection with
group A beta-hemolytic streptococcus (GABHS), clinically manifested by fever, enanthema and
characteristic exanthem, followed by desquamation.
Etiology
GABHS known as Streptococcus pyogenes due to the potential to cause suppurative
infections, is the only representative of the group A streptococci, according to Lancefields
classification. It is a sporulated, gram-positive cocci, arranged in piles or short chains, which on the
areas with blood, produces, around the colonies, complete hemolysis (beta).
The GABHS cells structure is complex, consisting of somatic components (capsule, cell
wall, cytoplasmic membrane, cytoplasm), expressing multiple antigens on its surface:
capsular antigens; the capsule is made up of hyaluronic acid, which opposes phagocytosis,
being a virulence factor; they are poorly antigenic, but have a role in pharyngeal colonization
cell wall antigens located in three layers:
- the inner layer, mucopeptidic (MP)
- the middle layer of polysaccharide nature protein C, according to which the streptococci in
19 Lancefield groups (AM) are classified
- the outer layer: contains the M protein, which confers type specificity, through its structural
variability (there are over 100 serotypes); it is the major virulence factor, through the
involvement in the process of bacterial attachment and the strong antiphagocytic effect, due to
binding to plasma fibrinogen
Both C and M proteins have structural and antigenic similarities to particular components of
human tissues (from the heart, synovial valves, kidney), having a crucial role in determining
the pathogenesis of post streptococcal diseases.
cytoplasmic proteins, with the role of cross-reactive antigens
On the other hand, GABHS produces and releases extracellular products, represented by
toxins and enzymes, with systemic toxic role and in the spread of infection. The most important
ones are: streptolysin O (strong antigen) and S, streptokinase (role in fibrinolysis) Spe-B cysteine
proteases (role in the production of toxic shock), hyaluronidase, DNase and pyrogenic exotoxins A,
B and C, which have a role in the destruction of cell membranes; they are highly immunogenic,
causing antitoxin antibodies and antitoxic immunity. In scarlet fever, the exotoxin (previously
known as erythrotoxin or erythrogenic toxin) is responsible for the rash..
Epidemiology
Scarlet fever is universally spread, but tends to predominate in areas with a temperate
climate, with predominant manifestation in the cold season. The source of infection is represented
by patients with scarlet fever or those with angina, or porting of GABHS.
The disease is commonly spread by airborne transmission, by direct contact or indirectly via
contaminated objects; in this case the gateway is the pharyngeal mucosa. The digestive transmission
is possible as well (through milk / milk contaminated with GABHS) and rarely the cutaneous one
through open, cutaneous or surgical wounds that serve as gateways ("the plague" scarlet fever).
44
The contagious effect of patients with scarlet takes 2-3 days in case of a correct treatment
with antibiotics; GABHS carriers retain this status for an indefinite period of time.
Responsiveness is general, but the disease prevails between children of 4-12 years old and
very rarely occurs in infants and elderly.
Immunity after scarlet fever is solid and lasting, conferred by eritrogen antitoxin antibodies,
so that reinfection with scarlet fever are extremely rare, produced by secretory serotypes of other
exotoxin type. However, reinfections with GABHS can be common, but with other types, the
antimicrobial immunity being serotype specific.
Pathogenesis
GABHS limits itself to the entrance gate - pharyngeal, rarely cutaneous or puerperal, where
after attachment multiplies and releases the toxins and enzymes mentioned above. Erythrogenic
exotoxin which is the one which broadcasts by blood, the streptococcus remaining stuck at the gate,
where produces inflammation with typical angina manifestation.
Exotoxin is responsible for specific manifestations of scarlet fever: exanthem followed by
desquamation, fever, digestive and neurological manifestations, which constitute the toxic
syndrome; hypertoxic forms of scarlet fever, with marked toxemia may lead to the installation of
the streptococcal toxic shock, being extremely serious, and s that can cause toxic complications by
damaging some of the organs (hepatitis, myocarditis, nephritis).
Septic syndrome of scarlet fever is caused by the streptococcal infection itself, GABHS
having the ability to spread in the neighboring tissues of the infectious outbreak, causing local
septic complications (adenitis, otitis, mastoiditis, sinusitis) or systemic ones (bacteremia,
septicemia), which are exceptional.
The immuno-allergic syndrome is the result of the occurence of cross-reactive antibodies
against streptococcal antigens at 14-21 days after the acute illness and can cause post-streptococcal
diseases. After the same period of time, the eritrogen antitoxin antibodies occur as well, which give
the specific antitoxic immunity against the scarlet fever.
Clinical picture
Incubation is from 1 to 10 days, on average 3-6 days.
The onset of the disease is typically sudden, even brutal, with 38-40 C fever, dysphagia,
headache, abdominal pain, vomiting; in severe forms agitation or delirium may occur when the
blood pressure lowers in hypertoxic forms.
Physical examination reveals pharyngotonsillar hyperemia, regional angulo-mandibular
lymphadenopathy (which persists), saburral tongue.
The pre eruptive period (the invasion period) is characterized by persistent changes from the
onset, in association with the pharyngeal enantema, consisting of angina and the changes that
constitute the lingual cycle.
Streptococcal angina during scarlet fever may have different aspects depending on the
enzyme equipment of GABHS:
erythematous angina, with an intense pharyngolaryngeal congestion being "red as a flame"
extended at the level of the tonsils, tonsillar pillars, lueta and the soft palate, where is suddenly
demarcated by the hard palate
erythematous pultaceous angina characterized by marked edema and erythema of the
tonsils, which have in their crypt a white-gray exudate
45
pseudomembranous angina the white-gray purulent deposits from the crypts confluents,
forming false membranes on the surface of the tonsils
necrotizing ulcerative Henoch angina, in which the affected area is the same with the
erythematous forms, but ulcers caused by tissue necrosis are present, these may be complicated by
local bleeding by the perforation of the blood vessela, which favors possible systemic
hematogenous disseminations; the general condition is profoundly affected, intensely fetid halitosis
is present; this severe form of angina is caused by strains of streptococci with increased virulence
gangrenous angina, determined by coinfection with anaerobes, most commonly by the
complication of the ulcerative necrotic forms; in these two severe forms, regional adenopathy is
important, intensely painful, extending laterocervical and submandibular; the prognosis is
unfavorable.
The lingual mucosa suffers a characteristic transformation, causing a lingual cycle of scarlet
fever, which is important for the diagnosis by the dynamic changes: on day 1, the tongue is white,
saburral; in days 2-3 desquamation starts from the top and sides of the tongue progressing to its
base, suggesting a lingual "V"; on days 4-5, the desquamated tongue has the pathognomonic aspect
of a "raspberry" due to lingual papillae which became prominent; subsequently the re-epithelization
gives the tongue the aspect of a lacquered, glossy mucosa - "cat tongue" that gradually fades until
days 10-12, when it normalizes.
The state period starts at 24-48 hours from the onset, with the advent of scarlet exanthema,
initially on the chest, extending in 24 hours on the trunk and limbs, where is proximally more
expressed; it respects the face, palms and plants. The exanthema consists of a diffuse erythema
with congestive micropapule giving the feeling of a rough skin at touch.
The facies has a characteristic aspect, slapped, with a contrasting perioral pallor with
flushing cheeks, called Filatovs mask.
At the level of the bending folds (axillary, inguinal, abdominal folds), haemorrhagic lines
are distinguished as a result of the microbleeds due to capillary fragility by the action of the
erythrotoxin, at mechanical stress places called Pastia-Grozovicis lines.
During the state period, fever and symptoms from the onset period are maintained, which
may be associated, in the absence of antibacterial therapy, to cardio-circulatory (tachycardia,
hypotension), hepatic (jaundice, hepatomegaly), renal (focal nephritis) , neuropsychological
(meningism, agitation, delirium) manifestations with a toxic mechanism.
The descuamation period occurs 1-2 weeks after onset and can last 2-3 weeks. The aspect
and intensity of the descuamation are significantly influenced by the early instituted antibiotic
treatment: squama, classic in glove flaps or fingers at the level of the extremities and furfuracea
aspect on the face and torso, are very discreet after proper therapy.
Clinical forms
depending on the severity of the disease
average, common shape - corresponds to the one described
benign forms: abortive, oligosymptomatic, forms without rash
severe, malignant forms:
- toxic form: hyperpyrexia, cyanotic or hemorrhagic exanthema, hypotension, tachycardia,
circulatory failure, oligo-anuria, shock, possibly fatal evolution
- septic form: necrotizing ulcerative angina, painful cervical adenitis, adenophlegmons,
septicemia
- toxico-septic form
depending on the aspect of the rash
miliary scarlet fever: rash covered by microvesicles
46
haemorrhagic/ purpura scarlet fever: haemorrhagic exanthema

cyanotic or livid exanthema: in severe, hypertoxic forms
after the gate (see Epidemiology, Pathogenesis)
Complications
toxics: myocarditis, nephritis, hepatitis
- these appear in the early days of the disease
septic:
near the tonsils: tonsillar / peritonsillar phlegmon, adenophlegmon, sinusitis, otitis,
mastoiditis
by propagation towards CNS by the perforation of the cribriform plate of the ethmoid bone:
thrombosis of cavernous sinus, meningitis, brain abscess
by hematogenous spread: endocarditis, bronchopneumonia, abscesses (hepatic, brain, lung),
septic arthritis, meningitis
- these appear in the second week of the disease
immuno-allergic: rheumatic fever, rheumatic carditis, Schonlein-Henoch purpura,
chorea,erythema nodosum, acute diffuse poststreptococcal glomerulonephritis
- these appear in weeks 3-4 of the disease
Diagnosis
Positive diagnosis is based on clinical data (fever, dysphagia, characteristic exanthema and
enanthema, digestive and nervous manifestations) in the presence of epidemiological data (contact
with patients with scarlet / streptococcal angina, or carriers of GAS), with confirmation based on
laboratory data: blood agar
highlighting GAS from throat swab or nasal secretion by cultivation on blood agar or
immunofluorescence
detection of GAS antigen by rapid tests of latex agglutination; the sensitivity of the method is
inferior to the cultural techniques (70%)
serological diagnosis; late: a positive ASLO titer (antistreptolysine O antibody)
nonspecific tests: leukocytosis with granulocytosis, increased ESR, CRP and fibrinogen
Differential diagnosis is done with: measles, enteroviruses, Kawasaki disease, erythroderma,
allergodermia, pre-eruptive rash of chickenpox.
Treatment
Hygienic-dietary treatment
Patients with scarlet fever are hospitalized and they stay in bed for 7 days; the diet is hydro
lacto mellitus all through the febrile period.
Etiologic treatment
The preferred antibiotic is Penicillin G, in doses of 50,000 IU / kg in children and 2-6 million
IU / day in adult, for 7 days. Alternatively, Penicillin V can be used, in double doses prior to the
anterior ones, with an every 6 hours administration. In the case of an allergy to Penicillin,
generation I or II cephalosporins are recommended for 7 days, or macrolides (erythromycin,
clarithromycin, azithromycin) or clindamycin for 10 days. In ulceronecrotic and gangrenous forms,
the antibiotic spectrum will be broadened in order to cover the anaerobic flora (Clindamycin or
association with Metronidazole).
Pathogenetic treatment
In common forms NSAIDs are recommended (Ibuprofen) in the first 3-5 days after onset.
Severe, toxic forms requiring emergency administration of steroids (hydrocortisone hemisuccinate
47
15 to 30 mg / kg / day); in parallel, the administration of standard intravenous immunoglobulins

(0.3-0.4 ml / kg) are recommended.
Symptomatic treatment: anti-pyretic, analgesics, oral disinfectants
Patients convalescent from scarlet fever require dispensary treatment for 3 months, clinical and
laboratory examination (urine test, ASLO titre, CRP, fibrinogen), in order to detect possible
poststreptococcal complications.
48
Erysipelas
Anca Georgescu
Erysipelas is a particular form of infectious acute dermita caused by group A betahemolytic streptococci (all GABHS serotypes - the same species that produce scarlet fever),
characterized by the presence of a plaque with a tendency to expand in a febrile state.
Epidemiology
Erysipelas occurs sporadically, being spread across the globe, but its incidence is higher in
the cold and temperate areas and in winter, as well as other forms of streptococcal infections. It
commonly affects older people, adults and males.
The source of infection is represented by patients with streptococcal infections (scarlet
fever, angina, sinusitis, pyoderma, impetigo) and GABHS carriers. Sometimes the patient may
be the source of infection (endogenous infection).
The transmission of the disease occurs directly (direct contact or by airborne transmission)
or indirectly through contaminated objects.
Infectiousness is reduced. The disease is not followed by the installation of immunity, but
rather, by a tendency to relapse at the same location, through a hypersensitivity effect of the
tissue to streptococcal C polysaccharide but as well because of the particular place the infection
occurs on.
Pathogenesis
The gateway is represented by continuity solutions at the tegumentary level (abrasions,
wounds, varicose ulcers, de-epithelization, interdigital mycosis, insect bites) or at the mucosal
level (dacryocystitis, rhinitis), where, by contiguity, GABHS spreads to the adjacent tegument.
Characteristic to streptococci is multiplication and spreading via the intradermal lymphatic
vessels, that become the premises of the inflammatory process by the presence of cellular
infiltration and vasodilatation, which are associated with edema.
The propagation of infection is centrifugal, in oil slick, so that the intensity of the
inflammatory phenomena in erysipelas is more pronounced at the periphery of the plaque where
there is an inflammatory burelet, compared to its center, which becomes pale.
The intensity of the edema determines particular clinical forms (bullosa, blister) by
cleavage of the epidermis to the dermis, respectively an array of cellulite by edematous
infiltration of the hypodermis.
Repeated episodes of erysipelas, maintained by the local sensitization phenomenon, will
gradually cause an irreversible impairment of the lymphatic microcirculation, which will lead to
a chronic lymphoedema as their sequel, and progressively to elephantiasis. On the other hand,
the lymphoedema itself is a predisposing factor to relapses, as well as the chronic venous stasis
in the varicose disease in case of post-thrombotic syndrome and venous circulatory failure.
Clinical picture
The incubation is 1-7 days.
49
The onset is extremely sudden, brutal, with fever preceded by chills, changing in the
general condition of the patient, sometimes vomiting, abdominal pain, headache. The only
change at the physical examination is the painful adenopathy, detectable in the area to be
interested in the onset of the plaque; if the adenopathy is deep, it may not be palpable but the
patient experiences local pain. In some cases the gateway to the proximity of this region may be
detectable or even obvious.
The state period is installed after a few hours, even 1-2 days after onset, together with the
occurence of the erysipelatous dermal inflammation: it is unique, well-defined, with a tendency
to rapid expansion,with clear edges where the inflammatory burelet is highlighted; it is
characterized by the presence of characteristic signs of acute inflammation: rubor, dolor, calor,
and it is accompanied by a degree of induration and edema. In the acute phase, the color of the
plaque is red; on the hairy skin of the head, it is white to gray and in cardiacs it is cyanotic or
purple. The plaque is warm but not painful, patients feel only a local tension. The pain occurs in
case of septic complications (abscess, phlegmon) and it is present in the location of erysipelas of
the scalp or auricle.
Painful regional adenopathy is present, taking into consideration the lymph nodes that
lymphatically drain the affected area.
Associated clinical signs are fever, digestive and nervous disorders (agitation, delirium,
headache), impaired renal function (proteinuria, oliguria, hematuria).
The evolution of the erysipelatous inflammation is of 10-14 days, according to the correct
antibiotic treatment, and may be extended in particular forms or on important lymphedema.
Relapses occur in 20-25% of patients, predisposing factors being the aforementioned local ones
(see Pathophysiology) but general as well: diabetes, obesity, cirrhosis.
Clinical Forms
Depending on the location:
Facial erysipelas: has the characteristic appearance of a butterfly, including
symmetrically the cheeks and the nasal pyramid. The edema is usually important, and
determines hypodermic infiltration (cellulitis) and evident frontal and eyelid edema
(palpebral fissure closed). The gateway is usually endogenous - an inflammatory process
of the skin or mucosa of the face
Lower limb erysipelas: is the most common, tends to recurrences by maintaining the local
predisposing factors
Post-partum or post-abortion perigenital erysipelas: severe forms
Erysipelas umbilicus of the newborn: potentially fatal
Upper limb erysipelas: occurs in mastectomized patients for breast cancer who develop
chronic upper limb lymphedema after axillary dissection; has a tendency to frequent
relapses
Depending on the aspect of the dermal plaque:
Blister and bullous erysipelas are forms caused by the marked edema; the break of the
blisters followed by the leaking of the content of a yellowish fluid or sero-citrine, which
dries and forms meliceric crusts
Gangrenous erysipela:: occurs in severe forms, by by necrosis of the overlying epidermis
of the placard
Migratory erysipelas: at least one placard from the initial one
Erratic erysipelas: some placards tangent to the lymphangitis route formed from the
gateway towards the inflammatory adenitis
Serpiginous erysipelas: with imprecise edges, wavy extensions
50
Diagnosis
Positive diagnosis concerning erysipelas is mainly clinical (dermal erythematous plaque
with described characters, important infectious syndrome), epidemiological data is missing or are
uncertain and the available laboratory data are often nonspecific: ESR, fibrinogen, CRP,
leukocytosis with granulocytosis; bacteriological examination is possible only in blister or
bullous clinical forms, respectively from throat or nasal swab in endogenous infections.
Differential diagnosis is made with: solar erythema, stasis dermatitis, contact dermatitis,
erythema migrans of Lyme borreliosis, erysipeloid of Rosenbach, acute varicophlebitis and
thrombophlebitis, herpes zoster, allergic exanthema, staphylococcus erysipelas (unique purple
plaque, cold, painful, imprecisely defined, with severe evolution, determined by the
compromised venous microcirculation by intravascular multiplication of staphylococci which
tend to form septic thrombi at this level).
In the erysipelas of the face the differentiation from the ophthalmic zoster, microbial
eczema, cavernous sinus thrombosis, malignant staphylococcal infection of the face (facial
cellulitis with marked edema, necrotic foci, pustules) is necessary to be made.
Complications
The incidence of complications is determined by the accuracy and timeliness of the
antibacterial therapy.
Septic complications
- Local:
a. Superficial: bacterial superinfection (with staphylococci, Gram-negative
bacilli), superficial necrosis, gangrene
b. Profound: abscesses, phlegmons, necrotizing fasciitis, suppurative
lymphadenitis
c. General: septicemia, nephritis
Local complications: lymphangitis, elephantiasis
Venous complications: phlebitis, thrombophlebitis
Immune-allergic complications: acute diffuse glomerulonephritis, rheumatic fever
(the same as after scarlet fever, but they rarely occur)
Treatment
In most cases it is recommended for the patient to be hospitalized, in particular in the
forms located in the lower limbs, which require bed rest throughout the duration of the disease or
in more serious / recurrent / complicated forms. Mild episodes and uncomplicated forms can be
cared for at home, with respecting the rules of hygiene.
Diet is unrestricted after overcoming the febrile period, limiting the intake of salt and
protein in case of renal disease.
Etiological treatment. Penicillin G is the antibiotic of choice in the dose of 4-8 MU / day
(80-100.000UI/kgc/zi) intravenously for 7-10-14 days. In some more severe forms, possibly
complicated ones, the therapeutic response is best on the second and third generation ofd
cephalosporins. In forms that are treated at home, macrolides,clindamycin, aminopenicillin with
beta-lactamase inhibitors (Augmentin) are indicated. In case of bacterial superinfections, the
associate of a quinolone or a aminoglycoside to the therapy with penicillin may be necessary (for
infections with Gram-negative staphylococcus) and metronidazole for the superinfections bz
anaerobes (or monotherapy with clindamycin).
51
Pathogenetic treatment. In common forms NSAIDs are recommended while in the severe
ones, with marked edema, glucocorticoids will be recommended (hydrocortisone hemisuccinate
3-4 mg / kg / day) for 3-5 days.
Symptomatic treatment, painkiller
- Therapy:
- Locally- with weak antiseptic solutions (Rivanol10%)
- Treatment of the entrance gate (varicose ulcer, interdigital mycosis, rhinitis)
- Surgical treatment of deep septic complications
- Prophylaxis of deep venous thrombosis with low molecular weight,with heparin
52
MEASLES
Cristina Grbovan
DEFINITION
Measles is a highly contagious acute, exanthematous respiratory disease with a characteristic
clinical picture and a pathognomonic enanthem : Koplik, s spots, an eruption on the buccal
mucous membranes.
ETIOLOGIC AGENT
Measles virus is the only member of the genus Morbilivirus, part of the family
Paramyxoviridae. On electron microscopy, measles virions are pleomorphic spheres with usual
diameters ranging from 120 to 250 nm. Virions consist of two structures , an inner nucleocapsid
that is a coiled helix of protein and RNA that has a diameter of 17 nm, and an envelope, 10-12
nm thick.
EPIDEMIOLOGY
Measles is seen in every country in the world. Countries in which measles vaccine is widely used
have experienced a marked decrease in the incidence of disease. The introduction and use of
measles vaccine has also changed the age group in which measles occurs. Before use of the
vaccine the incidence of measles in the United States was highest in young children, and the
disease was uncommon in adolescents and rare in adults. After the vaccine was introduction and
clinical cases of measles became less common, unvaccinated children had a greater opportunity
to reach adolescence and young adulthood without an exposure to measles. When a large group
of susceptibles is congregated , as in a college, a miniepidemic of measles may occur.
PATHOGENESIS
Measles virus infects by invasions of the respiratory epithelium, and spreads via the bloodstream
to the reticuloendothelial system , from which it infects white blood cells, thereby establishing
infection of the skin, respiratory tract and other organs. Multinucleated gigant cells with
inclusion bodies in the nucleus and cytoplasm (Warthin-Finkeldey cells) are found in respiratory
and lymphoid tissues and are pathognomonic for measles. After infection, initial replication
occurs in the respiratory epithelium with local spread by lymphatics and a primary viremia 2-3
days after infection. A secondary viremia occurs 3-4 days later and lasts for up to 7 days. The
peak viremia coincides with the prodromal symptoms. The rash results from the immunologic
reaction between the virus antigens and host antibody, with involvement of capillary walls.
IMMUNITY
Immunity to measles following an attack of the disease appears to be lifelong. Following
measles vaccine, immunity is similarly of many years duration and probably lifelong.
CLINICAL MANIFESTATIONS
The incubation period of measles is 10-14 days; it is often somewhat longer in adults that in
children. A prodromal phase lasting several days begins after the incubation period and it is
manifested by :
Malaise
Increasing Fever
Anorexia
Conjunctivitis
53
Nasal discharge
Respiratory symptoms (cough, coriza, )
Koplik spots appear at the end of prodrome

-is a pathognomonic feature of measles
- Bluish-gray specks on a red base
- Most often appear on the mucosa opposite the second molars
- This enanthem persists for several days and begins to slough as
the rash appears
The rash of measles
usually begins on the face and proceeds down the body involving the
extremities , including palms and soles last.
Is erythematous and maculopapular
It becomes confluent , especially on the face and the neck
Usually lasts about 5 days and starts to clear on the skin that was first
involved
The patients with measles is usually most ill during the first or second day of the rash.Several
days after the appearance of the rash the fever abates, and the patient begins to feel better. The
entire uncomplicated illness from late prodrome to resolution of fever and rash lasts 7-10 days;
cough may be the last symptom to disappear.
COMPLICATIONS
The complications of measles can be divided into three groups (according to the site involved):
1) The respiratory tract
2) The central nervous system (CNS)
3) The gastrointestinal tract
1) Respiratory tract involvement, manifested as :
-
Laryngitis
Croup
Otitis media
Pneumonia
2) Neurologic complications :
-
Convulsions
Encephalitis
Subacute sclerosing panencephalitis (SSPE)
3) Gastrointestinal tract complications:

-
diarrhea
DIAGNOSIS
54
Classic measles with cough, coryza, conjunctivitis, Koplik spots, and a maculopapular rash
beginning on the face is easily diagnosed clinically. Laboratory diagnosis of measles is helpful
when the clinician is unfamiliar with the illness due to the decline in cases of clinical measles
since introduction of measles vaccine.
Laboratory findings- lymphopenia and neutropenia are common in measles . Leukocytosis may
herald a bacterial suprainfection.
A specific diagnosis of measles can be made quickly by immunofluorescent staining of a smear
of respiratoy secretions for measles antigen . Measles virus can be demonstrated by culture or
polymerase chain reaction in respiratory secretions or urine. A serologic diagnosis by enzyme
immunoassay (EIA) cannot necessarily be made rapidly if acute and convalescentsphase serum
specimens are examined.
DIFFERENTIAL DIAGNOSIS
Includes:
Kawasaki disease
Scarlet fever
Infectious mononucleosis
Toxoplasmosis
Drug eruption
Mycoplasma pneumonia infection
PREVENTION
The vaccine was used in the United States since 1963 and induces seroconversion in 95% of
recipients and probably confers lifelong protection. For the past three decades measles vaccine
has been available as the combination vaccine measles mumps-rubella (MMR). This vaccine
should be administered to children at 12-15 months of age. A second dose of MMR vaccine is
recommended for school age children. Approximately 10% of healthy vaccines develop a fever,
with temperature up to 39,4 C, 5-7 days after vaccination; this fever lasts 1-5 days and is
accompanied by a transient rash.
Measles vaccine is contraindicated :
for persons with impaired cell-mediated immunity
for pregnant women
for persons with a history of anaphylaxis

neomycin.
due to egg protein and
TREATMENT
Therapy for measles is largely supportive and symptom based.
Patients with otitis media and pneumonia should be given standard antibiotics.
Patients with encephalitis need supportive care, including observation for increased intracranial
pressure.
55
RUBELLA
Cristina Grbovan
Rubella virus was first isolated in 1962 by Parkman, Beuscher, and Artenstein and by Weller
and Neva. Rubella virus is now classified in the Togaviridae family, based on its RNA
genome., icosahedral capsid, and lipoprotein envelope.
On electron microscopy rubella virus is roughly spherical. Its envelope, which has short surface
projections, has a diameter of about 60 nm. Inside is the nucleocapsid that has a diameter of
about 30 nm.
The rubella virus is relatively unstable and is inactivated by lipid solvents, trypsin, formalin,
ultraviolet light
EPIDEMIOLOGY
Rubella was not distinguished from certain other exanthematous infections clinically until the
late nineteenth century. Since postnatal rubella is such a mild illness, the disease was considered
to be of only minor importance for many years. However, in 1941 when Gregg recognized the
link between maternal rubella and certain congenital defects, a more complete picture of
ddisease due to rubella virus began to emerge.
The incidence of clinical cases of rubella is highest in the spring, and it has been traditionally
recognized to be most common in children 5 to 9 years.
Rubella is only a moderate contagious illness in contrast to measles.
Spread of Rubella
Rubella virus is spread in droplets that are shed from the respiratory secretions of infected
persons. Patients are most contagious when the rash is erupting, but they may shed virus from
the throat from 10 days before onset of the rash to 15 days after onset.
Patients with subclinical cases of illness may also transmit the infection to others.
Infants with congenital rubella shed large quantities of virus from body secretions for many
months. The babies continue to excrete rubella virus despite high titers of neutralizing antibody,
a puzzling phenomenon that has yet to be explained.
Persons who have received rubella vaccine do not transmit rubella to others, although the virus
may be isolated from the pharynx.
PATHOGENESIS
The incubation period of rubella ranges from 12 to 23 days, with an average of 18 days. Rubella
virus has been detected in leukocytes of patients as long as 1 week before the onset of symptoms
Age is the most important determinant of severity of rubella. Postnatally acquired rubella is
generally an innocuous infection, and as is true for many virl illnesses, children are apt to have
milder disease than adults. In contrast, the fetus is at high risk to develop severe rubella with
long- lasting sequelae, if infected transplacentally during maternal rubella in early pregnancy.
POSTNATAL RUBELLA
Many if not cases of these infections are subclinical.
56
Of those patients who are symptomatic, children do not experience a prodromal phase, but adults
may have a prodrome of malaise, fever, and anorexia for several days. The major symptoms of
postnatal rubella are adenopathy, which may last several weeks, and rash.
The lymph nodes involved include:
The posterior auricular
Posterior cervical
Suboccipital chains
On occasion splenomegaly also occurs.

The rash of rubella begins on the face and moves down the body. It is maculopapular but not
confluent, may desquamate during convalescence, and may be absent in some cases. An
enanthem , consisting of petechial lesions on the soft palate (Forscheimer spots) has been
described for rubella. The rash may be accompanied by mild coryza and conjunctivitis.
Complications of Postnatal Rubella
The most common complication is arthritis and/or arthralgia, due to rubella virus itself, which
may occur in up to one-third of adult women who contract rubella. This arthritis tends to involve
the fingers, wrists, and knees, and it occurs eithers as the rash is appearing or soon afterward.
Hemorrhagic manifestations occur as a complication in approximately 1 to 3000 cases of rubella.
In contrast to other complications of rubella, this occurs more often in children than in adults.
This complication may be secondary to both thrombocytopenia and vascular damage, and is
probably immunologically mediated.
Encephalitis is an extremely uncommon complication of rubella; it has been reported, during an
epidemic , to occur in 1 of 5000 cases. It occurs more frequently in adults than in children, and is
associated with a mortality of 20 to 50 percent.
Congenital Rubella
Rubella can be a disastrous disease in : early gestation
Leading to fetal death
Premature delivery
Array of congenital defects.
The effects of rubella virus on the fetus are, to a large extent, dependent on the time of infection;
generally the younger the fetus when infected, the more severe illness.
During the first 2 months of gestation the fetus has a 40 to 60 percent chance of
being affected, with an outcome of either multiple congenital defects and/or
spontaneous abortion.
During the third month of fetal life has been associated with a 30 to 35 percent
chance of developing a single defect such as deafness or congenital heart disease.
Fetal infection during the fourth months carries a 10 percent risk of a single
congenital defect.
Occasionally fetal damage is seen if rubella occurs up to the twentieth week of

gestation.
The specific symptoms of congenital rubella may be classified as temporary:

Such as low birth weight
57
Thrombocytopenic purpura
Hepatosplenomegaly
Bone lesions
Large anterior fontanelle
Meningoencephalitis
Generalized lymphadenopathy
Hemolytic anemia
The most common manifestations are deafness:
Cataract or glaucoma
Retinopathy
Patent ductus arterious
Pulmonary stenosis
Behavior disorders
Mental retardation
Microcephaly
Spastic diplegia
DIAGNOSIS
Since rubella is usually a mild disease with nonspecific symptoms, it is often difficult to
diagnose rubella clinically.
Routine laboratory studies are not helpful for diagnosis since the may reveal only a leukopenia
and atypical lymphocytes.
The laboratory diagnosis of rubella is most often made serologically. Hemagglutination
inhibition (HAI) is the most commonly used technique. It is sensitive and simple to perform, so
it is useful for determining whether a person is susceptible or immune to rubella. However ,
because this antibody is detected in high titer very soon after onset of rubella, the HAI test is not
always useful for diagnosis of acte rubella.
Antibody to rubella virus may also be measured by complement fixation (CF), a reliable but
less sensitive technique than HAI. Rubella antibody titers are not detectable by CF until 4 to 8
weeks after onset, so this technique may be most useful when testing acute and convalescent
serum specimens.
DIFERENTIAL DIAGNOSIS
The disease has been confused with other infections such as
Scarlet fever
Mild measles
Infectious mononucleosis
Toxoplasmosis
Roseola
Erythema infectiosum
Enteroviral infections
58
TREATMENT
Since postnatal rubella is such a mild infection in most instances no treatment is indicated. There
is not specific therapy, but for patients with fever and arthritis and/or arthralgia, treatment of
symptoms is indicated.
VACCINATION AGAINST RUBELLA
The rationale for use of the vaccine is to prevent congenital rubella .The vaccines, when properly
administered, produced a seroconversion rate of approximately 95 percent.
59
VARICELLA-ZOSTER VIRUS INFECTIONS

VARICELLA (CHICKENPOX)
Nina incu
Definition:
Highly contagious infectious disease, specifically human, caused by varicella-zoster virus
(VZV), characterized by maculo-papulo-vesicular exanthema and enanthema, fever and malaise,
followed by persistent immunity.
Etiologic agent:
Varicella-zoster virus (VZV) = type 3 Human Herpesvirus, belonging to Herpesviridae
family, subfamily Alpha-Herpesvirinae. It has double-stranded DNA structure.
Epidemiology
Ubiquitous infection, with sporadic or epidemic evolution. In temperate regions, it registers
epidemic peaks during the cold season. The highest incidence is registered among children, but
adolescents or adult seronegative persons may develop the disease as well. Attack rate: 95-100%
among susceptible individuals exposed to VZV (extremely contagious).
Reservoir: specifically human patients suffering from varicella or herpes zoster (VZV is
present in the naso-pharingeal secretions in case of patients with chickenpox and inside vesicular
fluid in case of chickenpox and / or herpes zoster patients). Following primary infection, the
virus persists in latent form at the site of sensorial ganglia, including dorsal roots of spinal
nerves. The patient is not contagious during this stage, but it becomes contagious again when the
infection reactivates, following immune suppression and herpes zoster appears.
Contagiousness: beginning with the last 3-5 days of incubation, until the stage of crusts
(overall 14 days).
Transmission route: direct transmission - airborne, via respiratory droplets (from patients
with chickenpox) or by direct contact with vesicular fluid, or indirect transmission via recently
contaminated objects (from varicella or herpes zoster patients).
Susceptibility: general
Immunity: both humoral (IgM and IgG anti-VZV antibodies) and cellular, follows disease
or vaccination. Immunity following disease is durable, life-long. Duration of vaccination-related
immunity is yet to be established. However, VZV infection reactivation (herpes zoster) occurs
following immune suppression, as VZV persists in latent form inside sensorial ganglia. Infants
born to immune mothers are protected against VZV infection during their first 4-6 months of life
due to transplacental transfer of IgG anti-VZV antibodies from their mothers.
Pathogenesis
VZV penetrates into the human organism through naso-pharingeal and / or conjunctival
mucosa, with local replication, followed by infection of the reticulo-endothelial system and
60
bloodstream penetration (viremia). VZV thus reaches the skin and mucosa, where it causes cell
degeneration, with the appearance of multinucleate giant cells, with eosinofilic inclusions, as
well as various other organs (visceralization).
Clinical manifestations
The incubation period lasts for 10-21 days. Prodrome / Invasion (24-48 hours),
characterized by fever, malaise, myalgia and headache may be absent. Clinical manifestations
include a characteristic pruriginous rash, which evolves in several successive crops, each
accompanied by fever, appearing over a period of 3-5 days. Erythematous maculo-papules
evolve over hours into dew-drop-like vesicles, with erithematous base. Initially, the vesicular
fluid is clear, but it becomes cloudy due to local accumulation of polymorphonuclear cells, fibrin
and cellular detritus. The vesicles centers umbilicate and the vesicles scab. Subsequent crusts
will be discharged spontaneously. The exanthema is generalized, covering trunk, face, limbs and
scalp, and polymorphic lesions at various stages of evolution may be found on the same skin
region (macula-papules, vesicles, crusts) It is accompanied by enanthema rash covering the
oro-pharinx, genital and sometimes conjunctival mucosa (aphtous lesions). In peculiar cases, e.g.
immunocompromised patients, severe forms of disease may occur, with hemorrhagic, bullous
or necrotic exanthema.
Clinical forms:
-
Varicella mitigate
Ordinary form
Hemorrhagic form
Bullous form
Necrotic form
Adults may develop more severe clinical forms than children. Severe forms of disease are
encountered in immunocompromized patients (congenital or acquired immune suppression, e.g.
HIV infection, malignancy, connective tissue disorders, diabetes mellitus, immunosuppressive
therapy, transplant recipients).
Perinatal varicella, occurring in newborns from mothers who developed chicken pox
within the first 5 days before or 2 days after delivery, is usually a severe form, as the newborn
did not benefit from transplacental antibodies transfer from his mother and is therefore not
protected against VZV infection).
Positive diagnosis
Based on:
-
Epidemiologic data: susceptible (seronegative) individual, exposed to VZV infection

by close contact with a patient with chickenpox or herpes zoster within the previous
10-21 days
Characteristic clinical manifestations: fever, rash (exanthema / enanthema)
Laboratory findings: leukopenia or normal white blood cells count. Leukocytosis
occurs in the event of bacterial secondary infection. Serum IgM anti-VZV antibodies
(ELISA, complement fixation test) reflect recent / acute infection, while IgG anti-VZV
antibodies reflect immunity following previous disease or vaccination. Detection of
VZV DNA by PCR from vesicle fluid and / or CSF (in case of VZV infection of the
central nervous system) is available in well-prepared laboratories. Tzanck smear
microscopic examination of cell-base scraping (from skin lesions) may depict
61
multinucleate giant cells. VZV isolation in cell cultures is rarely necessary, usually for
research purposes.
Differential diagnosis
-
herpes simplex virus infections

enterovirus infection (group A Coxsackie virus)
impetigo (Streptococcus / Staphylococcus)
bullous dermatitis
prurigo
multiple insect bites
rickettsialpox (Rickettsia akari)
smallpox or disseminated vaccinia (smallpox is nowadays eradicated; important in
case of biologic warfare)
Complications
Bacterial secondary infection of skin lesions (with Streptococcus / Staphylococcus strains)
the most frequent complication (poor hygiene), requiring antibiotic therapy.
Respiratory complications: varicella pneumonia, tracheo-bronchitis, bacterial pneumonia
due to superinfection. Varicella pneumonia with possible subsequent respiratory failure,
presents nodular infiltrates and interstitial pneumonitis on chest X-ray. It has peculiar severe in
pregnant women.
Central nervous system complications: meningitis, encephalitis, mielitis, Guillain-Barre
syndrome. Usually occurring following the first week of disease. Reye syndrome consists of a
fatty liver degeneration associated with encephalopathy following acetyl-salicylate (aspirin) use
in patients with VZV infection.
Other complications: corneal lesions, nephritis, hepatitis, myocarditis, bleeding diathesis.
Chickenpox in pregnant women: may cause spontaneous abortion, premature birth or
malformations. VZV is teratogenic it may cause central nervous system and limb
malformations, as well as skin lesions with remnant scars.
Treatment
Isolation: at home in mild cases. Hospitalization is compulsory in severe clinical forms or
immunocompromised subjects. Skin and clothes hygiene is required in order to prevent bacterial
secondary infections of skin lesions. Secondary bacterial infection of skin lesions or scratching
may lead to the development of permanent scars and should therefore be avoided. Diet should be
light, with good hydration, and rich in vitamins. Antihistaminic drugs are used to fight pruritus,
antipyretic substances to fight fever. Aspirin and aspirin derivatives is prohibited in chickenpox
due to the risk of Reye syndrome.
Etiologic treatment is indicated in immunosuppressed hosts, severe forms of disease or
complications. However, adolescents and adults are known to develop more severe forms than
children and may benefit from etiologic therapy. Acyclovir is a nucleosidic analogue (guanine
derivative) that inhibits DNA polymerase and thus viral replication. It can be administered in
doses of 30 mg/kg/day orally or via intravenous route, divided into 3-5 doses, for 5-7 days. In
case of renal function impairment, acyclovir doses must be reduced. Valacyclovir, famciclovir
and brivudine may also be used. Iv immunoglobulin administration is useful in severe cases or
immunocompromised patients. In case of neurological complications (meningitis, encephalitis),
62
a short course of corticosteroids is recommended, alongside iv immunoglobulins, depletion and

group B vitamins.
Prophylaxis
Vaccination live attenuated varicella vaccine (Oka strain), administered in two doses in
susceptible children (> 1 year-old), adolescents and adults. Universal vaccination of children
decreases the overall incidence of the disease. Vaccination is prohibited during pregnancy.
Pregnancies should be avoided for at least 3 months following anti-VZV vaccination.
VZIG specific, targeted iv anti-VZV immunoglobulins, recommended in
imunocompromised subjects exposed to VZV infection, within the first 96 (72) hours after
exposure.
Antiviral prophylaxis in patients at high risk who are not eligible for vaccination and
have lost the 96-hours post-exposure window for VZIG administration. It consists of 7-days
course of acyclovir / famciclovir / valacyclovir. It either prevents the onset of the diseases of
reduces its severity.
63
HERPES ZOSTER (SHINGLES)

Nina incu
Definition
Acute infectious disease, caused by a reactivation of varicella-zoster virus (VZV)
infection, subsequent to immune suppression, characterized by dermatomal vesicular rash,
usually accompanied by neuropathic pain.
Etiology and pathogenesis
Varicella-zoster virus (VZV) - type 3 human herpes virus. Following primary infection
(chickenpox), VZV persists in latent form in the sensorial ganglia of the cranial or spinal nerves
(posterior root) of the human host. VZV infection reactivates in case of immune suppression of
various origins: chronic illnesses, (e.g. HIV infection, malignant lesions, connective tissue
disorders, immunosuppressive treatment, transplant recipients, diabetes mellitus), acute diseases,
trauma / surgery, psycho-emotional stress, physical or psychological effort. Rarely, herpes zoster
may be the consequence of massive exposure to VZV from an external source. In cases of
extreme immune suppression, severe clinical forms, including generalization (herpes zoster
varicellosus) may occur.
Epidemiology
VZV DNA was detected in vesicular fluid. The patient may transmit the disease by
direct contact with skin lesions or indirectly, by recently contaminated objects, to susceptible
(seronegative persons) which will subsequently develop chickenpox. Contagiousness lasts until
all vesicular lesions are crusted. Unlike chickenpox, which registers its highest incidence among
children, herpes zoster is more common among persons > 60 years-old, but it may occur in
immunocompromised hosts of any age.
Unilateral vesicular exanthema, with dermatomal distribution, usually associated with
neuralgia. The initial erythematous maculopapular exanthema evolves into vesicles and then
scabs, after several days. Skin lesions usually evolve in one crop, so the exanthema is
monomorphic. As the basal membrane of the epidermis is altered, skin lesions usually result in
permanent pigmented scars, even in the absence of bacterial secondary infection or scratching.
Unlike chickenpox, dermitic rash is accompanied by pain, not pruritus. In case of generalization
of skin lesions, similar to chickenpox rash (herpes zoster varicellosus), the initial dermatomeric
rash can still be distinguished due to the local richness of skin lesions. The average duration of
skin lesions is 10-14 days.
Neuropathic pain (zoster-associated neuralgia), due to acute neuritis, usually precedes
the appearance of the exanthema by several days up to one week and lasts for several weeks or
even months after the resolution of skin lesions (post-herpetic neuralgia PHN). It is described as
a burning sensation, paresthesia or severely disturbing pain. In rare cases, especially in young or
diabetic patients, neuralgia may be absent.
64
Clinical forms
-
Zoster sine herpete neuralgia is present, without the rash (rare)

Herpes zoster without accompanying pain in children
Recurrent herpes zoster multiple episodes of herpes zoster occurring in the same
immunocompromised host over time (e.g. HIV infection)
According to the location of skin lesions:
- Thoracic herpes zoster the most frequently encountered location
(intercostal nerves)
- Herpes zoster ophtalmicus exanthema along the dermatome correspondent
to the ophthalmic branch of the trigeminal nerve (Vth cranial nerve)
predisposes to the risk of keratitis and blindness
- Other locations: cervical, brachial, sciatic, etc
- Ramsay-Hunt syndrome exanthema and pain within the external auditory
meatus or on the auricular pavilion, accompanied by ipsilateral facial palsy
and loss of taste in the anterior two thirds of the tongue (affects the
geniculate ganglion, VII bis cranial nerve)
According to the type of exanthema:
- Bullous herpes zoster
- Hemorrhagic herpes zoster
- Necrotic herpes zoster
- Herpes zoster varicellosus secondary generalization of skin lesions, but
the initial dermatome can still be distinguished
(all in severely immunosuppressed patients).
Positive diagnosis
Mainly clinical.
-
Epidemiologic data: history of chickenpox in the past

Clinical manifestations: dermatomal vesicular rash accompanied by neuralgia
Laboratory findings: detection of VZV-DNA inside vesicular fluid (PCR technique),
or serological tests: serum IgG anti-VZV antibodies (ELISA, FAMA fluorescent
antibody to membrane antigen assay, adherence hemagglutination assay). VZV
isolation in cell-cultures for research purposes.
-
Herpes simplex virus (HSV) infection

Coxsackie virus infections
Contact dermatitis
Burns
Streptococcal / staphylococcal impetigo
Complications and sequelae

-
Central nervous system (CNS) complications: meningitis, encephalitis, transverse

myelitis, Guillain-Barre syndrome,
Granulomatous cerebral angiitis: often involves the internal carotid artery, with
controlateral hemiplegia; it is more frequent in case of herpes zoster ophtalmicus
Respiratory complications: pneumonitis (visceralisation)
65
Ocular complications (ophthalmic herpes zoster): keratitis (leading to blindness),

iridocyclitis, optic neuritis, hemorrhagic / necrotizing retinitis, retinal vascular
occlusion
Other complications: hepatitis (visceralisation), myositis
PHN = post-herpes neuralgia: debilitating, it may persist for weeks / months
following an episode of herpes zoster, even after the resolution of skin lesions;
requires antialgic therapy
Bacterial superinfection of skin lesions (Streptococcus, Staphylococcus)
Scarring
Treatment
Patients should either be isolated at home (mild cases) or hospitalized (severe cases,
complications). Isolation period should last for 10-14 days, until skin lesions have overpassed the
stage of crusts.
Etiologic (antiviral) treatment: acyclovir, a nucleosidic analogue which inhibits DNApolymerase and viral replication. It can be administered orally: 5x800 mg/day in adult patients,
for 7-10 days, or via intravenous route, in severe or complicated cases: 30 mg/kg/day, divided
into 3 doses, for 7 days. Valcyclovir, a prodrug of acyclovir, 3x1g/day 7-10 days orally, or
famciclovir, a prodrug of penciclovir, administered orally 3x500 mg/day for 7-10 days, are also
useful. Acyclovir doses must be modified according to the parameters of the renal function
(creatinine clearance). Acyclovir resistance, due to the impairment of timidine-kinase, a viral
enzyme which phosphorilates acyclovir into its active form, may be extended to famciclovir and
valacyclovir. Brivudine may represent a therapeutic alternative.
Acyclovir topical administration (ophthalmic ointment) is recommended in herpes
zoster keratitis. Corticosteroids are recommended in case of central nervous system
complications and / or uveitis, but only accompanied by antiviral treatment.
The management of PHN (post-herpetic neuralgia) is particularly difficult. It requires
non-narcotic or narcotic analgesics, ranging from natrium metamisole, paracetamol
(acetaminophen), NSAIDs, to narcotic derivatives. Lidocaine patches, amitriptyline
hydrochloride, pregabalin and gabapentin are frequently used substances. Group B vitamins may
be helpful in reducing the course of PHN.
Prophylaxis
Zoster vaccine (containing 18 times the amount of viral antigen contained by Oka antivaricella vaccine) administered to aged subjects (> 60 years old) was reported to reduce the
incidence of herpes zoster by 50% compared to patients who had not received vaccination, by
boosting cell-mediated immune response.
66
MUMPS
Cristina Grbovan
Definition
Mumps is an acute viral infection whose most distinctive feature is swelling of one or both
parotid glands. Involvement of other salivary glands, the meninges the pancreas, and the gonads
also is common. The disease is benign and self-limited, one-third of the persons having
subclinical infection. Meningitis and epididymoorchitis represent the two most important of the
less frequent manifestations of this disease. As the characteristic of many viral infections,
mumps in the postpubertal p erson is usually a more severe illness than in children and more
commonly leads to extrasalivary gland involvement.
Etiologic agent
Mumps virus , is a member of the Paramyxovirus genus of the Paramyxoviridae family which
includes the following genera : paramyxovirus (mumps, parainfluenza, and Newcastle disease
virus), morbillivirus (measles) and pneumovirus (respiratory syncytial virus.)
EPIDEMIOLOGY
Before widespread vaccination, the incidence of mumps was highest in the winter and spring,
with epidemics every 2-5 years. In the prevaccine era 50% of children aged 4-6 years and 90%
of children aged 14-15 years had positive serology of mumps. One attack of mumps usually
confers lifelong immunity. Long- term immunity is also associated with immunization.
PATHOGENESIS
The virus is naturally transmitted via direct contact, droplet nuclei, or fomites and enteres
through the nose or mouth. More intimate contact is needed to transmit mumps than either
measles or varicella. Replication of the virus in the epithelium of the upper respiratory tracts
leads to viremia, which is followed by infection of glandular tissues and/or the central nervous
system (CNS).
The incubation period of mumps generally ranges from 14-18 days with extremes of 7 and 23
days.
The prodromal symptoms are nonspecific and include:
Low-grade fever
Anorexia
Malaise
Headache
Myalgia
Within a day the patients complains of an earache, and tenderness can be elicited by palpation of
the ipsilateral parotid.
Parotitis it is generally bilateral
The orifice of Stensen s duct is frequently edematous and erythematous.
Trismus may result from the parotitis, and the patient may have difficulty
with pronunciation and mastication.
67
The submaxillary and sublingual glands are involved less often than the parotid and are almost
never involved alone.
Epididymoorchitis is the most common extrasalivary gland manifestation in the adult man. It
develops in 20-30% of postpubertal men undergoing mumps infection and is bilateral in one of
six of those with testicular involvement. Gonadal involvement may precede parotitis or occur as
the only manifestation of mumps.
The onset is abrupt
with temperature in the range of 39-41 C
chills
headache
vomiting
testicular pain
Genital examination reveals :
warmth
swelling
tenderness of the involved testicle
erythema of the scrotum
Oophiritis develops in5% of postpubertal women with mimps.A

Pancreatitis is manifested: epigastric pain
Tenderness
Accompanied by fever, nausea, and vomiting.
Mumps pancreatitis is difficult to diagnose because an elevated serum amylase level can be
associated with either parotitis or pancreatitis.
Central nervous system involvement is the most common extrasalivary gland manifestation of
mumps.
Meningeal symptoms, like any of the other manifestations of mumps infection, may occur before
during after, or in the absence of parotitis. Onset averages 4 days after appearance of salivary
gland involvement, but may occur as early as 1 week before or as late as 2 weeks after parotitis.
The typical clinical features associated with viral meningitis are present:
Headache
Vomiting
Fever
Nuchal rigidity
Lumbar puncture yields CSF :
containing 10-2000 cells/mm3
The predominating cells are usually lymphocytes
20-25 percent of the patients have a polymorphonuclear leukocyte

predominance.
68
Protein levels are normal to mildly elevated
Hypoglycorrhacia is reported in 6-30% of the patients, and appears

to be more common than in other viral meningitidies.
More rarely, mumps virus may cause encephalitis.

Other CNS problems occasionally associated with mumps include:
Cerebellar ataxia
Facial palsy
Transverse myelitis
Guillain-Barre syndrome
Aqueductal stenosis leading to hydocephalus
A variety of other manifestations have accompanied mumps infection:
Migratory polyarthritis
Thyroididtis
Mastitis
Hepatitis
Thrombocytopenia
Prostatitis
DIAGNOSIS
In the majority of instances, the diagnosis of mumps is made on the basis of a history of
exposure and on the presence of parotid sweeling and tenderness accompanied by mild to
moderate constitutional symptoms.
The white blood cell and differential counts in mumps are normal, or there may be a mild
leukopenia with a relative lymphocytosis. When meningitis, orchitis, or pancreatitis is
present, leukocytosis with a shift to the left is most commonly encountered.
Serum amylase level is elevated in the presence of parotitis and may remain abnormal for
2-3 weeks.
Laboratory confirmation in typical mumps is unnecessary.
The definitive diagnosis of mumps depends on serologic studies or viral isolation.
PCR also is used to detect mumps virus in clinical specimens.
Highly sensitive enzyme-linked immunosorbent assays are useful for serologis diagnosis
of mumps and for determination of susceptibility to the disease.
Differential Diagnosis of Parotitis

ETIOLOGY
COMMENTS
Systemic infections
Mumps
Rare in countries with vaccination programs
Coxsackievirus infection
Particularly likely in children
HIV infection
In HIV positive-children
antiretroviral therapy
69
receiving
no
Parainfluenza virus type 3 infection
Particularly likely in children associated with

acute respiratory tract symptoms
Influenza A virus infection
Seasonal ; associated with acute respiratory

tract symptoms
Cat-scratch disease
Unusual but described
Epstein-Barr virus infection
Unusual but described
Systemic Noninfectious Causes

Sarcoidosis
Additional manifestations of disease likely
Sygren, s syndrome
Uremia
Diabetes mellitus
Drugs
Thiouracil, Phenylbutazone
Unilateral Parotitis
Ductal obstruction duo to stones or strictures
Unilateral, gradual, onset, suppurative
Parotid cyst
Unilateral, gradual, onset,
Parotid tumor
Unilateral, gradual, onset,
Acute Suppurativ Parotitis

Staphylococcus aureus, Streptococcus species, and gram-negative bacteria, anaerobes
Therapy
-Therapy of mumps parotitis is limited by symptomatic and supportive measures.
-The administration of analgesics and the application of warm or cold compress to the parotid
area may be helpful.
-Intravenous fluid administration is indicated for those patients with meningitis and pancreatitis
who have persistent vomiting.
PREVENTION
Live attenuated mumps vaccine induces antibodies that protect the recipient against infection in
95% of cases. Mumps vaccine is usually administered as part of the measles-mumps-rubella
(MMR) vaccine at the age 12-15 months and again at 4-12 years of age.
As with most other live virus vaccines, mumps vaccine should not be administered to:
Pregnant women
Patients receiving immunosuppressive therapy
Persons with a severe febrile illness, malignancy, or congenital or

acquired immunodeficiency.
70
WHOOPING COUGH
Carmen Chiriac
Definition: Acute contagious infectious disease, determined by Bordetella pertussis

cocco-bacillus (rarely by Bordetella parapertussis), with several weeks of evolution, clinically
characterized by paroxysmal fits of spasmodic coughing preceded by a noisy inspiration.
Coqueluchoide syndrome: - a clinical syndrome similar to paroxysmal whooping cough
crisis determined by adenoviruses, parainfluenza viruses, respiratory syncytial virus.
Etiology
Bordetella pertussis, a small, strictly anaerobic, Gram-negative cocco-bacillus belongs to
genus Bordetella. It is cultivated on the Bordet-Gengou medium (agar + blood + glycerol +
potato). The biologically active products of the bacillus are:
-pertactin: adhesion,enhance protective immunity
- thermostable endotoxin:lipopolysaccharide
-adenylat cyclase toxin:activation of cAMP, antiphagocytic, anti-inflammatory,
haemolytic
- agglutinogens: stimulate the production of antibodies
- filamentous hemagglutinin: are adhesion, antigenic, with immunizing effect,
component of acellular pertussis vaccines.
- pertussis toxin (pertussigen): contains the factors:
- histamine-sensitizing factor,
- lymphocytosis-promoting factors,
- protective antigen
- hypoglycemiant effect- neurotoxin
- mitogenic factors
Specific antibodies: agglutinins, complement-fixating antibodies appear after the second
week of illness.
Susceptibility to antibiotics: the most active substances are Erythromycin, Ampicillin,
Cotrimoxazole.
Epidemiology
The disease is spread all over the world. Its maximum incidence is reported during winter
and spring. Overall morbidity and mortality have dramatically decreased since the initiation of
children immunization.
Source of infection: sick persons, including those with mild clinical forms and the carriers
of B. pertussis.
Transmission: directly, through airborne droplets. Rarely, B. pertussis is transmitted via
freshly contaminated objects.
71
Contagiousness period: 7 days after infectious contact + 4 weeks after onset. Its duration
is reduced to 10 days in cases receiving antibiotic therapy. Maximum attack rate is achieved
during the catarrhal period of the disease, high: 90 % among unimmunized family contacts.
Receptivity is general newborns may get sick immediately after birth, because the
immunoglobulins transmitted from mother do not cross the placenta.
Immunity after disease is durable. Re-infection is possible, with another type of
Bordetella. It is more serious in girls than boys.
Pathogenesis
The germ is not invasive, it attaches to the ciliated epithelial cells in the nasopharynx,
tracheobronchial mucosa, determining local inflammation, irritation of vagal nerve terminations
with initiation of cough reflex-phase of bronchogenic cough. On a cortical level, a dominant
focus of arousal is created (neurogenic period): cough sets off at sensory stimuli. The toxins
released by Bordetella are dispersed in the organism. Systemic manifestations (lymphocytosis)
are the result of toxin activity. The pathogenesis of neurologic events, such as seizures and
encephalopathy, is influenced by:
-
toxic factors
- hypoxic factors by coughing fits with apnea
- hemorrhagic factors
- allergic factors: sensitized at the nucleoprotein complex of coccobacillus.
Pertussis is a prolonged coughing illness, the clinical manifestations vary by age. Pertussis is
most often seen in preschool and school-age children.
The average incubation period: 7-10 days
Catarrhal phase the: week 1-2. It is indistinguishable from the common cold and is characterized
by the following: - high contagiousness
- duration 7-14 days
- ordinary catarrh of respiratory airways
- hyperemic conjunctiva
- mild fever
The cough: initially ordinary. At the end of the catarrhal stage it becomes mainly nocturnal,
spastic and accompanied by vomiting. It is not influenced by symptomatic therapy.
Paroxysmal stage: duration 2-4 weeks. Paroxysmal episodes consist of: aura (the child
anticipates the access), sudden inspiration followed by (5-10) spasmodic expiratory bursts,
expiratory pause (face is congested and cyanotic), resumption: deep prolonged wheezing
inspiration. There may be several cycles of prolonged inspiration and jerky expiratory bursts.
Sputum expectoration is difficult: slimy mucus, accompanied by vomiting. During paroxysmal
episode, the patients face is congested, livid, eyes are injected. He may develop ulceration of
lingual frenum.
The number of paroxysmal episodes within 24 hours:
-
mild forms: 4-6 episodes

72
medium forms 10-30 episodes
severe forms 30-40 episodes, bloated facies with

periorbital edema
Convalescent phase: is characterized by gradual resolution of coughing episodes.

Particularities of episodes in suckling infants and newborns: atypical aspect: prolonged
apnea, glottic spasm, cyanosis, paroxysmal sneezes, seizures.
Physical examination pulmonary auscultation: bronchial rales.
Convalescence stage: - paroxysms become rare in number and intensity.
- vomiting may persist as a phenomenon of conditioned reflex
Clinical forms: severe, medium, mild
- in suckling infants: forms are serious, atypical, lack of resumption, prolonged apnea,
paroxysmal sneezes
- abortive and atypical forms are difficult to diagnose, appear following incomplete vaccination
Complications:
a) Mechanical: intra-cerebral, conjuctival, pulmonary, nasal hemorrhages, rectal prolapse,
umbilical hernia, pneumothorax, emphysema, seizures, atelectasis.
b) Bronchopneumoniae, pneumoniae, otitis,
c) Encephalitis: severe in infants, it has complex pathogenesis, appears in week 3-4 of illness,
with seizures
Sequelae: bronchiectases, emphysema, asthma, psychic retardation, motor sequelae
Positive diagnosis
If the epidemiologic data and the classic symptoms of pertussis are present ,the diagnostis is not
difficult.
Laboratory findings: leukocytosis 20-50.000/mm3 with lymphocytosis (60-80%), normal ESR
Characteristic chest X-ray image: hilar and basal infiltrates in the cardio-frenum angle, Gotche
triangle or heart in flame.
Bordetella pertussis isolation from naso-pharyngeal secretions, during catarrhal phase and at the
beginning of paroxysmal phase, by cultivation on Bordett-Gengou medium(gold standard of
diagnosis) or using fluorescent antibodies
-Real-time PCR methods are more sensitive than culture,result can be available within hours.
-
Serologic tests: agglutination and complement fixation test
-
during catarrhal stage: influenza, measles, adenoviroses
during paroxysmal stage: compressive mediastinal formations, laryngeal spasm, spastic

cough: adenoiditis, intralaringeal / intrabronchial foreign body
Prognostic: severe in children younger than 2 years old.

Treatment
73
-Early treatment of pertussis is very important. If treatment for pertussis is started early in the
course of illness, during the first 1 to 2 weeks before coughing paroxysms occur, symptoms may
be lessened.
-Isolation at home or at hospital
-Diet: fractioned meals in reduced amounts
-Antimicrobial treatment: Erythromycin, 40-50 mg/kg/day, Clarithromycin, Azithromycin,
Ampicillin, Cotrimoxazole
Pathogenic treatment: cough tranquilizers, antihistamines, oxygen therapy, assisted breathing,
postural drainage, aspiration of respiratory secretions, vitamins. Bacterial superinfections:
antibiotics therapy Encephalitis: cerebral edema control, anticonvulsants.
Prophylaxis
Regarding patients and contacts:Compulsory to declare
Isolation of contacts, 7-10 days prophylactic course of antibiotics
The best way to prevent pertussis is to get vaccinated. There are vaccines for infants, children,
preteens, teens and adults. The childhood vaccine is called DTaP (a combination vaccine that
protects against three diseases: diphtheria, tetanus and pertussis).
The development of acellular pertussis vaccines have replaced whole-cell pertussis vaccine.The
acellular pertussis vaccines are less reactogenic than whole-cell pertussis vaccine and may be
used for booster immunization in older childrens and adults. The pertussis booster vaccine for
adolescents and adults contains also protection against tetanus, diphtheria and pertussis.
74
EPSTEIN-BARR VIRUS
(INFECTIOUS MONONUCLEOSIS)
Cristina Grbovan
Epstein-Barr virus (EBV) is a member of human herpesvirus group consists of a linear

DNA core surrounded by a nucleocapsid and an envelope that contains glycoproteins. Infection
with EBV is common, world-wide in distribution and largely subclinical in early childhood.
EBV has been established as the etiologic agent of heterophile-positive infectious mononucleosis
(IM), which occurs most frequently in late adolescence or early adulthood. EBV is also
associated with several human tumors, including nasopharyngeal carcinoma, Burkitt, s
lymphoma, Hodgkin, s disease, and B-cell lymphoma.
EPIDEMIOLOGY
EBV infections occur worldwide. The virus persists indefinitely in their B Lymphocytes
and is shed oral secretions. Transmission of EBV occurs when susceptible individuals come in
close oral contact with infectious saliva. Casual contact is generally insufficient to transmit
infection, and spread of EBV among susceptible, household contacts is infrequent. Occasionally,
the virus is transmitted by blood products or donor tissues.
PATHOGENESIS
EBV is transmitted by salivary secretions. The virus infects the epithelium of oropharynx
and the salivary glands and is shed from these cells. Although B cells may become infected after
contact with epithelial cells, studies suggest that lymphocytes in the tonsillar cripts can be
infected directly. The virus then spreads through the bloodstream. The proliferation and
expansion of EBV infected B cells along with reactive T cells during IM result in enlargement
of lymphoid tissue. During the acute phase of IM, up to 1 in every 100 B cells in the peripheral
blood is infected by EBV;after recovery ,1-50 in every 1 million B cells is infected. During IM
there is an inverted CD4+ /CD8+-cell ratio. Data suggest that memory B cells, not epithelial
cells, are the reservoir for EBV in the body. Cellular immunity is more important than humoral
immunity in controlling EBV infection.
EBV induces a broad spectrum of illness in humans. Classic or typical infectious mononucleosis
is an acute illness characterized clinically by sore throat, fever, and lymphadenopathy;
serologically by the transient appearance of heterophile antibodies; and hematologically by a
mononuclear leukocytosis that consists, in part,of atypical lymphocytes.
The age of the patient has a profound influence on the clinical expression of EBV infection. In
children, primary EBV infection is often asymptomatic. In patients of college age, the ratio of
clinically apparent to inapparent EBV infection ranges from 1:3 to 3:1 . Because of previously
existing immunity, the disease is less common in older patients.
Fever is present in over 90 percent of the patients with infectious mononucleosis . In most cases
fever resolves over a 10-to 14 day period. A rash, which may be macular, petechial,
scarlatinaform, urticarial or erythema multiformelike, is present in about 5 percent of patients.
Periorbital edema has been reported in up to one-third of the cases in some series.
Tonsillar enlargement is usually present, occasionally with tonsils meeting at the midline. The
pharynx is erythematous with an exudate in about one-third of the cases . Palatal petechiae may
be seen in 25-60 percent of the cases, but are not diagnostic of infectious mononucleosis.
75
Cervical adenopathy, usually symmetric, is precent in 80-90 percent of the patients. Posterior
adenopathy is most common, but submandibular and anterior adenopathy are quite frequent as
well, and axillary and inguinal adenopathy also occur.
Abdominal examination may detect hepatomegaly in 10- 15 percent of the cases. Splenomegaly
is present in about one-half of the cases, and is usually maximal at the beginning of the second
week of illness and regresses over the next 7-10 days.
COMPLICATIONS
The vast majority of patients with infectious mononucleosis recover uneventfully.
Hematologic complications:
Autoimmune hemolytic anemia
Thrombocytopenia
Splenic rupture is a rare but dramatic complication of infectious mononucleosis. The incidence
of rupture is highest in the second or third week of illness, but may be the first sign of infectious
mononucleosis.
Neurologic complications:
Aseptic meningitis
Encephalitis
Guillain-Barre syndrome
Bell s palsy
Transverse myelitis
Hepatic complications:
Consist largely of self-limited elevations of hepatocellular enzymes.
Cardiac complications:
Clinically significant disease is very uncommon
ECG abnormalities-confined to S-T wave abnormalities
Pericarditis
Myocarditis
Pulmonary complications:
Interstitial infiltrates in 3-5 percent of the cases
Clinical Course
The vast majority of cases of infectious mononucleosis resolve spontaneously over a 2- to 3
week period. The sore throat is usually maximal for 3-5 days and then gradually resolves over
the course of a week to 10 days. Patients remain febrile for 10-14 days, but in the last 5-7 days ,
the fever is usually low grade and associated with little morbidity.
LABORATORY DIAGNOSIS
Hematologic Findings
The central hematologic manifestation of the illness is the circulating lymphocytosis. At
presentation, a relative and absolute mononuclear lymphocytosis is found in about 70 percent of
76
the cases. The lymphocytosis peaks during the second or third week of illness, and monocytes
and lymphocytes account for 50-70 percent of total white cell counts of 12-18 000/mm3.
Higher white cell counts are not uncommon, and occasional cases manifest 30-50 000
leukocytos/mm3 .
Atypical lymphocytes are the hematologic hallmark of infectious mononucleosis , and account
for about 30 percent of the differential count at the height of the atypical lymphocytosis.
Syndromes in which Atypical lymphocytosis may be found
Epstein-Barr virus-inducted infectious mononucleosis
Cytomegalovirus infections
Toxoplasmosis
Acute viral hepatitis
Rubella
Roseola
Mumps
Drug reactions
A relative and absolute neutropenia is evident in 60-90 percent of the cases. In most cases, the
neutropenia is mild, with total granulocyte counts of 2000-3000/mm3 .
Thrombocytopenia is also common , and 50 percent of the patients in one series manifested
platelet counts of 140 000/mm3.
Heterophile Antibodies, originally described by Paul and Bunnell as sheep erythrocyte
agglutinins, are present in about 90 percent of the cases at some point during the illness. Beef
erythrocyte hemolysins and agglutinating antibodies to horse, goat and camel erythrocytes are
also demonstrable in infectious mononucleosis.
Heterophile antibodies may be demonstrable at the onset of illness or may appear later in the
course of illness.
EBV-Specific Antibodies
In addition to the transient heterophile antibodies, infection with EBV results in the development
of virus specific antibodies. Antibodies to viral capsid antigen (VCA) measured by
immunofluorescence arise early in the course of the illness and are demonstrable at presentation
in the majority of cases. IgG antibodies to VCA are usually present at titers of 80 or greater on
the first visit to a physician. On the other hand, IgM antibodies to VCA are sensitive and specific
for infectious mononucleosis but are difficult to measure.
Antibodies to EBNA appear late in the course of all cases of infectious mononucleosis and
persist for life. The appearance of EBNA antibodies in a patient who was previously VCA
positive and EBNA negative, is strong evidence of recent EBV infection.
Detection of EBV
Epstein-Barr virus may be cultured from oropharyngeal washings or from circulating
lymphocytes of 80-90 percent of the patients with infectious mononucleosis. Cultivation of the
virus is, however, not routinely in most diagnostic virology laboratories. Rapid diagnostic
77
techniques based on DNA hybridization or monoclonal antibody techniques are currently under
development.
DIFERENTIAL DIAGNOSIS
CMV Infection (CMV is the most common cause of heterophile-negative

mononucleosis , usually presenting in older patients)
Acute infection with

-
Toxoplasma
HIV
Human herpes virus 6
Hepatitis viruses
drug hypersensitivity reactions
rubella
lymphoma or leukemia
TREATMENT
Treatment of infectious mononucleosis is largely supportive since more than 95 percent of the
patients recover uneventfully without specific therapy. Contact sports or heavy lifting should be
avoided during the first 2-3 weeks of illness, especially splenomegaly is present.
Aspirin or acetaminophen, are helpful in relieving the sore throat and in suppressing the fever.
Corticosteroids are often advocated, but their use in uncomplicated illness is still controversial.
Most infectious disease consultants prefer not to administer corticosteroids in this self-limited
disease of certain specific indications.
Corticosteroids are generally used in the following situations:
1) Impending airway obstruction
2) Severe thrombocytopenia
3) Hemolytic anemia
4) CNS involvement
5) Myocarditis
6) Pericarditis
Acyclovir has had no significant clinical impact on IM in controlled trialls. Acyclovir, at
a dosage of 400-800 mg five times daily, has been effective for the treatment of oral hairy
leukoplakia.
78
Diphtheria
Iringo Kezdi
Diphtheria is an acute disease manifested by both local infection of the upper respiratory tract
and the systemic effects of a toxin, which are most notable in the heart and peripheral nerves.
ETIOLOGY
The etiologic agent, C. diphtheriae is the principal human pathogen of the Corynebacterium
group, an aerobic gram-positive bacillus with irregular shape. C. diphtheria strains are divided
into three biotypes (mitis, gravis, intermedius). As referring to the toxin synthesis, there are
toxin-producing and non-producing strains. Diphtheria toxin is the primary virulence factor of
C.diphtheriae, the structural gene, tox, being carried by a family of bacteriophages. Under the
action of heat (40 C) or formalin 4%, the toxin may be transformed after a month in anatoxin,
an untoxic but immunizing substance. In nature, C. diphtheria is only rarely an invasive
organism; it is encountered in the respiratory tract, in wounds or on the skin of infected persons
in normal carriers. It is spread by droplets or by contact to susceptible individuals; the bacilli
then grow on mucous membranes or skin abrasions and those that are toxigenic start producing
toxin.
PATHOLOGY
All human tissues may suffer by the toxin because all human cells have receptor sites.
Accordingly, there is no specific target organ for the toxin, but clinical consequences generally
result from myocardial and neural abnormalities. Death often results from cardiac failure, but
necrotic and often hemorrhagic lesions are usually found in many organ. Except from the local
site of infection, the lesions are sterile. Diphtheria toxin is absorbed into the mucous membranes
and causes destruction of epithelium and a superficial inflammatory response. Locally, toxin
induces tissue necrosis, leukocyte response and formation of a tough, adherent pseudomembrane
composed of a mixture of fibrin, dead cells and bacteria-commonly over the tonsils, pharynx, or
larynx. Any attempt to remove the pseudomembrane results in bleeding. The diphtheria bacilli
within the membrane continue to produce toxin actively. This is absorbed and leads to distant
toxin damage, particularly parenchymatous degeneration, fatty infiltration and necrosis in heart
muscle, liver, kidneys (tubular necrosis), and adrenals, sometimes accompanied by important
hemorrhage. The toxin also produces nerve damage (neuronal demyelination), resulting often in
paralysis of the soft palate, eye muscles, or extremities. Wound or skin diphtheria occurs chiefly
in the tropics. A membrane may form on an infected wound that fails to heal. However,
absorption of toxin is usually slight, the small amount of toxin promotes development of
antitoxin antibodies, so that the systemic effects are negligible. There are 2 phases of diphtheria:
the initial local presentation as a severe pharyngitis with tough membranes that can cause
suffocation and a late systemic phase caused by the effects of the circulating exotoxin on tissues
of the host. Nondiphtheriacorynebacteria produce localized or systemic diseases principally by
colonizing foreign bodies introduced into the human tissue (prosthetic valves, catheters, etc).
CLINICAL FINDINGS
Incubation period is usually less than 1 week.
Pharyngitis. The initial form of diphtheria manifests as an infection of upper respiratory tract.
During the onset period that is abrupt, symptoms like malaise, sore throat, anorexia, fever
79
appear, as a result of the substantial systemic absorption of toxin. Physical exam includes
erythema of the posterior pharynx, followed by the development of a pseudomembrane, that is
usually asymmetric and extend, to involve the soft palate and uvula. As the membrane spreads,
the patient may develop significant oedema of the submandibular areas and the anterior neck
with the lymphadenopathy giving a characteristic bull neck appearance. Laryngeal
diphtheriacan occur as a result of membrane extension, or may be the only site of infection,
manifested by: hoarseness, stridor, dyspnea that may need intubation or tracheostomy. Nasal
diphtheria presents with purulent and serosanguinolent discharge. Cutaneos infection often
appears as a secondary infection of a previous wound (pustule, ulcer and oedematous rolled
borders that may evolve as a chronic non-healing ulcer). Other organ involvement includes: ears,
conjunctiva, cornea. The disease may progress if enough toxin enters the bloodstream, causing
severe prostration, striking pallor, rapid pulse, stupor and coma. The absorbed toxin can also
cause delayed damage at distant sites.
COMPLICATIONS
1. Cardiovascular complications
Myocarditis may occur in the second week of evolution early myocarditis ( 20-65% of
patients): progressive weakness, dispnea, congestive heart failure, muffled heart sounds, gallop
rhytm, and circulatory collapse, conduction disturbances (prolongation of PR interval, complete
atrioventricular block), and sometimes cardiac arrest.
Late myocarditis occurs between the third and fourth week of illness withmilder clinical
findings.
2. Neurologic complications
a. Palatal paralysis begins 1-2 weeks after the onset of symptoms, followed by paralysis of
swallowing and involvement of the other cranial nerves.
b. Oculomotor paralysis later ( weeks 4-5th), there may be difficulties with vision (paralysis of
accommodation)
c. Peripheral polyneuritis with a glove-and-stocking distribution of motor and sensory loss may
resemble Guillain-Barre syndrome (weeks 7-10). All of these manifestations tend to subside in a
few weeks and sometimes months, or may evolve with ascending syndrome (Landry) which is
lethal.
LABORATORY TESTS
1. Isolation of C. diphtheria from different specimens such as swabs from the nose, throat, or other
suspected lesions that must be obtained before antimicrobial drugs are administered ( culture on
Loeffler or Pai agar and cysteine tellurate). Any diphtheria-like organism culture must be
submitted to a virulence test before the bacteriologic diagnosis of diphtheria is definite.
Biotyping and toxigenicity testing has not been maintained in all countries. Toxin production
may be demonstrated in vivo by the guinea pig lethality test, or by the more rapid Elek test in
vitro.
2. Stained smears show beaded rods in typical arrangement.
DIAGNOSIS
The presence of an asymmetric grey, adherent membrane with lymph node enlargement and soft
tissue swelling, in a toxic-looking person is suggestive for diphtheria. Several predisposing
factors will make the diagnosis more likely:
- an unimmunized patient or who has not received the recommended booster immunizations;
- a history of contact with a diphtheria case;
80
-a history of recent travel to an endemic region for diphtheria;

- the pre-treatment antitoxin titre is below 0.01 IU/ml.
Other pharyngeal diseases: herpes simplex virus, Epstein-Barr virus, adenoviruses, Vincents
angina, Candida infection, Ludwig angina, epiglottitis but, the asymmetric appearance of the
membrane, and involvement of the soft palate and uvula are helpful diagnostic signs.
Retropharyngeal and peritonsillar abscesses can resemble diphtheria.
A foreign body in the larynx, viral laryngitis could cause confusion with laryngeal diphtheria.
TREATMENT
Specific treatment must never be delayed for laboratory reports if the clinical picture is strongly
suggestive of diphtheria.
1. The imperative in diphtheria treatment is to administer the antitoxin as soon as possible, as it is
the only mean to neutralize toxin that has not already bound to cells. The mainstay of therapy is
prompt administration of equine diphtheria antitoxin: 20.000- 100.000 IU, i.v. the test for
hypersensitivity consists of administration of one drop of antitoxin diluted 1:10 in one eye.
If the antitoxin is administrated in the first day of illness, the mortality is less than 1%.
2. Antibiotics are used to stop toxin producing in infected patients with clinical disease:
PENICILLIN or ERYTHROMYCIN will eliminate the organism and consequently prevent
further toxin production and its transmission. Patients are expected to be non contagious within
48h after antibiotic is administered. In a recent study all strains were susceptible to:
erythromycin, penicillin, ampicillin ,cephalotin, chloramphenicol, ciprofloxacin, gentamicin,
tetraciclin and to trimethoprim and rifampicin in 97% of strains.
Treatment should continue for 14 days, and elimination of the organism should be confirmed by
three consecutive negative cultures after completion of therapy.
3. Supportive care and maintenance of an airway.
4. Strict bed rest during the acute phase of diphtheria.
PREVENTION
Diphtheria was the first bacterial disease for which toxic cause was demonstrated and the first to
be treated successfully with an antitoxin. In 1913 a vaccine was created, composed of treated
diphtheria toxin, called anatoxin, later transformed in diphtheria toxoid. In 1940 a combined
vaccine appeared: DTP (Diphtheria toxoid+ Tetanus toxoid+ Pertussis vaccine).
Active immunization in childhood with diphtheria toxoid yields antitoxin levels that are
generally adequate until adulthood. Levels of antitoxin decline with time; for booster injection of
adults, only Td toxoids are used; these combine a full dose of tetanus toxoid with a tenfold
smaller dose of diphtheria toxoid in order to diminish the likelihood of adverse reactions.
Regular boosters with Td are particularly important for adults who travel to developing
countries, where the incidence of clinical diphtheria may be 1000-fold higher than in developed
countries, where immunization is universal. In the most developing countries, immunization with
diphtheria and tetanus toxoids and pertussis vaccine was introduced by the late 1970s; in
countries with low immunization coverage, diphtheria continues to be endemic.
81
INFLUENZA
Andrea Incze
Definition
Influenza is a moderate or severe infectious disease produced by the influenza viruses. It can
affect the upper and lower respiratory tract, it is accompanied by severe systemic symptoms
(fever, myalgia, weakness, headache). It can be endemic, or cause epidemics, pandemics, with a
peak in winter.
Etiologic agent
Influenza viruses belong to the family of Orthomyxoviruses, they are RNA viruses. There are 3
separate types of viruses, A, B and C, classified based on the characteristics of nucleoprotein
(NP) and matrix (M) antigens.
Each type, subtype and strain of influenza virus has similar morphology. The shape of the virion
is either spherical or elongated. The structure of the virus consists of:
-
nucleocapside: RNA fragments and a nucleoprotein (NP)
the matrix protein (M) surrounds the nucleocapsid, and provides the stability of the
virion
these are surrounded by the envelope, a double-layer lipid structure, covered with
projections on its surface
the projections consist of 2 glycoproteins:

o hemagglutinin (H) plays a role in attachment of the virus to receptors of the
host cells
o neuraminidase (N) - plays a role in release of the virus from infected host cells
polymerases, other non-structural proteins
Based on the structure of hemagglutinin (H) and neuraminidase (N) antigens influenza A is
further subtyped. There are 16 H subtypes and 9 N subtypes. All of the H subtypes can be found
in avian influenza viruses, however, only H1, 2, and 3 were associated with influenza epidemics
in humans. Regarding the N subtypes, only subtype 1 and 2 were associated with human
epidemics.
Influenza B and C viruses do not have subtype designations, because there are no antigen
variations in case of influenza virus C, and these variations are minor in case of influenza virus
B.
The designation of the influenza virus consists of:
-
type of nucleoprotein (A, B or C)
host of origin (if it is not specified, it means that is human)
geographic origin
isolate number
year of first isolation
type of H and N
82
For example: influenza virus A/California/10/1978/H1N2, A/Hiroshima/52/2005/H3N2.

Antigenic variations of influenza virus
Antigenic variations appear especially in the case of influenza virus A. They might occur in
influenza virus B also, but they were not described in influenza virus type C. These variations
can be major or minor. The variations are linked mostly to the surface antigens (H, N), however,
other proteins can be modified also, but without clinical or epidemiologic impact.
Major variations (shift)
In this case the surface antigens (H or N) are completely replaced with new subtypes of antigens.
This happens due to a genetic rearrangement. The gene segment that encodes a subtype of H or
N is completely replaced with another gene segment, which might come from a virus originating
in an animal host (swine or avian influenza virus). The newly formed viral subtype has no or
minor relationship with the former subtype, therefore there is no immunity against it in the
population, and pandemics can occur.
Minor variations (drift)
Minor antigenic changes occur every year or every few years (more frequently than major
variations). These are caused by point mutations of the genes encoding H or N. These mutations
appear sequentially during the interpersonal transmission of the virus. As a result minor aminoacid changes occur in the structure of the surface antigen (H especially), however their basic
structure remains unmodified. Antibodies formed due to exposition to the previous strain do not
neutralize the new one as effectively as they neutralized the former strain, therefore epidemics
occur.
Due to these antigenic variations it is not possible to elaborate a long-lasting influenza vaccine.
Influenza virus is destroyed by direct sunlight, ultraviolet light, drought, usual disinfectants.
During the winter the virus reaches high concentrations in aerosols, which contributes to the
appearance of outbreaks.
Amanatadine and rimantadine are antivirals with virostatic effect, whereas the neuraminidaseinhibitors are active against the A and B types of influenza viruses.
Epidemiology
Influenza can be endemic, or it can appear in epidemics, that occur every year or every 2-3 years,
and pandemics that occur every 10-15 years.
Sources of infection can be ill people (at the end of incubation and the first 3-4 days of the
disease), asymptomatically infected persons, and animal hosts (swine, horses and birds).
The virus is transmitted via the air, and through direct contact with the secretions of the patient,
or through contaminated objects.
Receptivity is universal, however children, pregnant women the elderly and the
immunosuppressed patients have a higher degree of receptivity.
Immunity is type and subtype specific.
Influenza A virus is the etiologic agent of the most severe outbreaks, due to the H and N
antigenic variations. Antigenic shifts have resulted in pandemics, with many fatal cases of
influenza. In some epidemics influenza B viruses have circulated simultaneously with type A
viruses.
83
Influenza epidemics have a rapid onset, reach their peak in 2-3 weeks, last for 2-3 months and
subside abruptly. Influenza epidemics occur during the winter in the temperate zones, although
rarely they can occur during the warm months also. In the tropics they can occur during the
whole year. Rapid transport facilities contribute to the widespread of influenza to geographic
areas that are at a long distance.
The last influenza pandemic started in March 2009, ended in August 2010 (according to WHO).
It was caused by an A/H1N1 virus, which was a recombinant between a North American swine
virus and a Eurasian swine virus. The new virus was antigenically different from the A/H1N1
viruses that had circulated in the years before 2009, thus vaccines elaborated against the
circulating A/H1N1 strains were not efficient. A new vaccine was elaborated against the
A/California/07/2009/H1N1 virus. This virus was sensitive to the neuraminidase inhibitors
(oseltamivir and zanamivir), but resistant to amantadine and rimantadine. The clinical illness did
not differ from that caused by seasonal influenza A virus. Severe forms appeared in children,
young adults, pregnant women and patients with comorbidities.
Avian influenza is transmitted to humans through direct contact with infected poultry, in case of
poultry outbreaks of influenza. Human to human transmission is possible in case of close,
prolonged unprotected contact, but is very rare. According to CDC reports, since November
2003, 600 sporadic human cases of avian influenza have been noted, with a mortality rate of
60%.
Influenza B causes less extensive epidemics than influenza A, and the disease is milder. It affects
communities, such as schools, institutions for elderly, and the army. Reyes syndrome was
described as the most important complication of B influenza.
Influenza C causes mainly upper respiratory symptoms, it affects rarely the lower respiratory
tract, and there are many asymptomatic infections.
Pathogenesis
Influenza virus infects the organism through the respiratory epithelium. The ciliated columnar
epithelial cells become infected, and the infection can spread towards the alveolar cells,
macrophages, and mucous gland cells also. This process can be prevented by the action of
secretory IgA, nonspecific nucleoproteins that attach to the virus, and mechanic action of the
mucociliary apparatus.
Neuraminidase (N) reduces the viscosity of the mucosal layer, and uncovers the hemagglutininreceptors. The next step is viral-cellular fusion, followed by intracellular penetration. The virus
replicates in the cell within 4-6 hours, the newly formed virions leave the host cell, and the
infected cells are destroyed due to viral replication and apoptosis. The new virions infect other
epithelial cells, thus in a few hours a great number of respiratory epithelial cells are destroyed,
and desquamated. An inflammatory mononuclear infiltrate and edema appears in the submucosal
layer.
Although the systemic symptoms (headache, fever, myalgias) are prominent in influenza, the
virus has rarely been detected in extrapulmonary areas.
The immune response of the host consists of serum antibody production (antibodies against
hemagglutinin seem to be the most important), local secretory IgA antibodies, antigen-specific
and antigen-nonspecific cellular immune response (TCD4+, TCD8+, NK cells), interferons. In
most of the patients viral shedding stops in 2-5 days after the onset of disease, when the antibody
level is still low. Therefore it was supposed that interferon, cell-mediated immune response and
nonspecific inflammatory responses are responsibile for the recovery.
84
The incubation is short, 3-4 days. The disease starts with severe, abruptly onset general
symptoms: fever with shivering and sweating, discomfort, prostration, arthralgia, myalgias, and
headache. The fever is high, 38-41C, lasts 2-3 days, until 1 week. The persistence of fever
above a week is sign of complication.
The respiratory tract symptoms are sore throat, cough, substernal discomfort. Tracheitis,
laryngitis, croup, otitis, sinusitis, conjunctivitis can also occur.
Vomiting, diarrhea, shortness of breath can also be present.
Ocular symptoms are present: burning of the eyes, photophobia, and pain at the movement of the
eyes.
As the general symptoms subside, the respiratory symptoms become more prominent.
Physical findings are minimal: hyperemic face and conjunctivae, dry skin, nasal discharge,
enlarged cervical lymph nodes, wheezes, rhonchi, scattered rales can sometimes be heard on
chest examination.
Dyspnea, hyperpnea, cyanosis, diffuse rales, and pulmonary consolidation are signs of
complications.
Patients recover from uncomplicated influenza in a week, however, cough may persist 1-2
weeks. Postinfluenzal asthenia may persist for several weeks.
Complications
The elderly, children under 2 years, pregnant women and patients with comorbidities such as
chronic cardiac, renal or pulmonary disorders, hemoglobinopathies, immunosuppression,
diabetes mellitus are prone to have complications.
Pulmonary complications
Pneumonia can be primary viral pneumonia, secondary bacterial pneumonia, or the mix of the
former two.
Viral pneumonia is characterized by a progressive worsening of influenza, with dyspnea,
cyanosis, hypoxia, bloody sputum, diffuse infiltrates on the chest X-ray, acute respiratory
distress syndrome. There is an important inflammatory reaction, necrosis and hemorrhage at the
level of alveoli.
In secondary bacterial pneumonia fever reappears after an afebrile period, cough, purulent
sputum, signs of consolidation can be found. The etiologic agents can be Streptococcus
pneumoniae, Staphylococcus aureus, Haemophylus influenzae.
In case of mixed pneumonia the involvement of the lung might be less extensive, compared to
viral pneumonia. The chest examination and X-ray reveals patchy infiltrates or consolidation.
Other pulmonary complications: croup, bronchiolitis (especially in children), worsening of
chronic pulmonary obstructive disease, exacerbation of asthma.
Extrapulmonary complications
Reyes syndrome, which appears in case of Aspirin administered to children with influenza
(especially B).
85
Skeletal myositis, rhabdomyolysis, myoglobinuria can appear. It is characterised by severe

myalgias, swelling of the muscles, elevation of serum CPK, aldolase, and rarely renal
insuffieciency.
Myocarditis is frequent, with a slightly modified ECG. Pericarditis can be present.
Complications of the nervous system: encephalitis, transverse myelitis, Guillain-Barr syndrome,
peripheral neuritis, cranial nerve palsies were noted.
Toxic shock syndrome appeared due to staphylococcal superinfection.
Pregnant women have a double risk of mortality compared to the general population. Fetal
malformations due to influenza virus were described.
Decompensation of the chronic comorbidities during influenza might lead to death.
Complications of avian influenza
Avian influenza conducts to pneumonia in 50% of the cases, diarrhea, CNS complications are
frequent, multisystem dysfunction, cardiac and renal failure can occur.
Diagnosis
During influenza epidemics the appearance of high fever, cough, sore throat, headache,
myalgias, pain of the ocular globes, prostration is correlated with the diagnosis of influenza.
Laboratory diagnosis
Etiologic diagnosis
Detection of influenza virus in throat swabs, nasopharyngeal washes, sputum:
-
isolation on tissue culture or chick embryos, detection of neuraminidase by

immunologic or enzymatic methods
PCR detection of viral nucleic acid
determination of the type of virus (A, B, C), and hemagglutinin subtype: with specific
antisera, detection of or neuraminidase activity rapid tests
Serologic tests: comparison of acute and convalescent antibody titers (during the acute illness
and after 10-14 days) 4x or greater titers are diagnostic
Nonspecific laboratory tests
-
the leucocyte count can be low early in illness, normal or slightly elevated later
relative lymphopenia can occur in children
severe leukopenia: in severe viral or bacterial infection
leukocytosis: in bacterial superinfection
transaminaze-levels of liver and tissue origin may be elevated
amylase levels may be raised
CPK levels may be elevated
troponin may be raised in myocarditis
Influenza should be differentiated from:
86
other viral respiratory infections (produced by rhinovirus, HRSV, adenovirus,

parainfluenzae virus, enterovirus)
atypical pneumonias (Mycoplasma, Chlamydia, Rickettsia)
acute febrile diseases in the invasion period (eg. measles, brucellosis, leptospirosis,
meningitis)
streptococcal pharyngitis
bacterial penumonia
Treatment
Etiologic treatment
Neuraminidaze inhibitors:
-
Oseltamivir: 2x75 mg/day given orally for 5 days
Zanamivir: 2x10 mg inhaled for 5 days
Side effects:
-
oseltamivir: neuropsychiatric side effects in children, nausea, vomiting
zanamivir: exacerbates bronchospasm in asthmatic patients
M2 protein inhibitors (membrane ionic channel): Amantadine, rimantadine are no longer used
due to the multiple resistant strains, their use may be reconsidered in case of sensitive strains.
Antibiotics should be used in case of bacterial superinfection.
Pathogenetic and symptomatic therapy:
Antivirals are not needed in the treatment of uncomplicated influenza. These cases are isolated
and treated at home. In this case NSAIDs (with the exception of Aspirin, which might lead to
Reye syndrome) should be used.
Codeine-based therapy can be applied against cough.
Rest and appropriate hydration are important.
In severe cases it is essential to maintain oxygenation, to treat the patient in an intensive care
unit, to provide respiratory and hemodynamic support.
Prophylaxis
Vaccination with inactivated or live attenuated vaccines can be applied.
Most of the vaccines are inactivated, derived from influenza A and B influenza strains that
circulated during the previous season. They provide 50-80% protection.
The vaccines might have side effects: fever, systemic symptoms, local reaction at the vaccination
site, allergic reaction (in case of egg-sensitivity), Guillain-Barr syndrome (rarely).
It is recommended to vaccinate the persons, who are elderly, have comorbidities, are
immunosuppressed, and their contacts, healthcare personnel.
Vaccination should be applied in the autumn, before the influenza outbreak, and should be
administered annually.
A live, attenuated vaccine is available, that can be given to the age group 5-49 years, and is
highly protective (92%).
87
Antivirals can be used as chemoprophylaxis. Oseltamivir and zanamivir can be given at half the
therapeutic dose, however, amantadin and rimantadin are not recommended, due to resistance.
Chemoprophylaxis is used in unvaccinated persons with high risk for influenza. It can be used in
vaccinated persons also, has an additive effect to the inactivated vaccine, but it should not be
administered closer than 2 weeks after the administration of live attenuated vaccine.
References:
1. Mandell GL, Bennett JE, Dolin R Principles and practice of infectious diseases, 6th
Edition, 2005, Elsevier
2. Kasper DL, Fauci A - Harrisons Infectious diseases, 2010, McGraw Hill Medical
3. Cupsa A Boli infecioase transmisibile, 2007, Editura Medical Universitar Craiova
4. Bannister B, Gillespie S, Jones J Infection Microbiology and Management 3rd Edition,
2006, Blackwell Publishing, London
5. http://www.cdc.gov/flu/avianflu/h5n1-people.htm
6. http://www.who.int/influenza/gisrs_laboratory/terminology_ah1n1pdm09/en/index.html
88
VIRAL RESPIRATORY INFECTIONS

Introduction
Acute viral respiratory illnesses are among the most frequent diseases. Their incidence is 3-6
episodes per person per year, higher in children aged below 6 years (6-8 episodes per year) than
in adults (3-4 episodes per year).
The etiological spectrum of acute viral respiratory illnesses is wide, as they are caused by more
than 200 viruses that have different antigenic structures.
In most of the cases the acute viral respiratory illnesses manifest clinically as upper respiratory
infections, however the lower respiratory tract can also be involved, especially in young children
and the elderly.
Classification
According to the etiology
Acute viral respiratory illnesses can be caused by:
-
rhinoviruses
adenoviruses
parainfluenza viruses
human respiratory syncitial virus (RSV)
human metapneumoviruses
coronaviruses
enteroviruses
influenza viruses
According to the clinical syndrome

Acute viral respiratory illnesses can manifest clinically as:
-
common cold (acute rhinopharyngitis sinusitis, otitis, tracheobronchitis)
pharyngitis
laryngitis
croup (laryngotracheobronchitis)
tracheitis
bronchitis
bronchiolitis
pneumonia
Rhinovirus infections
Etiologic agent
89
Rhinoviruses are the etiological agents of about 50% of the common cold cases. They are RNA
viruses and take part of the Picornaviridae family.
Epidemiology
Rhinovirus infections are more frequent in lower age groups. Children under the age of 6
introduce the infection into their families, with a subsequent spread of the infection among
family members.
There is a higher seasonal incidence in the autumn and spring in temperate areas.
Rhinoviruses are transmitted through contact with infected secretions, such as infectious droplets
suspended in the air, infected surfaces, hand to hand contact. Close physical contact is needed in
order to transmit the virus.
Studies have demonstrated that lack of sleep, fatigue and exposure to cold do not facilitate the
appearance of illness caused by rhinovirus, but stress might conduct to the disease.
There are multiple serotypes of rhinoviruses that circulate together. Despite the presence of
multiple neutralizing antibodies in adults, further infections can still occur.
Pathogenesis
Rhinoviruses enter the human organism through the nasal mucosa, which becomes hyperemic,
edematous, with a mucoid discharge. On the second and third day large quantities of virus are
produced at this level.
In 8hours - 2days after the nasal inoculation clinical symptoms appear. Virus shedding begins
shortly before or together with the onset of symptoms.
Immunity develops after infection, however not in every individual. In case of massive
inoculation infection with the same serotype is possible despite the presence of antibodies.
The symptoms that characterize the common cold are present: rhinorrhea, sneezing, nasal
congestion, sore throat, cough, hoarseness. Systemic symptoms (fever, headache) are mild and
uncommon. The recovery is spontaneous after 4-9 days. Lower respiratory tract might be
affected in children.
Complications
-
exacerbation of asthma and chronic pulmonary disease
otitis
sinusitis
severe pneumonia in immunosuppressed patients
Diagnosis
Etiologic diagnosis cannot be made based on the clinical symptoms.
Laboratory diagnosis:
-
isolation of the virus from nasal secretions in tissue culture (it is rarely applied)
PCR to detect the RNA of rhinovirus (research procedure only)

90
detection of serum antibody (it has no diagnostic value due to the many serotypes)
Treatment
There is no etiologic (antiviral) treatment.
Pathogenic and symptomatic therapy: nonsteroidal anti-inflammatory drugs (NSAIDs),
antihistamines, hydration, cough suppressants, nasal decongestants.
Antibiotics are recommended only in case of bacterial superinfection.
Prevention
Intranasal interferon is efficient, however causes local irritation.
In order to reduce the transmission rate appropriate hand washing, covering coughs and sneezes
with disposable nasal tissues, and environmental decontamination is useful.
Adenovirus infections
Etiologic agent
Adenoviruses are DNA viruses that belong to the genus Mastadenovirus. They can cause acute
respiratory infections and conjunctivitis.
Epidemiology
Adenoviruses cause infection especially in childhood, infancy and among the military recruits.
Neonates in most of the cases receive maternal antibodies that provide protection until the age of
6 months.
The route of transmission is the same as that of rhinoviruses, but adenoviruses can be transmitted
by fecal-oral route or inoculation into the conjunctiva also.
There are many serotypes of adenoviruses. Immunity after infection is serotype-specific, and
incomplete.
Pathogenesis
Adenoviruses can cause:
a. lytic infection in human epithelial cells that conducts to virus multiplication at high level and
cell death
b. latent, chronic infection in lymphoid cells (for example in the tonsils), with a low level of
virus multiplication and cell death, that can be overcome by cell multiplication
c. oncogenic transformation with the viral DNA integrated in the structure of the cellular DNA.
In this case viral DNA replicates together with the cellular DNA, with no new virion production.
In respiratory tract infections adenoviruses migrate from the upper towards the lower segments
of the respiratory tract, however they can reach the respiratory tract by the means of viraemia
also. Gastrointestinal infections might be associated to respiratory tract infections. In this case
the virus is swallowed, and can be isolated from the stool.
The immune response is based upon the production of IgA at the level of mucosa and serum
antibodies.
91
Adenoviruses can cause several types of clinical manifestations, such as:
-
pharyngitis (with fever, tonsillar exsudate, enlarged cervical lymph nodes)
acute upper respiratory tract infection (rhinitis)
pharyngoconjunctival fever (fever, sore throat, rhinitis, bilateral conjunctivitis,

cervical adenopathy diarrhea, otitis) which occurs in outbreaks during the summer,
related to swimming pool usage
acute laryngotracheitis
acute bronchiolitis (severe, might be fatal)
whooping cough syndrome (no evidence of Bordetella pertussis, pertussis-like cough,

leucocytosis with lymphocytosis)
epidemic keratoconjunctivitis
hemorrhagis cystitis
infantile diarrhea
intussusception in children
encephalitis, meningoencephalitis
fatal disseminated infections in immunosuppressed patients and neonates
Diagnosis
Adenovirus infection can be suspected based on epidemiological and clinical data.
-
cytopathic changes
immunofluorescence
in
tissue
culture,
identification
of
the
virus
with
detection of viral antigen from nasopharyngeal, conjunctival, respiratory secretions,

urine, stool (ELISA, immunofluorescence)
detection of viral DNA (PCR, nucleic acid hybridization)
detection of serum antibody rises
Treatment
There is no etiologic therapy, only symptomatic and pathogenic treatment can be used.
Prevention
Parenteral vaccines containing live attenuated or inactivated virus were used, but given up
because of the oncogenic character of the virus in animal models. Live attenuated oral vaccines
were used among the military recruits, with no availability of the vaccine in the last decade.
General methods such as current disinfection in hospitals, appropriate disinfection of the
swimming pools, health education can be applied.
92
Parainfluenza virus infections

Etiologic agent
Parainfluenza viruses are RNA viruses that belong to the Paramyxoviridae family. Parainfluenza
infection manifests as croup (serotype 1 and 2), lower respiratory tract infection (bronchiolitis,
pneumonia - serotype 3), or mild respiratory infection (serotype 4).
Epidemiology
Parainfluenza viruses type 1 and 2 produce epidemics in the autumn, whereas parainfluenza
virus type 3 is detected throughout the year, with a peak in spring, the seasonality of
parainfluenza virus type 4 has not been well established.
Symptomatic and asymptomatic people are the source of infection. It is transmitted by the means
of infectious droplets in the air, or contaminated hands.
Children are most affected by the infection. Immunity following infection is not long lasting, and
is serotype-specific. Despite the presence of maternal antibodies serotype 3 can produce
infection in neonates.
Pathogenesis
Parainfluenza virus penetrates the human organism through nasal, oral and pharyngeal mucosa, it
multiplies in the mucosa of the respiratory tract, but viraemia is rarely produced. The
multiplication rate is slower than that of influenza virus. Cell fusion is produced, and syncitial
multinucleate cells appear in the mucosa.
The immune response is based on the local production of IgA, neutralizing antibodies in the
serum, and T-cell mediated immunity.
Parainfluenza viruses produce a wide spectrum of diseases, severe diseases such as croup and
bronchiolitis, and there are asymptomatic infections also:
-
common cold (coryza), hoarseness (in older children and adults)
tracheobronchitis (in adults)
pneumonia, bronchiolitis (type 3) - It appears in children and manifests with cough,

wheezing, tachypnea, intercostal retractions, with rhonchi, wheezes, coarse breath
sounds.
croup in children (type 1) It manifests as severe laryngotracheobronchitis, requires

urgent hopsitalization. It is characterized by fever, barking cough, stridor,
occasionally airway obstruction and hypoxia. Bacterial superinfections worsen the
prognosis.
mild respiratory disease (type 4)
severe, prolonged infection (in immunosuppressed patients)
Diagnosis
Epidemiologic and clinical data are not sufficient for the diagnosis.
93
-
detection of the virus in tissue cultures (from throat swabs, nasopharyngeal or

respiratory tract secretions) the virus can be detected through its cytopathic effect or
hemagglutination
detection of viral antigen in the exfoliated cells of the respiratory tract

(immunofluorescence, ELISA)
PCR assays
serologic diagnosis - the antibody level is determined from acute and convalescent
sera
Treatment
The therapy is symptomatic and pathogenic. Antibiotics are used in case of bacterial
superinfection. Severe cases need hospitalization, in case of acute respiratory distress
epinephrine aerosols, systemic and aerosolized glucocorticoids and humidified oxygen are given.
There is no antiviral therapy, however ribavirin was used in immunosuppressed patients.
Prevention
There is no vaccine available, general preventive methods should be applied.
Human respiratory syncitial virus infections

Etiologic agent
Human respiratory syncitial virus (HRSV) is an RNA virus, and it is part of the Paramyxoviridae
family. It affects children especially, and is the most frequent etiologic agent of lower respiratory
tract infections in infants.
Epidemiology
Epidemics are present in the cold season (autumn, winter, spring).
Although newborns receive maternal antibodies, the rate of illness is high in the age group of 1-6
months. All children become infected with HRSV until the age of 2 years.
HRSV is responsible for epidemic outbreaks in day care centers and pediatric hospitals. It
spreads among family members also.
The route of transmission is through contaminated hands or objects, or by large particles of
aerosols. Virus shedding lasts for 2 weeks. Severe diseases and longer periods of viral shedding
characterize the immunosuppressed patients.
Pathogenesis
Incubation is 2-8 days. The virus penetrates into the human organism through the nasal mucosa
and conjunctiva. HRSV affects the respiratory tract, from the upper to the lower parts.
Despite the presence of maternal antibody or vaccination, severe HRSV infections can occur.
The immunity after infection is short lived and incomplete. After multiple reinfections a
94
temporary protection appears, and the disease is milder. The musosal IgA, serum antibodies and
cell-mediated immunity have a role in protection.
HRSV causes a wide spectrum of diseases:
-
pneumonia
bronchiolitis
tracheobronchitis
common cold (in adults)
The disease has a mild form in the beginning, with low fever, cough, rhinorrhea, wheezing,
followed by recovery. In severe cases tachypnea, dyspnea, hypoxia appears, with wheezing,
rhonchi and rales at the physical examination. Hyperexpansion, infiltrates can be seen on the
chest radiograph.
Severe forms appear in premature infants, in those with congenital heart disease, or in the
immunosuppressed. The elderly can develop severe HRSV pneumonias.
Diagnosis
Epidemiologic findings can facilitate the diagnosis (outbreaks of severe respiratory diseases
among infants).
-
isolation of the virus in tissue culture from respiratory secretions, identification by

ELISA, immunofluorescence
detection of viral antigen in respiratory secretions, nasopharyngeal swabs

(immunofluorescence, ELISA)
serologic tests: comparison of the antibody levels of acute and convalescent sera
Treatment
Treatment is symptomatic, in case of hypoxia oxygen, hydration, antibronchospastic agents are
given. In severe hypoxia mechanic ventilation is needed.
Aerosolized ribavirin may be efficient in severe diseases in infants.
Prevention
In premature infants, children with cyanotic heart disease or bronchopulmonary dysplasia who
are younger than 2 years anti-HRSV immunoglobulin can be administered every month. In
pediatric wards protective barriers for the conjunctivae and disposable gloves should be used.
Human metapneumovirus infections

Etiologic agent
Human metapneumovirus (HMPV) is an RNA virus that belongs to the Paramyxoviridae family.
95
Epidemiology
Infection affects the children at early ages, and they develop antibodies until the age of 5 years.
Other age groups, elderly people, and immunosuppressed patients can also be affected.
Two genotypes circulate in parallel.
HMPV affects the upper and lower respiratory tract, croup, bronchiolitis, pneumonia might
develop. In older children and adults the infection can be asymptomatic, or a common cold might
appear. Pneumonia can be present in the elderly. Severe diseases appear in the
immunosuppressed patients.
Diagnosis
-
tissue cultures from respiratory secretion
PCR from respiratory secretions
serologic diagnosis (ELISA)
Treatment
Treatment is symptomatic and pathogenetic.
Prevention
There are no specific preventive methods.
Coronavirus infections
Etiologic agent
Coronaviruses are RNA viruses that are part of the Coronaviridae family. They have 3 antigenic
groups, and infect a wide range of animals. Coronaviruses from serogroups 1 and 2 infect
humans also. The coronavirus responsible for the severe acute respiratory syndrome (SARSCoV) belongs to serogroup II.
SARS-CoV survives 1-2 days on dry surfaces at room temperature, in pathological products it
can survive for 21 days at low temperatures. It is sensitive to heat and disinfectants.
Epidemiology
Human coronavirus infections are ubiquitary, they occur usually in childhood. They produce the
symptoms of common cold, and appear more frequently in the cold months.
In 2002-2003 there was a pandemic due to SARS-CoV. It had animal origins, the natural host
was the horseshoe bat, and the outbreak started in southern China due to human contacts with
infected partially domesticated animals (such as the palm civet).
96
In contrast with other viruses, after crossing the border between species the virus was transmitted
very efficiently among humans. The virus was transmitted at high rates by persons with severe
disease, whereas those with asymptomatic infections seemed not to transmit it. Therefore the
outbreak could be controlled by correctly applied preventive measures. It affected more than
8000 people in 28 countries, with a 9.5% fatality rate.
The route of transmission was fecal-oral, respiratory through aerosols, and by the means of
wastewater.
Pathogenesis
Coronaviruses that cause common cold symptoms infect the epithelial cells of the nasopharynx,
replicate there, with subsequent local inflammatory response.
SARS-CoV penetrates the cells of the respiratory tract, with subsequent systemic infection. It
was detected in the stool, blood, urine, kidneys, CSF. The viral load increases progressively until
the 10th day of the illness, after that it decreases in parallel with the appearance of antibodies.
Despite of the decrease of viral load the symptoms can still worsen in this period. This might
suggest an immunpathologic mechanism of the lesions in the lung.
Hyaline membranes are formed in the alveoli, with descuamation of the pneumocytes, and there
is a mononuclear interstitial infiltrate. Giant cells are also present.
In the patients sera elevated levels of inflammatory cytokines and chemokines were detected.
Necrosis of the white pulp of the spleen and generalized arteritis of the small vessels were
described.
The incubation period is 2-7 days, can be prolonged until 20 days. The symptoms are nonspecific
in the beginning: fever, myalgia, headache, malaise. The chest x-ray shows peripheral and
inferior interstitial infiltrates. After a short, transient recovery fever reappears with dry cough
and dyspnea, and in 25% of patients diarrhea develops. The radiological findings evolve to
bilateral multifocal infiltrates. The symptoms can progress towards adult respiratory distress
syndrome (ARDS) and multiorgan dysfunction. Illness is severe in the elderly, patients with
chronic diseases, pregnant women, however it is less severe in children.
Non-SARS coronaviruses produce common cold, in military recruits lower respiratory tract
disease, pneumonia in infants.
Diagnosis
Epidemiological data: contact with confirmed or suspect cases of SARS in the last10 days before
the onset of symptoms, travel history in the affected geographic regions.
Clinical data: the presence of fever, chills, myalgias, headache, malaise, dyspnea, acute
respiratory distress.
Laboratory findings in SARS:
-
leucopenia, CD4+, CD3+, CD8+lymphopenia, thrombocytopenia
elevated LDH, CPK, AST levels
isolation of the virus on cell cultures (from respiratory secretion, urine, stool, blood)
97
RT-PCR (from respiratory secretions and blood in the early phases, from stool and
urine in the later phases of illness)
serum antibody detection (ELISA, immunofluorescence)
The detection of non-SARS coronaviruses is rarely necessary, antigen detection in clinical

samples (ELISA, immunfluorescence), and RT-PCR can be used.
Treatment
Ribavirin and high dose of glucocorticoids were used to treat SARS, but their efficacy has not
been proven.
Patients have to be isolated until 10 days have passed after the decrease of fever and
improvement of respiratory symptoms. General supportive care, symptomatic, pathogenetic
therapy must be applied. Oxygen administration or mechanic ventilation might be necessary.
Antibiotics are given in case of bacterial superinfection.
Prevention
There is no vaccine against SARS-CoV. The preventive measures are: the establishment of case
definitions, travel advisories, quarantines. Health care workers who get into contact with SARS
patients have to wear disposable gloves, gowns, protective barriers for the eyes, filtering face
masks.
References:
98
CHAPTER 3
Central nervous system infections
Brndua ilea
Acute meningitis
Meningitis is the most common and important infection of the central nervous system (CNS)
being a severe disease with high mortality, requiring urgent diagnosis and immediate treatment.
Etiology
Theoretically, any agent can affect the leptomeninges, causing meningitis. But meningitis is a
rare disease occuring whenever infectious agents with specific pathogenic qualities meet
vulnerable organisms most likely due to favorable factors: immunological, age-related or
external conditions. Infectious agents that can cause meningitis are listed in Table I. The most
common meningitis is the viral one caused by enteroviruses (80%) and of the bacterial ones the
most frequent are produced by pneumococcus, meningococcus, Haemophylus influenzae (70% Fig. 1). Other etiologies are less frequent (Table II), depending on predisposing factors (Table
III).
Viruses
DNA viruses:
Herpes viruses
Herpes simplex type 1,

2
Varicella-zoster
Epstein-Barr
Cytomegalovirus
RNA viruses
Enteroviruses
Polio,
Coxsackie
unclassified
ECHO,
AND
Togaviruses: rubella
Myxoviruses: mumps,
measles, influenza and
parainfluenza
Arenaviruses:
Armstrong virus
Rhabdoviruses: rabies
Retroviruses: HIV
Bacteria
Gram positive cocci Streptococcus

pneumoniae
Staphylococcus aureus
Gram-negative cocci Neisseria meningitis
99
Gram positive bacilli Lyster monocytogenes, B.

anthracis
Gram negative bacilli Haemophilus influenzae,
Enterobacteriaceae
pseudomonadaceae
Mycobacteria
Mycobacterium
tuberculosis
Spirochetes
Borrelia,
leptospire
Fungi
Cryptococcus
neoformans, Candida
Protozoa
Toxoplasma
Plasmodium
falciparum
Treponema,
gondii,
Chlamydia Chl. psittaci

Mycoplasma M. pneumoniae
Rickettsia
Various species
Metazoans Cysticercus
cellulosae,
Angiostrongylus
cantonensi
Table I - Agents involved in the etiology of infectious meningitis
New born and <2 months
Gram negative bacteria (60%)

Sterptococi group B
Lyster monocytogenes
Children 2 months - 15 years
Haemophylus influenzae (35-70%)

Neisseria meningitis (30-40%)
Streptococcus pneumoniae (10-20%)
Adults
Streptococcus pneumoniae (30-50%)

Neisseria meningitidis (10-30%)
Staphylococcus aureus (5-15%)
Elderly
Streptococcus pneumoniae (48%)

Lyster monocytogenes
Gram negative
Table II - Etiology of meningitis by age

Anatomical defects
Congenital
defects Staphylococcus aureus,
(spina
bifida, epidermidis
meningomyelocele,
Gram negative bacilli
congenital fistulas)
100
Acquired defects
(posttraumatic,
postsurgical)
Streptococcus
pneumoniae
Haemophylus influenzae
Neisseria meningitidis
Meningeal skin fistula Staphylococcus aureus,

epidermidis
ENT infection
mastoiditis)
(otitis,
sinusitis,
Streptococcus
pneumoniae
Anaerobes
Maternal genital infection
Group B Streptococcus
Listeria monocytogenes
Herpes simplex 2
Localized infection ii neighborhood

(epidural abscess, subdural)
Staphylococcus aureus,
epidermidis
Gram negative
Anaerobes bacteria
Table III - The etiology of meningitis according to contributory factors

Humoral immune deficiency (multiple Streptococcus pneumoniae
myeloma, leukemia)
Cellular immune deficiency (lymphoma, Listeria monocytogenes
AIDS, corticosteroids)
Mycobacterium tuberculosis (or atypical)
Cryptococcus neoformans
Deficiency of complement (C 5-C 9)
Asplenia
Streptococcus pneumoniae
Chronic alcoholism, cirrhosis
Streptococcus pneumoniae
Neutropenia
Gram-negative
bacilli,
staphylococci, pneumococci
pathogenic
Table IV - The etiology of meningitis based on immune status

Epidemiology
Meningitis is a sporadical illness which can be community based. Meningococcal meningitis is
endemic in Saharian Africa.
The infectious source is usually the ill person.
101
Mode of transmission: air borne (meningococcus),

mucocutaneous (leptospirosis, herpes simplex).
digestive
path
(enteroviruses),
Responsiveness deponds on age, immune system, predisposing factors.

Immunity is weak or absent due to the scarcity of antibodies in the subarachnoid cavity, some
meningitis is recurrent as the pneumococcal one due to the persistance of predisposing factors
(fistulas).
Pathogenesis
A. Pathogeny of bacterial meningitis.
Germs invade the subarachniod cavity after breaking several barriers:
1. the anatomical barrier: mucous membranes, self defense mechanisms, gateway.
2. the immunological barrier: non-specific defense reaction (phagocytosis, complement) and
specific humoral and celular immunity.
3. the blood-brain barrier (BBB) that is partially impaired by citokynes release (Il-1 beta, TNF
alpha), lipopolysaccharides or other components of the bacterial cell wall. To overcome these
barriers bacteria must possess virulence traits of their own, the most important being: the
presence of the capsule (having an anti phagocytic role), fimbriae (performing adhesion), etc.
Once inside the subarachnoid cavity, germs survive due to favorable local conditions: low
complement and immunoglobulins, ineffective leucocytes because of low opsonization
occurance of inflammation in the subarachnoid cavity lesions in nerve cells (fig. 2)
Routes of infecting the leptomeninges:
The hematogenic route: arterial, venous
The lymph route: lymph surrounding the olfactory threads that cross the lamina cribrosa of the
ethmoid bone or related neighboring cavities.

The direct route: iatrogenic (post lumbar puncture, neurosurgery), traumatic, brain abscess
(fistulizing into the subarachnoid cavity), osteomyelitis through local extension.

B. Pathogenesis of viral meningitis
Viruses get into the subarachnoid cavity after overcoming the same obstacles, the routes of entry
of infectious agents:
Hematogenous route (viremia)
Nervous path: olfactory nerve (herpes simplex), peripheral nerves (rabies virus, polio)
Clinical manifestations:
Meningitis being the infection of leptomeninges, is commonly associated with the following
syndromes:
infectious syndrome
meningean syndrome
intracranial hypertension syndrome
encephalitic syndrome
102
Infectious syndrome includes signs such as fever, chills, myalgia, malaise, high fever and
relative bradycardia with a possible diphasic evolution.
The meningean syndrome is based on symptoms whose intensity are related in part to the degree
of ICH: headache (continuous, violent, accompanied by rachialgia), jet vomiting, photophobia,
and physical signs: cutaneous hyperesthesia, vasomotor disorders, signs of menigean irritation.
Signs of meningean irritation specific to the disease are caused by the inflammation of the
meninges that surround the spinal nerve roots. In meningitis rachialgia is so intense that the
patient takes antalgic positions,"gun cock" position, head is in extension and knees are flexed
(lateral decubitus) and sitting in "tripod position" (lying on the bed with his hands behind the
trunk).
Signs of muscle contraction are:
stiff neck: the examiner trying to make passive flexion of the head on the trunk,
limitation or incapacity is noticed.
Kerning sign is performed with the patient lying down (fig. 4)

Kerning one positive: when the trunk is lifted in sitting position knee flexion
occurs
2 positive Kerning: when trying to lift the limbs on the vertical plane of the bed
flexion of legs on the thighs.
Brudzinski sign is performed with the patient lying down (fig. 3)
Bruzinski 1: the lower limbs in extension, forced passive flexion of the head leads to
flexion of legs on thighs
Brudzinski 2: the lower limbs in extension,triple flexion of the leg produces a similar
response in the contralateral limb
Intracranial hypertension syndrome
ICP is the result of constant equilibrium established between the volume of cerebral blood
volume, the volume of nerve mass and the volume of CSF. The increase in volume of one of the
components mentioned leads to ICH syndrome with pathophysiological consequences such as
cerebral ischemia and cerebral herniation.
ICH clinical symptoms:
headache, exacerbated by standing or head movements
vomiting jet, drowsiness, bradycardia, disturbances of consciousness, seizures.
ICH meningitis syndrome is based on:
Increase in volume of CSF due to inflammatory component
Multiple pathogenesis of cerebral edema: cytotoxic, vasogenic, interstitial
vascular homeostasis disorder: arterial vasodilation, stasis
obstruction of CSF circulation: the case of clogging.
ICH syndrome accompanies meningitis and it can be objectively detected in advanced forms by
fundus examination by papillary edema and stasis. The presence of the latter warns against spinal
puncture because of the risk of brain substance migration.
Encephalitic syndrome
103
Manifestations of encephalitic syndrome include loss of consciousness, coma, seizures,

psychiatric symptoms (hallucinations, agitation, crying,) pyramidal syndromes, extrapyramidal,
sensory motor deficits, abnormal reflexes.
Clinical Forms
A. newborn and infant meningites
Meningitis symptoms in the newborn presents less characteristic symptoms and serious
complications. The onset is insidious, the infectious syndrome is reduced, signs meningeal signs
are absent, replaced with: generalized hypotonia, marked hyperesthesia, agitation, unwillingness
to be breastfed, uncessant crying, vasomotor disorders, bulging fontanelle outside periods of
crying. Encephalitic syndrome is emphasized: impaired consciousness, capping eyes,
encephalitic cry, seizures, coma. Sometimes the clinical signs can be misleading with
predominant digestive symptoms: vomiting, diarrhea, respiratory distress (cyanosis, apnea).
B. meningitis in the elderly
They also show peculiarities by decreased inflammatory responsiveness, meningean syndrome
may be absent. Sensor disorders may occur with greater frequency without actual encephalitis
involvement, coma is quick and neurological complications are common.
C. meningitis in immunocompromised patients raises the same issues as above, the common
element being the lack of defense against infection.
According to the intensity of the inflammatory syndrome the following forms were described:
exacerbated forms usually bacterial meningitis associated with infectious and toxic
syndrome with high mortality rate due to the encephalitis component and lesions of the
vital organs (eg meningococcemia with purpura fulminans Waterhouse-Friderichsen
syndrome)
acute forms, classical ones violent onset while the health status seems perfect
apparently, infectious and meningean syndrome
attenuated forms - often of viral etyology, the infectious syndrome is modest and signs of
meningeal irritation are absent or discrete. Diagnosis is validated by lumbar puncture.
subtle forms - may go undiagnosed, being spontaneous and having rapid remission,
usually of viral etiology.
Diagnosis
Diagnosis of meningitis constitutes a major clinical emergency, subject to starting immediately
the etiological therapy. Positive diagnosis has two major objectives:
diagnosis of the disease (recognition of meningitis itself).
etiologic diagnosis (identification of the causative agent).
Diagnosis of meningitis as such shall be based on clinical data (presence of infectious syndrome
of HIC, meningeal signs of brain damage) and laboratory confirmation of meningitis by
examination of CSF obtained by spinal puncture:
a. examination begins right from puncture by assessing the appearance of CSF and pressure of
elimination. The jet flow of CSF points to high pressure of CSF, confirming the suspicion of
meningitis. Normal aspect or hipotension do not invalidate the diagnosis of meningitis.
b. Laboratory examination of CSF consists of:
104
qualitative assessment proteinorachia by Pandy reaction (usually negative) any increase

of proteinorachia is expressed by turbidity of the reactive substance in contact with a
drop of CSF;
existing cell count in CSF (pleocytosis). Any increase above 5/mm indicates an
inflammation. The number of these cells can be indicative in diagnosis:
- between 10-1500 elements - viral etiology, fungal, leptospirosis etc..
- between 200-400 items - specific etiology (TB) or protozoal
- thousands or tens of thousands - bacterial etiology
identification of elements by examining smears made from the sediment obtained by

centrifuging the CSF out of which usual staining (Gram, methyl blue), special staining
(Ziehl Nielsen, China ink), cytological staining (Giemsa), fluorescent staining (acridine
orange, special microscope is needed) are performed. Mononuclear predominance
characterises viral meningitis and leptospirosis, while the predominance of polynuclear
neutrophils is specific to bacterial meningitis.
cultures performed at the patients bedside or in the laboratory under sterile conditions on
blood agar, Chocolat, Mueller-Hinton, Loewenstein, Sabouraud
immunological examination is designed to detect bacterial antigens in CSF: countercurrent immuneelecxtrophoresis (CIE), latex agglutination test, ELISA technique,
immunofluorescent techniques, the detection of specific DNA sequences in CSF by
means of gene amplification (PCR)
virological exam: performed in virology laboratories, aiming to isolate and identify the
virus in CSF
Biochemical CSF: spinal fluid protein/glucose/chlorine/lactic acid concentration.
Other laboratory tests in meningitis: lung X-ray examination, ENT examination, CT scan, MRI,
EEG route. A special mention should be blood culture which is mandatory in patients with
bacterial or fungal meningitis.
Meningitis
CSF
type
appearance
Normal
CSF
Clear
Bacterial Cloudy
Meningitis
Cytology
Bacteriological
Biochemical
Proteins Glucose Chloride
<3-5 elem / mm Sterile

3
<45mg%
glucose
Approx.
700mg%
Thousands, tens Germ smear

of
thousands> Positive cultures
80% PMN
Much
Much
Normal
increased + decreased or low
++
TB
Clear,
200-600 elem / Positive
stain Much
Much
Meningitis xantochrome mm 3 small and Ziehl-Nielsen
increased + decreased
medium-sized
+++
Lwenstein +
Low
mononuclear
lymphocytes
Viral
Clear,
meningitis opalescent
800 - 2-3000 Negative

elem / mm 3
polymorphic
mononuclear
105
Moderately N
increased +
+
N
or
higher
Fungal
Clear
Meningitis
Hundreds elem / Fungi Giemsa stain Raised + + Slightly N

mm
3
most and China ink +
decreased
lymphocytes
positive
cultures
Sabouraud
Table III - Characteristics of the main types of meningitis CSF

Differential Diagnosis
Before the spinal tap/lumbar puncture the differentiation will be performed on the basis of
intracranial expansive processes (abscesses, tumors), which may cause high fever but generally it
evolves slowly with focal neurological signs and intracranial pressure (IP).
After lumbar puncture differential diagnosis is made with:
meningismus - meningean syndrome moderately or intensely present, CSF is eliminated

with high pressure without showing inflammatory changes. It can occur in acute
infectious diseases, especially in children (viruses, angina, sinusitis, ear infections, sun
stroke, etc..)
meningeal reaction - slight inflammatory reaction with early changes of CSF (10-100
lymph / mm3). May occur in many acute infectious diseases.
Intracerebral hemorrhage,subarachnoid
insolation (sun-stroke)
cerebral thrombophlebitis
Other causes of cerebral edema (iatrogenic, toxic)
Post-puncture syndrome
Complications
The most common complications occurring in bacterial and fungal meningitis are correlated with
age, germ virulence, immune system conditions, related diseases, early onset and correct
treatment.
Early complications:
septic shock
seizures
cerebral vasculitis
purulent exudate (fig. 6)
hydrocephalus (fig. 5)
brain abscess
cranial nerve injury (III, VI, VII, VIII)
Late complications:
memory impairment, concentration

106
mental retardation
motor deficit
deafness, blindness
water on the brain
epilepsy
Treatment
A correct treatment in acute meningitis requires the following:
early diagnosis and etiology of disease
possibility to verify in vitro the germs sensitivity
antibiotics that penetrate the blood-brain barrier
possibility to monitor antibiotic levels in CSF for an efficient antibacterial titer at this
level
monitoring the effectiveness of therapy
etiological therapy is associated with the control or pathogenetic correction of

inflammation, cerebral edema, or other manifestations of imbalance (infectious shock,
DIC) and the symptomatic ones as well.
4% 3%
7%
2%
2%
S. pneumoniae
33%
18%
29%
N. meningitidis
Group B
Streptococcus
E. coli
H. Influenzae
Alti bacili gram
negativi
Fig. 1 - Prevalence of etiologic agents in

Europe
Fig. 2 - Barriers crossed by etiological agents

up to the neuraxis
Fig. 3 - The Brudzinski sign
Fig. 4 - Mark Kerning Sign
107
Fig. 5 - Hydrocephalus
Fig. 6 - Subdural empyema
Meningococcal disease
(Epidemic cerebrospinal meningitis)
Meningococcal disease is a major clinical manifestation of infection with Neisseria meningitidis,
which can take the following forms fulminant meningococcemia (purpura fulminans),
nasopharyngitis and healthy carrier of meningococ.
Etiology
Neisseria meningitidis (meningococcus) is a Gram negative diplococci, aerobes, 0.6 to 1 micron
with typical alignment (the "beans" that fit the concave side) of different sizes and extracellular
location, but frequently intracellular, belongs to the Neisseria type of Neisseriaceae family (Fig.
50). Meningococcus is a pretentious germ, he develops only on blood cultures (Socol agar,
serum agar). The medium used universally is Mueller-Hinton. Meningitis is extremely fragile in
external environment being destroyed rapidly by cold, heat, dryness. The optimum temperature
for growth is 36-37 C. To obtain the culture it is necessary that from the sampling point to the
thermostat, the cerebrospinal fluid (CSF, and so on) to be transported at 37 C.
Classification
After the antigen 12 serogroups structures have been identified A, B, C, E, H, I, K, L, X, Y, Z
and W-135. Identification is made with specific antisera. The most common meningococcal
disease is caused by the serotypes A, B, C and Y. In Africa and Europe the epidemic type is
represented by meningococci of group A, while groups B and C produce epidemics elsewhere
sporadically, meningococii of other groups are less virulent and of lesser importance.
Meningococii contain strong endotoxin (lipopolysaccharide) with pathogenic role in
meningococcal purpura and other clinical manifestations.
Epidemiology
Meningococcal infection is spread across the globe. Infections occur sporadically throughout the
year, but with a higher incidence in winter and spring.
108
The source of infection is only the human being: meningococci carriers and patients with
meningococcal nasopharyngitis disease.
Transmission is by direct contact through infected Pflugge droplets or indirectly through recently
contaminated objects.
Contagiousness is high, but virulence is generally weak and variable, which explains the low
number of disease compared with those infected.
Susceptability to infection is general, maximum at children decreasing with age.
Immunity. Based on studies it is known that there is a group meningococcal immunity expressed
by serum bactericidal activity and the presence of agglutinins and complement fixers antibodies.
Immunity is achieved through group polysaccharide antigen vaccines.
Pathogenesis
The gate for meningitis is nasopharynx and respiratory mucosa. An inapparent infection usually
follows or meningococcal nasopharyngitis. Overcoming the body's defense may result in
bacteremia, possibly followed by dissemination of meningococci in the form of metastases in
different organs and tissues: skin, meninges, joints, endocard, lung. Serum bactericidal activity
against meningococci belong to IgM fraction and this fraction deficit favors dissemination. Thus
meningococcal septicemia is produced; injuries that occur are predominantly vascular wall lesion
with vascular necrosis and thrombosis, resulting large petechiae and hemorrhagic areas. The
most severe form is fulminant meningococcemia with Waterhouse-Friderichsen syndrome in
which there is bleeding into the adrenal glands and death occurs in 24 hours. In most cases of
Waterhouse-Friderichsen syndrome microthrombi have been found in large numbers,
particularly in the kidney, liver, lung, choroid plexus.
Disseminated intravascular coagulation (DIC) is today considered a major pathogenic factor in
producing rapid death in meningococcemia. The syndrome can be detected by indentifying the
following: thrombocytopenia (20.000-30.000/mm3), increased prothrombin time (over 15
seconds). A consumptive coagulopathy with significant deficiency of coagulation factors (V,
VII, VIII and X) is noted. Intravascular microtrombi are formed causing difficulties in
microcirculation and a generalized bleeding diathesis.
Responsible for producing Waterhouse-Friderichsen syndrome is meningitis endotoxin. Against
meningococcal antigen sensitization phenomena may occur as fever, arthritis and vasculitis with
exanthematic aspect.
Complement is an important component of resistance against meningococcal illness. A decrease
in complement function is noted in the forms of invasive infection. Genetic deficiencies of
complement C3, C5, C7, C8 favor recurrent meningococcal meningitis. Another contributing
factor is gender, the disease being more common in males.
Clinical manifestations of meningococcal infection are varied. The disease can occur in the
following forms: pharyngitis, sepsis or meningitis.
Meningococcal nasopharyngitis is the most common manifestation of meningococcal infection,
bacteriological exam contributes to identify the etiology by isolating meningococci. They have a
considerable epidemiological importance.
Meningococcal sepsis (meningococcemia). In its acute state it usually presents itself as the
worst option being extremely virulent, although chronic forms may exist as well.
109
Acute meningococcemia. Onset is sudden with fever, chills, myalgia, arthralgia. The patient
becomes apathetic, hallucinating or becomes comatose. The skin develops a rash with dark red
spots as closed, bleeding, unevenly distributed (Fig. 8). In severe cases with vascular thrombosis
the aspect is that of necrotic appearance or gangrene of the skin. Meningococii can be isolated by
culture from eruptive elements. The patient presents arthralgia or suppurative arthritis, herpes
labialis, splenomegaly.
In 20-30% of cases, these clinical manifestations are identified as meningoencephalitis.
Sudden onset of Meningococcemia. Onset is brutal with bacterial shock, massive purpura wide
spread bleeding. The patient may be febrile or hypothermic, in shock, with pallor, cyanosis,
tachycardia, hypotension, dizziness, agitation, coma. DIC is present most often manifested by
large gastrointestinal and cutaneous areas of bleeding. Death can occur quickly within a few
hours. (Fig. 9)
Chronic meningococcemia. Rare for meningococcemia evidenced by repeated fevers, chills,
arthralgia, headache, petechiae and purpura on the skin nodules. The clinical picture may suggest
vasculitis or collagen.
Meningococcal disease. Incubation: 2-5 days.
Onset: sudden, with chills, high fever, headache, nausea, vomiting, convulsions, coma.
The patients condition. The patient presents the picture of an acute meningitis: persistent fever,
headache, delirium, agitation, cutaneous hyperesthesia, photophobia, drowsiness, stupor. The
position of the patient is usually in the "cock of the rifle" patient showing signs of muscle
stiffness (stiffness of neck, Kerning signs, positive Brudzinski). Frequently there is an oral or
peribucal expanded herpes. Children have a characteristic cry ("encephalitic cry"), frequent
seizures, bulging fontanelle. CSF is high, turbid, purulent, containing hundreds or thousands of
cells / mm3, most neutrophils and intra-and extracellular meningococci identified on smears
(blue methylene, Gram). Neutrophilic leukocytosis are found in blood.
Clinical Forms
attenuated form
the acute common form
the chronic form
the sudden Waterhouse-Friderichsen syndrome (Fig. 9).
Other meningococcal clinical manifestations
pneumonia
pericarditis
Arthritis
endocarditis
conjunctivitis.
Complications
110
Blockage of CSF circulation through blockage of communication spaces between the

subarachnoid space and ventricles or intraventricular blockage leading to internal hydrocephalus,
cerebral cortex atrophy, psychiatric sequelae.
Impairment of cranial nerves may be followed by important sequelae.
Deafness after meningitis varies between 3-5% and it can be acute or permanent.
Strabismus (lesion pair of cranial nerves III).
Blindness (optic neuritis).
Psychiatric Sequelae persistent headache, depression, memory impairment, etc..
Diagnosis
Positive diagnosis is based on clinical data (acute meningitis, petechial exanthema, arthralgia,
herpes labialis), plus epidemiological data. Diagnosis indicated by laboratory data: CSF
examination (cytology, bacteriology, smears, culture, latex agglutination tests,
counterimmunoelectrophoresis).
Differential diagnosis: purulent meningitis of other etiologies, otogenic, with clear CSF,
subarachnoid hemorrhage, meningism, meningeal reaction, brain tumors, cerebral abscess.
Meningococcal rash should be distinguished from Henoch-Schnlein, various vasculitis
septicemia, endocarditis, AAR, etc..
Prognostic
The prognosis depends on the clinical form of meningococcal meningitis (meningococcal
serogroup) and the precocity of diagnosis and treatment. The prognosis remains serious for the
sudden debut, Waterhouse-Friderichsen syndrome. "Meningococcemia kills faster than any other
infectious disease."
Treatment
Treatment should be initiated very urgently, therapeutic success depends on the accuracy and the
early diagnosis. The patient should be isolated in a department of infectious diseases and
intensive care.
Penicillin G is the antibiotic of choice in meningococcal infection. The dose of penicillin is
100000-200000 MU / kg / day iv for a period of 10-14 days.
Ampicillin has similar results in doses of 150-200 mg / kg bw / day iv.
Chloramphenicol site (50-100 mg / kg / day iv) or Cotrimoxazole is used generally for those
with allergies.
Ceftriaxone at a dose of 100 mg / kg body weight / day in the case of penicillin-resistant
Meningococci.
Pathogenetic therapy is carried out with anti-inflammatory steroids, hydrocortisone
hemisuccinate (5 mg / kg / day iv), dexamethasone (0,1 - 0,3 mg / kg / day iv), solumedrol and
depletion (mannitol, furosemide).
Symptomatic treatment: antipyretics, analgesics, vitamins.
Prophylaxis
111
Meningococcal disease is part of the list of contagious diseases with compulsory admission. For
family contacts and close contacts chemoprophylaxis with one of the following antibacterial
substances is recommended:
Rifampicin 600 mg / day in adults, 5 days
Spiramycin, 2g/day in adults, 50 mg / kg / day in children, 5 days
sulfonamides only if there is clear evidence of sensitivity of meningococci to this class
Specific prophylaxis. Lately we obtained effective vaccines against group A,C meningococcal
infection, which is administered in a single dose subcutaneously or intradermally.
Fig. 7 - Neisseria meningitidis - cocci arranged in

diplo (smear Gram)
Fig. 8 meningococcemia - petechiae,

bruises
Fig. 9 sudden onset meningococcemia Waterhouse Friderichsen syndrome
Pneumococcal Meningitis
Definition
Pneumococcal meningitis is a type of meningitis with the extremely severe evolution due to
Streptococcus pneumoniae. It can be primary (in this case nasopharyngeal entry gate ) or
secondary to pneumococcal outbreaks or parameningeal (ORL). Patients with splenectomy, head
trauma, chronic diseases (cirrhosis, diabetes), fistulas with subarachnoid communication, the
elderly are especially susceptible.
The onset is usually sudden with an infectious syndrome, intracranial hypertension phenomena,
brain damage and rapidly evolving to coma, seizures, focal neurological signs.
Diagnosis is supported by CSF examination, Gram positive cocci in diplo are detected,
lanceolated, coated, extracellular and positive cultures as well (fig. 10, 11). Pneumococcus can
be identified in blood cultures.
The evolution of the disease is severe, since there are frequent relapses because of uncared for
fistula. The most common complications are hydrocephalus, subdural empyema, vasculitis. The
death rate, despite treatment, is 30% especially in the elderly.
Treatment is primarily etiologic because of additional issues such as:
112
Deposits of fibrin in early stages which leads to decreased access of antibiotics and of
active concentrations below the necessary bactericidal level;
the risk of resistance to penicillin; a percentage of 30-40% of cases of pneumococcal

resistance to this antibiotic have been reported lately.
Treatment usually combines two substances prior to antibiogram:
Penicillin G at a dose of 150000-200000 U / kg / day in children and in adults 200,000 U

- 300,000 U / kg / day administered iv at 6-8 hour intervals;
Chloramphenicol hemisuccinate iv at a dose of 50 mg / kg / day (not to exceed the dosage

of 3 g / day in adults or 50 mg / kg in children);
Ceftriaxone at a dose of 2-4 g / day iv in adults, 100 mg / kg bw / day in children;
Cefotaxime at a dose of 6-8 g / day for adults and 100 mg / kg / day for children;
Meropenem at a dose of 30-40 mg / kg in 8 hours in special cases where there is evidence

of a resistant strain.
Antibacterial treatment duration is at least 10 days, preferably 14 days depending on the clinical,
biological constants and changes in CSF.
Pathogenetic treatment is performed by administering anti-inflammatory steroids: hydrocortisone
hemisuccinate, dexamethasone, solumedrol.
Depletion therapy is oral mannitol, furosemide.
Symptomatic treatment: anti-pyretic, analgesic and neuroroborant.
Prophylaxis
In addition to the prevention of pneumococcal infection particular attention is given to cases of
patients with high risk due to favorable conditions. In patients with relapses of chronic diseases
splenectomised vaccination with polyvalent (Pneumovax) is recommended because it includes
23 of the most common and pathogenic serotypes.
Fig. 10 - Streptococcus pneumoniae Culture
Fig. 11 lancet-shaped cocci arranged in chains,

Gram smear
Haemophilus influenzae meningitis

It is characteristic of children under 2 years most frequently of type B (90%).
Haemophilus influenzae is a Gram-negative coccobacillus, aerobes, non-sporing.
Besides meningitis the germ may cause epiglottitis, pneumonia, septic arthritis and various
cellulite as well.
113
Diagnosis is based on historical data supported by clinical and CSF examination where small
pleomorphic Gram negative cocobacilli have been detected as well as positive cultures. (Fig. 12,
13)
Treatment
A reconsideration of the etiologic treatment has been necessary in recent years triggered by
strains resistant to Ampicillin and Chloramphenicol in 30-40% of cases. Prior to antibiogram in
case of suspicion it is recommended to begin treatment with one of the following thirdgeneration cephalosporin: Ceftriaxone (100 mg / kg / day iv) ceftazidime, cefotaxime, ampicillin
(100 - 200 mg / kg / day iv) Amoxicillin. Added to these the cortisone, depleted, symptomatic
therapy is recommended as well. Antibacterial treatment duration is 14 days.
Prophylaxis
A vaccine (antihaemophilus influenzae type B) is currently available on the market, with
parenteral administration and satisfactory immunogenicity. Unfortunately immune reaction is
estimated to be effective only for children over the age of 1.5 years.
Nonspecific measures target children's communities by avoiding access of pharyngeal carriers,
especially in care units with chronic illness or immunological deficiencies.
Fig. 12 - Haemophilus influenzae - culture
Fig. 13 - Haemophilus influenzae

Gram smear
Listeria monocytogenes meningitis

Listeria monocytogenes is a coccobacillus, pleomorphic Gram-positive rods having a diameter of
0.5 - 1.5 micron non-sporing, aerobes and facultative anaerobes.
Having O and H antigens it differs from most serotypes, the most frequent being types I and IV.
No exotoxins are secreted, but an endotoxin with necrotizing action is produced. (Fig. 14, 15)
Epidemiology
It is spread across the globe.
The source of infection is of animal origin, the cocobacillus being isolated from 44 species of
animals, birds and shellfish.
114
Man is infected by eating or contact with sick animals or inhalation of contaminated dust.
The real incidence of the disease in humans is unknown because of the large number of
unapparent infections. The most frequent infection period is summer. It generally affects
immunosuppressed persons.
Positive diagnosis is established on the basis of epidemiological, clinical data and confirmation
is possible by isolating the germ of CSF from blood cultures, throat swabs, conjunctival
secretions.
Identification of isolated germ is carried out by immunofluorescence, ELISA technique.
Treatment
Moncytogenes Listeria generally responds to Ampicillin, Cotrimoxazole, Chloramphenicol. It is
usually resistant to cephalosporins and polimyxin. In such cases bi-therapy with Ampicillin and
Cotrimoxazole is recommended as well as anti-inflammatory steroids, depleted, symptomatic
therapy.
Fig. 14 - Listeria monocytogenes - culture
Fig. 15 - Listeria monocytogenes

Electronic microscopy
Staphylococcal meningitis
It is a particularly severe form of meningitis in adults, elderly, newborn.
Etiology
Staphylococci (staphs) are Gram-positive cocci, aerobes, immobile, non-sporing that are
arranged charactheristically in "piles", "bunches", both in pathological products and in solid
cultures. (Fig. 16, 17)
Staphylococcus species is divided into: Staphylococcus aureus, epidermidis and saprophyticus.
From a clinical point of view the pathogenetic classification is more important since it creates
two categories:
Staphylococci coagulase producers (highly pathogenic);
Coagulase-negative staphylococci (except pathogens: S. epidermidis, S. saprofiticus).
Positive diagnosis requires clinical examination of an array of staphylococcal sepsis or by
identifying a vulnerable entry gate. Bacteriological laboratory confirmation is given by viewing
staph in CSF and especially the cultivation of CSF, blood or metastatic foci.
Treatment
115
Etiologic treatment requires staphylococcal antibiotics in combination: oxacillin (100 - 200 mg /

kg / day IV) with rifampicin or nafcillin, third generation cephalosporins and ciprofloxacin (400600 mg / day iv) or Cotrimoxazole and in the case of plurirezistent germ Meropenem will be
used (30-40 mg / kg / day to 8 hours) with vancomycin (10-30 mg / kg / day iv every 12 hours).
Duration of treatment is at least 14 days, depending on the clinical and biological progress.
Pathogenetic therapy, anti-inflammatory steroid treatment, depleting drugs (Mannitol 20%,
Furosemide) should be administered as early as possible. In cases of early heparinisation DIC is
recommended.
Prophylaxis
It requires basic personal hygiene measures, proper care of staphylococcal lesions especially
those at risk of "malignant staphylococcal face."
Fig. 16 - Staphylococcus aureus - culture
Fig. 17 - Staphylococcus aureus

Gram smear
Meningitis caused by Leptospira

Leptospirosis is an infection of organism with pathogenic leptospire that evolves diphasic
initially with systemic manifestations, and in the second phase with visceral locations, including
meningitis. No significant changes of CSF are noted (hundreds of elements / mm 3 with
predominance of mononuclear polymorphic cells) with no biochemical changes.
Diagnosis is suggested by epidemiological arguments and the coexistence of other visceral
determinations (liver, kidney). Serological confirmation is required, RAL, RFC, ELISA,
immunofluorescence, electron microscopy, PCR. (Fig. 18, 19)
Evolution is generally favorable.
Etiological treatment is carried out with penicillin G (100,000 U / kg / day), ampicillin, thirdgeneration cephalosporins (Ceftriaxone - 100 mg / kg / day iv).
116
Fig . 18 - Leptospira interrogans
Fig. 19 - Leptospira interrogans
Electronic microscopy
Western Blot test
Meningitis with Borrelia burgdorferi

Spirochaetosis borreliosis is transmitted by ticks of the Ixodes species. It has a gradual
development at skin, neurological, cardiac, articular level. Untreated the disease becomes
chronic, with recurrent persistent headache, paralysis of cranial nerves (II, III, V, VII) but with
moderate or absent meningean syndrome. Acute borreliosis meningitis has the following
characteristics: clear CSF, with tens or hundreds of lymphocytes with slightly increased
proteinorachia and normal glicorachia. The serological diagnosis is clarifying (specific
antibodies, anti Bb, IgM, IgG in CSF, blood), ELISA, IFI, Western-blot or gene amplification
methods (PCR) (Fig. 20).
Etiological treatment of choice is the Penicillin G, Ceftriaxone, cefotaxime, amoxicillin,
doxycycline. Duration of therapy is 14 days in acute forms, and 30 days chronic forms.
Pathogenetic treatment with NSAIDs is performed; corticosteroidian treatment is recommended
only in major cases.
Fig. 20 - Borrelia burgdorferi indirect immunofluorescence

Meningitis Streptococcus agalactiae (group B)
It is considered characteristic of the neonatal period, but it can occur up to 6 months of age, the
explanation consisting of the immaturity of the newborn immune system, lack of maternal
antibodies, knowing that streptococcal infections in immunocompetent individuals do not
develop protective antibodies. The evolution is as severe as with Gram-negative meningitis, CSF
is of purulent aspect, intensely positive Pandy reaction, thousands of cellular elements with PMN
predominance, increased proteinorachia low glicorachia.
117
Diagnosis is supported by anamnesis, confirmed by clinical and laboratory data (CSF, blood
culture), blood culture, latex agglutination, ELISA serology, PCR (Fig. 21).
Etiological treatment involves the combination of ampicillin (100 - 200 mg / kg / day iv) with
aminoglycosides (gentamicin, netilmicin - 5-7 mg / kg / day iv) or third-generation
cephalosporins, and vancomycin phosphomycine rifampicin in cases of intolerance to beta
lactams.
Pathogenetic treatment is carried out with anti-inflammatory steroids, depleting, symptomatic
drugs.
The treatment duration is of at least 14 days depending on the clinical status and laboratory
results.
Fig. 21 - Culture of Streptococcus agalactiae
Pseudomonas aeruginosa meningitis

It is a rare disease but with a severe evolution, with a greenish turbid CSF. Iatrogenic meningitis
(of innoculation) occurs more frequently in adults, after septic spinal puncture.
Treatment consisting of: Meropenem 30-40 mg / kg / day iv every 8 hours in combination with
Ciprofloxacin 400-600 mg / day at 8 hours interval. In case of iatrogeny where plurirezistent
germs are suspected Colistin is administered as well 100,000 U / kg / day in 2-3 divided doses.
Other alternatives: Ceftazidim, Cefoperazone, cefepime, piperacillin / tazobactam, Amikacin
intraspinal.
Enterobacteriaceae meningitis
Species of Enterobacter, Salmonella, Proteus, Klebsiella cause particularly serious meningitis,
they occur more frequently in neonates, infants, the elderly, people with compromised immunity.
CSF has a purulent aspect containing thousands, tens of thousands of polys (polymorphonuclear
leukocytes).
Treatment: third generation cephalosporin (Ceftriaxone, ceftazidime) in combination with
fluoroquinolones (ciprofloxacin, levofloxacin) or Meropenem, fourth generation cephalosporin
(cefepime) when the germs are pluriresistent.
Anaerobes Germs Meningitis
They are particularly severe meningitis (Bacteroides spp etc.).
118
Treatment consists of the combination of penicillin G 200,000 U / kg / day iv metronidazole 50

mg / kg / day IV or Chloramphenicol 50-100 mg / kg / day iv. If there are suspicions of
Peptostreptococcus Meropenem should be administered (30-40 mg / kg / day iv every 8 hours).
Meningoencephalitis tuberculosis (TB)
Tuberculous meningoencephalitis is one of the most severe forms of extrapulmonary
tuberculosis whose evolution in the absence of treatment, is invariably fatal.
Definition
It is caused by the Koch bacillus characterized by a subacute or chronic evolution with ICH
syndrome and intense meningeal irritation, moderate inflammatory syndrome and early
association of neurological symptoms such as impairment of cranial nerves or bladder retention,
highly indicative to the correct diagnosis.
Etiology
It is represented by Mycobacterium tuberculosis (M. bovis rarely). It is an intracellular germ.
The bacillus is morphologically imobile with a wall rich in lipidic structures that render it acidalcolo-resistant.
Epidemiology
Tuberculosis is now the most common infectious disease in the world, tightly connected with the
dramatic extension of AIDS in the world.
The source of infection is the human being, rarely animal.
The route of transmission is airborne directly or indirectly, rarely digestive or cutaneous.
Responsiveness depends on the contact time. There are periods of maximum receptivity,
Childhood, adolescence, elderly. The most important factor favoring cell immunosuppression.
Pathogenesis
Meningeal infection disseminates in two ways:
The hematogenus path during primary infection (in children), if it is generalized (miliary
TB);
Lympho-hematogenic dissemination or contiguity out of juxta-meningeal outbreaks

(bone, kidney, pleuropulmonary).
Incubation is long, a few weeks in its reactive forms, but it can be shorter, of only a few days in
the primary disseminated forms, especially in immunocompromised bodies.
The onset is insidious. It takes 2-4 weeks until the onset of the meningean syndrome, during
which the patient accuses headache, fatigue, loss of appetite, drowsiness, low fever.
State of patient while illness is in progress: infectious syndrome is moderate; meningean
syndrome is gradually increasing in intensity. The stiffness of the neck becomes extreme
119
("wooden backhead"), the clinical manifestations are predominantly the result of the encephalitic
syndrome. The patient is drowsy, confused, exhausted, cranial nerve palsies may occur
(especially abducens, oculomotor), globe bladder, pyramidal motor deficits. HIC syndrome is
most often present.
Laboratory data: blood examination may be normal, and CSF has the following features:
clear or xantocrom;
hypertension;
pleocytosis with 2-600 cells / mm3 lymphocytes having monomorphic aspect;
increased albuminorachia;
glicorachia greatly reduced;
low chloride;
fibrin coated.
Cultures become slowly positive in 4-6 weeks, and Ziehl-Nielsen stained smear may reveal acidalcolo-resistant bacilli. Supporting diagnosis can be made based on fluorescent staining of
smears, detection of mycobacterial antibodies in CSF, Lowenstein culture, mycobacterial
detection of DNA fragments in the CSF by PCR (Fig. 22).
Laboratory tests can support the diagnosis namely: lung X-ray examination may reveal miliar
aspect or pulmonary modifications, fundus examination may detect the presence of choroidal
tuber and cerebral CT scan may reveal brain edema, hydrocephalus, cerebral softening zone.
Positive diagnosis is supported by epidemiological data (history of TB contact,
immunocompromised diseases), clinical data, prolonged meningean syndrome, encephalitic
syndrome, CSF aspect.
Differential diagnosis is carried out taking into account, such as:
intracranial hypertension in tumors and other diseases;
viral, fungal, bacterial meningitis;
previous subarachnoid hemorrhage.
Treatment
Etiological treatment is established as early as possible at the slightest suspicion, by associating
the first 4 major anti-tuberculosis preparations:
Isoniazid (HIN) in doses of 5-8 mg / kg / day iv, po;
Rifampicin dose of 8-10 mg / kg / day po;
Pyrazinamide at a dose of 20-25 mg / kg / day po;
Ethambutol at a dose of 20 mg / kg / day po;
This regimen can be modified over time in two cases: in case of therapeutic inefficiency or by
analysing the isolated bacillus or in case of some forms of intolerance or adverse reactions. In
these situations the solution is to resort to the use of alternative anti-TB drugs such as
ciprofloxacin, capreomycin.
Duration of daily administration is 3 months, after which an intermittent dosing schedule 3 days /
week (3/7) or 2 days / week (2/7) is recommended, the dose is thereafter appropriately modified,
for a period of up to 9 months.
120
Pathogenesis therapy is carried out with anti-inflammatory steroids, depleting drugs.

Symptomatic treatment is carried out with antipyretics, analgesics, vitamins group B drugs with
trophic effects.
Fig. 22 - Culture bacillus Koch - Lowenstein
Viral meningitis
The feature that distinguishes viral meningitis from other types of meningitis is the particular
way of evolution, namely the tendency to spontaneous healing. The pattern of the evolution of
viral meningitis includes:
The route of transmission is predominantly respiratory (mixoviruses, adenoviruses,

influenza and parainfluenza viruses), gastrointestinal (enteroviruses) or mucous
membranes (HIV, herpes viruses);
incubation varies depending on the etiology from 5 days to over 3 weeks;
the invasion phase lasts a few days (3-7 days), thereby being obviously different from
bacterial meningitis, tuberculosis, fungal;
the inflammatory syndrome with meningeal irritation is prevalent, while ICH syndrome
and encephalitis syndrome are diminished or absent.
Complications and sequelae: persistent headaches, intracranial ICH, manifestations of

psychiatric disorders, arachnoiditis, seizures, abnormal behavior.
Treatment of these meningitis is the same, regardless of etiology, none of the viruses involved do
not require etiologic treatment, except VZV.
In these cases the treatment requires :
hygienic-dietary (isolation, bed rest, diet adapted to digestive tolerance);
pathogenic - in severe cases antiinflmator steroidal depletion therapy;
symptomatic - pain relievers, sedatives, anti-pyretic, anti-emetics.
Benign lymphocytic meningitis

121
It is considered the prototype of the entire group of viral meningitis.

Etiology: Armstrong virus, RNA virus of the arenavirus family.
Epidemiology
The natural source are the rodents (especially mice) from which it is transmitted to humans.
The route of transmission is respiratory (aerosol).
Responsiveness is unknown, the disease is more common in young people and staff working with
rodents.
Incubation lasts 5-10 days.
The onset of illness is of the pseudo-flu type with 3-5 days of fever, malaise,
micropoliadenopathy sometimes transient erythematous exanthema.
Illness development after a brief reduction of fever, malaise, intense headache, meningian overt
syndrome are prevalent.
CSF: clear or opalescent hypertensive, hundreds of cellular elements / mm3 with mononuclear
predominance of polymorphic aspect; proteinorachia is moderately increased or normal, normal
or slightly low glicorachia. Sometimes an encephalitic syndrome is associated.
Complications
Acute myocarditis, orchitis, reactive arthritis in the small joints.
Diagnosis is supported on the basis of epidemiological, clinical, laboratory, and certified by the
serologic diagnosis (ELISA), virological PCR.
Treatment
Pathogenetic with Hidrocortizonn hemisuccinat 5mg/kgc, dexamethasone: 0.1-0.3 mg /

kg, prednisone 1 mg / kg, 10-14 days depending on clinical status and laboratory.
Depleting drugs: Mannitol 20%, 5 mg / kg / day, furosemide.
Antacids, anti-pyretic medication, vitamins group B.
Sodium diet.
Clinical Forms
Mumps Meningitis - described in case of epidemical parotitis.
Poliomyelitic Meningitis described in poliomyelitis
Coxsackie virus meningitis, Echo described in case of enteroviruses
West Nile virus meningoencephalitis
Herpes virus meningitis - occurs mostly as a meningoencephalitis, with a severe evolution in

children. This Meningitis benefits from etiologic treatment: acyclovir 30-40 mg / kg / day iv 3-4
times / day that will be associated and pathogenetic, symptomatic treatment.
122
Fungal meningitis
Etiology
More than one species may be involved: Cryptococcus neoformans, Candida albicans,
Histoplasma capsulatum. These agents have in common the fact that they attack
immunocompromised organisms immunocompromised (AIDS, lymphoma, cancer,
immunological diseases).
Pathogenesis
In the absence of the defense capacity of the body, fungi can become invasive, moving from
colonization to systemic forms. Brain lesions are located mainly basal, fibrin coated, causing
vascular, necrotic injury, cloasonation and obstructions.
Clinical manifestations:
Onset: usually insidious. Moderate meningeal syndrome, the encephalitic syndrome when
present is severen and an indication of increased severity. The clinical manifestations are
determined by the ICH syndrome is often dominated by ICH and neurological (extreme
headache, nausea, vomiting, photophobia, bradycardia, cranial nerve impairment, convulsions,
paralysis).
Diagnosis
Examination is based on the CSF: clear, hypo-or hypertension, cellular elements 400-600
lymphocytes / mm 3 , proteinorachia greatly increased, glicorachia low. Giemsa stained smears,
China ink can identify fungi. The culture medium used for fungi is Sabouraud medium. For the
determination of the fungal antigens latex agglutination technique is used.
Etiologic treatment
Amphotericin B in progressive dose administered IV, 0,1 - 0,3 mg / kg / day, 2-3 weeks.
Flucytosine 150 mg / day orally, and IV.
Fluconazole 200-800 mg / day, 4 weeks iv then po.
Pathogenetic treatment
Anti-inflammatory, symptomatic treatment, depleting drugs.
123
References:
1. Bartlett J. Pocket Book of Infectious Disease Therapy. Lippincott Williams & Wilkins,
2002;167-270.
2. Bartlett J. Pocket Book of Infectious Disease Therapy. Lippincott Williams & Wilkins,
2007;120-240.
3. Chiotan M. Boli infecioase. Ed. Naional, 2002; 149-200.
4. Gilberd D, Moellering R, Eliopoulos G, Sande MA. The Sanford Guide to Antimicrobial
Therapy 37th ed. 2007; 167-190.

TM
5. Gopa B Green, Ian S Harris, Grace Lin. Manual de terapeutic medical Washinghton
Lippincott Williams & Wilkins, Ed. Medical, Ediia 31, 2006; 358-399.
6. Koedel U, Scheld WM, Pfister HW. Pathogenesis and pathophysiology of pneumococcal
meningitis. Lancet Infect Dis 2002;2:721-736.

7. Lutsar I, Friedland IR, Jafri HS, et al. Factors influencing the anti-inflammatory effect of
dexamethasone therapy in experimental pneumococcal meningitis. J Antimicrob Chemother

2003;52:651-655.
8. Pilly E. Maladies Infectieuses et Tropicales, 20e ed. 2006; 464-497.
9. Ronald TD Emond, Hak R, Welsby PD. Color Atlas of Infection Disease 3rd ed. 1995; 10340
10. Streinu Cercel A. Boli infeciose. Note de curs pentru studeni i medici practicieni. Ed.
Sigma, 2004; 80-120.
11. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of
bacterial meningitis. Clin Infect Dis 2004;39:1267-1284.
12.
Tunkel AR. Bacterial meningitis. Philadelphia: Lippincott Williams & Wilkens, 2001;
40-84
13.
ilea B. Patologie Infecioas. Fundamente de licen n medicin. . Ed. University Press,
Tg. Mure, 2009, 73-97
14. van de Beek D, de Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M. Clinical
features and prognostic factors in adults with bacterial meningitis. N Engl J
Medm2004;351:1849-1859.
15. van de Beek D, de Gans J. Prognostic factors in adults with bacterial meningitis. N Engl J
Med 2005;352:514-525.
16. Voiculescu M. Tratat de boli infecioase. Ed. Medical, Bucureti, 1989; vol. I: 324-359,
403-445.
17. Voiculescu M. Tratat de boli infecioase. Ed. Medical, Bucureti, 1989; vol. II: 254-267,
438-470.
124
ENCEPHALITIS
Carmen Chiriac
Definition.
Encephalitis represents an inflammation of the brain parenchyma, characterized by focal or
diffuse neuro-psychic symptoms. Encephalitis is distinct to meningitis although on clinical
evaluation both of them have similar manifestations: headache, photophobia, neck stiffness.
Enchephalitis is also distinct to cerebritis which appears in the stage preceding the formation of a
brain abscess and implies a bacterial infection with massive destruction of the brain tissue.
Most frequently, encephalitis is a viral infection, injuring the brain parenchyma in various
degrees, of mild to severe gravity. Patients with encephalitis may also suffer from meningitis
meningoencephalitis, lesions of the spinal cord - encephalomyelitis, or lesions of the spinal nerve
roots encephalomyelo-radiculitis.
Etiology.
The most common etiology of encephalitis is viral. The most important viruses that might
determine sporadic encephalitides are the herpetic viruses:herpes simplex virus (HSV) 1 and 2,
varicella-zoster virus (VZV), Epstein-Barr virus (EBV), enteroviruses (includes Coxackieviruses,
Echoviruses, enterovirus 71) the measles virus, influenza viruses, mumps virus, rubella virus.
These viruses are transmitted by interpersonal contact. An important category of encephalitides
is due to the group of arboviruses, transmitted to humans by means of some vectors: ticks,
mosquitoes. Rabies is a particular form of encephalitis due to the rabies virus transmitted by
animal bite.
The bacterial etiology is not very common, implying species of Mycoplasma, rickettsi,Borrelia
burgdorferi. Other etiologic agents could be fungi, protozoa or prions.
Classification of encephalitides
-
According to the type of production: - primary

- secondary
According to the etiology: - prions

- viruses: arboviruses, enteroviruses, herpetic viruses
- mycoplasmas, chlamydia
- fungi
- protozoa-toxoplasma gondi
- metazoa Trichinella spiralis, Echinococcus, Cysticercus
- According to the most injured tissue:
- polioencephalitis (gray matter lesions)
- leucoencephalitis (white matter lesions)

- panencephalitis (both gray and white matter
125
lesions)
- encephalomyelitis (brain and spinal cord lesions)
- encephalo-myelo-radiculo-neuropathy
spinal cord / peripheral nerves lesions)
(brain
Pathogenesis
1. Direct invasive mechanism Primary, viral encephalitis
The virus replicates at the entrance gate: respiratory tract(e.g.measles virus), digestive tract
(e.g.enteroviruses) or skin(e.g.arboviruses) and produce a local infection, followed by
dissemination via bloodstream (viremia),leading to invasion and replication in the Central
Nervous System (CNS).The arboviruses probable enter the CNS via cerebral
capillaries,determining vascular endothelial cell infection,preceding infection of the neural
parenchyma.
Rabies virus and polioviruses gain acces to the CNS trough neuronal networks.
When the virus across the blood-brain barrier, the virus can infect the neural cells, with resultant
disruption in cell functioning,neuronal death, perivascular congestion, hemorrhage, and a diffuse
inflammatory response that disproportionately affects gray matter over white matter. Certain
viruses have a particularly tropism to a specific brain area due to neuron cell membrane receptors
found only in specific portions of the brain, with more intense focal pathology in these areas.
Herpes simplex virus has predilection for the inferior and medial temporal lobes.
2. The indirect immune-mediated mechanism Post-infectious encephalitis(ADEM)
that follows an infection,most common :measles,varicella,rubella,mums and mor recent were
involved influenza A and B viruses,hepatitis viruses,Mycoplasma. The pathogenic mechanism
generates immune, inflammatory reactions with demyelination, perivascular mononuclear
inflammatory infiltrates(T cells,macrophages),after a delay of 1-4 weeks.Postvaccination cases
of ADEM are rare with the newer vaccines now in general use.
3. Chronic encephalitis the etiology of slow virus infections, such as subacute
sclerosing panencephalitis (SSPE) and progressive multifocal leukoencephalopathy (PML), is
poorly understood, appear in a few months or years after the accute viral infection. SSPE is a
chronic degenerative disease of, more common in older children / teenagers who have suffered
from measles before the age of 2 years.
Prion-induced encephalitis: Creutzfeldt-Jakob disease, Kuru disease, Gerstman syndrome, fatal
familial insomnia.
The prions proteinaceous infectious particles, totally free of nucleic acids, which do not
stimulate the production of antibodies. They are a 100 times smaller than the smallest known
viruses. In mammals, they reproduce by the selection of the normal cellular prion protein (PrPc)
and the stimulation of the transformation into its isoform (PrPSc). Each different conformation of
PrPsc is associated with a different type of prion disease. In animals, they produce scrapie, a
denomination coming from the English verb to scrape = to scratch, to rub, to graze.
Humans can catch prion disease in several ways: from contaminated food, iatrogenically
(neurosurgical interventions, cornea transplant) or genetically transmitted.
Creutzfeldt-Jakob disease described in the year 1921 is characterized by a deep alteration of the
intellect, memory, social conduct, temporo-spatial disorientation. It appears in persons with ages
over 60 years, having a progressive evolution, with myoclonia, blindness, insanity. Death occurs
after a few months. Diagnosis is confirmed histopathologically by detecting PrPSc inside brain
parenchyma.
126
4. Encephalopathies refers to diffuse cerebral dysfunction without inflammation.There

are clinical entities caused by toxins, cerebral circulatory disorders, electrolytic disorders,
uremia, liver failure, unbalanced diabetes mellitus. Most of patients with encephalopathies have
extra-CNS findings that suggest the underlying disease process.
Regardless of their pathogenetical mechanism, the clinical symptoms are associated in 3 major
syndromes:
-
infectious syndrome: acute febrile illness
syndrome of intracranial hypertension: headache, vomiting, photophobia, bradicardia,

elevated blood pressure
encephalitic syndrome:
- consciousness disorders (confusion, behavior troubles, agitation, personality
changes, hallucinations, lethargy, coma)
- seizures (focal / generalized)

- focal signs: upper or lower neuron patterns of weakness, involuntary movements
(tremor, myoclonic jerks), cranial nerve deficits (facial palsy, ocular palsy), lesions
of the hypothalamic-pituitary axis (diabetes insipidus, temperature dysregulation,
SIADH syndrome of inappropriate secretion of antidiuretic hormone)
medullar lesions may be associated (myelitis): flaccid paralysis, osteotendinous
areflexia, sphincter disorders.
Positive diagnosis
Encephalitis is one of the most challenging pathology for clinicians to diagnose and manage. The
etiology of many cases of encephalitis remain undiagnosed.
Epidemiological and clinical data, complementary examinations should be performed.
The initial laboratory testing include a complete blood count,test of renal and hepatic
function,cogulation studies.Serum electrolyte levels are usually normal unless dehydration is
present; The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is the result
of hypothalamic dysfunction. The serum glucose level should be determined to rule out
confusion due to treatable hypoglycemia and to compare with the cerebrospinal fluid (CSF)
glucose value.
CSF examination should be performed in all cases of encephalitis, except for cases with severely
increased intracranial pressure (ICP). It allows differentiation from a possible purulent
meningitis. It generally reveals a minimum pleocytosis of 10-100/mm3, lymphocytes, moderate
or inconstant elevation of CSF proteins. However, CSF may be normal!
Isolation of the pathogen agent from the CSF:
-
antigen detection
determination of IgM specific antibodies from CSF and serum
Polymerase Chain Reaction (PCR) technique:high sensitivity and specificity for
identifying a specific viral etiology:herpes simplex virus (HSV-DNA), varicella-zoster
virus (VZV-DNA), JC virus, Epstein Barr virus (EBV-DNA)
Neuroimaging.Patients with encephalitis suspicion should be referred for neuroimaging

investigations: CT, MRI.The sensivity and specificity of different patterns of neurimaging
abnormalities in encephalitis have not been formally defined.
127
CT examination allows differentiation from other diseases: abscess, subdural effusion,

thrombo-phlebitis, hemorrhage. CT examination may be normal! It may reveal: focal hypodense
lesions or cerebral edema of the white substance.
MRI examination of the brain allows the visualization of some abnormalities, more
precociously than by CT, demyelinating lesions,multifocal hemorrhagic infarctions.
Brain biopsy: rarely performed, in patients with focal lesions on MRI examination, whose
diagnosis could not be established by noninvasive techniques and who did not respond to
acyclovir and supportive therapy.
Electroencephalography (EEG) should also be performed,results can be helpful in identifying
the degree of cerebral dysfunction,may provide information about the specific area of the brain
involved.
Metabolic comas
Accidental or volunteer intoxications
Brain tumors
Brain hemorrhages
Systemic vasculitis
Evolution
Encephalitis may have various evolving patterns and severities.
Primary encephalitides are severe diseases, with deaths rates between 20-30% and 70%.
Sequelae: their incidence and severity is directly correlated to the patients age (young patients
have higher recovery rates) and mental status (GCS < 6 points predicts unfavorable outcome:
death or severe sequelae) at the time of therapy initiation.
The most frequent sequelae are- paresis, paralysis
- epilepsy
- psychomotor retardation
- cognitive impairment
- behavior disorders
Treatment
Isolation of patients in intensive care units: monitoring and support of the vital functions
Rigorous hygiene of the skin and mucous membranes
Diet parenteral nutrition, nasogastric intubation
Pathogenic medication Corticosteroid therapy (Dexamethasone, Methylprednisolone,
Prednisone)
Elimination of brain edema (depletion) and ICP monitoring: Manitol, 1-2g/kg/day
Anticonvulsant medication
128
Hydro-electrolytic and acid-base re-equilibration

B vitamins, neurotrophics
Fever suppression.
Etiologic treatment: Acyclovir etiologic therapy in herpetic encephalitis, but should be
initiated empirically in all patients with suspected viral encephalitis. Doses: 10 mg/kg
every 8 hours, for at least 14 days. Gancyclovir and Foscarnet are used in CMV-related CNS
infections.
HERPES SIMPLEX VIRUS ENCEPHALITIS

Herpes Simplex Virus (HSV) is a common cause of sporadic encephalitis.HSV type 1 and 2 are
members of the Herpesviridae,with VZV,EBV,CMV,HHV-6,HHV-7,HHV-8,and simian herpes
virus B.The mechanism by which HHV-1 and HHV-2 invade the CNS is unknown.
Clinical features
Patients may have a prodrome of malaise, fever, headache, and nausea, followed by acute or
subacute onset of an encephalitis whose symptoms include lethargy, confusion, and delirium.
The following are typically the most common symptoms of HSE : fever (90% to 100%),altered
consciousness,headache (81%), vomiting(46%), psychiatric symptoms:behavoir or personality
change (71%),seizures (67%), focal weakness hemiparesis, ataxia,memory loss,speech
disturbances.In neonatal HSV appears to arise from maternal genital infection with the
virus.Signs and symptoms of neonatal HSE develop about 6-12 days after delivery, at which
time lethargy, poor feeding, irritability, tremors, or seizures may be noted. Those with
disseminated disease also have abnormal liver function test results and thrombocytopenia. In
contrast to older patients, neonates often have herpetic skin lesions.
Diagnostic tests
Cerebrospinal Fluid Analysis. Once a space-occupying lesion has been excluded by imaging,
lumbar puncture always should be performed in suspected HSE.A typical viral profile is
identified: mononuclear pleocytosis of 10-500 white blood cells (WBCs)/L, protein levels are
elevated to the range of 60-700 mg/dL, glucose values may be normal or mildly decreased (3040 mg/dL). In about 5-10% of patients, especially children, initial CSF results may be normal.
However, on serial examinations, the cell counts and protein values increase.
The procedure of choice is the PCR of HSV-DNA in the CFS.
Neuroimaging. Approximately one third of patients with HSE have normal CT findings on
presentation. Head CT may show changes in the temporal and/or frontal lobe, but CT is less
sensitive than MRI.
MRI of the brain is the preferred imaging study. MRI may be normal early in the course of
illness. Temporal lobe involvement sometimes hemorrhagic, and early involvement of white
matter are typical. The inferomedial portion of the temporal lobe is most commonly affected on
MRI, sometimes in association with abnormalities of the cingulate gyrus. Findings of localized
temporal abnormalities are highly suggestive of HSE, but again, confirmation of the diagnosis
depends on the identification of herpes simplex virus (HSV) by means of PCR or brain biopsy.
129
Treatment.Acyclovir,10mg/kg every 8 hours,14-21 days is the durg of choise for the treatment of
HSV encephalitis.
Prognosis.Several factors influence the prognosis of HSVE,including patient age,level of
consciousness,duration of clinical encephalitis before initiation of acyclovir therapy.
ACUTE ENCEPHALITIS CAUSED BY ARBOVIRUSES

Arbovirosis are zoonosis, transmitted to humans, from animals, birds, by means of a
hematophage vector: mosquitoes, ticks, phlebotomes.
Arboviruses(ARthropod- Borne viruses) have brain (acute panencephalitis produced by invasive
mechanism) hepatic and vascular tropism.
More than 500 arboviruses are known.The arboviruses that infect humans cause nonspecific
symptoms,the main patterns of arbovirosis in humans are:fever,rash,arthritis,retinitis,encephalitis
and viral haemorragic fevers.
Classification of Arboviruses
-
Togaviridae
Bunyaviridae
Reoviridae
Flaviviridae
Pathogenesis: after the bite from an infected mosquito,the virus replicates in the local
tissue,lymph nodes-primary viremia.Dissemination of virus to the reticuloendothelial system
results in a secondary viremia that allows the virus to invade the CNS and other organs.
Clinical manifestations: The incubation period is between 4 and 10 days.

Beginning: influenza-like syndrome, fever, myalgia, neck stiffness
State of disease encephalitic syndrome
Clinical forms:Taiga encephalitis, West-Nile encephalitis, Central European tick encephalitis,
Scottish encephalitis, Japanese encephalitis, West / East equine encephalitis.
Denga, hemorrhage fevers: hemorrhage fevers (others tan African hemorrhagic fevers)
Yellow fever (serious acute hepato-nephritis, hemorrhagic syndrome and encephalitis)
Treatment: Ribavirin, 2g, then 1g every 6 h, Acyclovir
130
WEST NILE VIRUS ENCEPHALITIS

The West Nile virus is an arbovirus, from Flaviviridae family, spread by hematophage
mosquitoes.
The natural reservoir of West Nile virus migrating birds
Seventeen species of wild birds transmit West Nile virus to humans via the Culex, Aedes, and
Anopheles mosquitoes.
Patients may not provide a mosquito bite history.
The incubation period of West Nile encephalitis (WNE) is 1-6 days ( 14 days in
immunosuppressed patients). West Nile virus(WNV), like other arthropod-borne viruses,
traverses the blood-brain barrier and infects the brain parenchyma, clinically manifesting as viral
encephalitis.
WNV may also affect the leptomeninges, resulting in a clinical presentation of aseptic meningitis
(viral meningitis). Patients with WNE may present with features of encephalitis and aseptic
meningitis (meningoencephalitis).
Approximately 50% of children in Egypt have West Nile virus seropositivity. West Nile
encephalitis (WNE) is the most common cause of viral aseptic meningitis or encephalitis in
patients presenting to emergency departments in Cairo. WNE is common in the Middle East,
Asia, and Africa,USA,Europe.
Epidemic evolution was, in 1996, in Romania, with over 400 cases of manifested clinical cases.
Worldwide, most cases occur in young children or young adults. The elderly patients are affected
more severely.
Many patients describe prominent GI symptoms, especially vomiting and diarrhea. Nonspecific
symptoms may include sore throat, myalgias, and arthralgias
Onset acute: fever, headache, myalgia, quick progress to coma. Concomitantly, patients
presented signals of multiple organ failure; bronchopneumonias, cardiovascular manifestations,

hypertrophy of thymus.
During Romanian epidemics, the evolution was usually favorable, with cure without sequelae,
but death rate was 18%.
Serological tests revealed the frequency of rough/minor/asymptomatic forms of disease: 300
cases/1clinically manifest case.
Common disorders with CNS manifestations that may mimic West Nile encephalitis (WNE)
include subacute bacterial endocarditis, Legionnaires disease, Rocky Mountain spotted fever,
Epstein-Barr virus infectious mononucleosis, human herpesvirus type 6 infection, and systemic
lupus erythematosus cerebritis
WNVE is usually diagnosed by demonstration of WNV-specific IgM antibodies in CSF by
ELISA.
CSF-PCR for WNV is highly specific,but less sensitive than serologic studies.
There is not specific therapy.
131
CHAPTER 4
LEPTOSPIROSIS
Cristina Grbovan
Leptospirosis is an acute generalized infectious disease, characterized by extensive vasculitis,
caused by spirochetes of the genus Leptospira. Infections are most commonly caused by
Leptospira interogans, of which more than 200 serovars infect humans. It is primarily a disease
of wild and domestic mammals; humans are infected only occasionally through direct or indirect
contact with animals. People become infected by exposure to animal urine or urine-contaminated
surface water.
MICROBIOLOGY
Leptospires are finely coiled, motile spirochetes, approxiomately 0,1 um in with by 6-20 um in
length, with bent or hooked ends. Leptospires survive for days or weeks in warm, damp, slightly
alkaline conditions
EPIDEMIOLOGY
Leptospirosis is a zoonosis of worldwide distribution, affecting many species of wild and
domestic mammals. Most cases occur in young adult men, and the peak incidence is in summer
and early fall. Indirect contact with infected animals, via water or soil contaminated with
infected urine, is a more common cause of human infection than direct contact animal contact.
Occupational exposure (farmers, veterinarians, abattoir workers) and recreational exposure
(campers, swimmers) are common. Worldwide rats are the most common source of human
infection.
The serotypes found most commonly in human infection include:
Canicola
Icterohaemorrhagiae
Pomona
Autumnalis
Grippotyphosa
Hebdomidis
Ballum
Australis
PATHOGENESIS
Leptospira penetrate intact mucous membranes and abraded skin and disseminate widely via the
bloodstream.The major clinical manifestations of disease result from infection of capillary
endothelial cells leading to vasculitis. Symptoms develop 7 to 12 days after exposure. Most
patients have an abrupt onset of a self-limited, 4-to 7-day anicteric illness characterized by fever,
132
headache, myalgias, chills, cough, chest pain,neck stiffness, and/or prostration. An estimated
10% of patients will present with jaundice, hemorrhage, renal failure, and/or neurologic
dysfunction (Weil, s disease).
Classically, leptospirosis has been considered a biphasic illness.
Symptoms and Signs of leptospirosis:
Abrupt onset (70%-100%)
Fever chills (98%)
Headache(93%-97%)
Myalgias, muscle tenderness (40-60%)
Vomiting, diarrhea, abdominal pain (30%-95%)
Conjunctival suffusion (33%-100%)
Hepatomegaly (5%-22%; 80% of icteric cases)
Spenomagaly (5%-25%)
Meningeal signs (12%-44%)
Mental status changes (7%-21%)
Oliguria (10%)
Cough (10%)
Chest pain (11%)
Skin rash (9%-18%)
Jaundice (1,5%-6%)
Many patients with mild disease will not have symtoms of the secondary immune phase of
illness, and patients with very severe disease will have a relentless progression from onset of
illness to jaundice renal failure, hemorrhage, hypotension, and coma. The illness is biphasic in
about half of patients with relapse occurring approximately 1 week after resolution of initial
febrile illness. A late complication is anterior uveits, seen in up 10% of patients month to years
after convalescence.
DIAGNOSIS
Leptospirosis most often manifests as a nonspecific flulike illness, so recognition of
epidemiologic risk factors is essential. Epidemiologic risks should be sought in patients with a
flulike illness, respiratory illness, aseptic meningitis, acute hepatitis, acute renal failure,
pericarditis, atrioventricular block, or anterior uveitis.
Laboratory findings of Leptospirosis
Renal failure-acute interstitial nephritis ; related findings range from urinary sediment
changes (leukocytes, erythrocytes, and hyaline or granular cats), mild proteinuria.
Peripheral leukocyte counts range from 3000 to 26 000/ul, with a left shift
Thrombocytopenia
133

Jaundice with only 2-to-3 fold elevations in transaminases and alkaline phosphatases,
conjugated bilirubinemia
Myositis with elevated creatine phosphokinase
Cerebrospinal fluid pleiocytosis: 300 cells/ml, lymphocyte predominance; the protein

concentration in the CSF may be elevated; CSF glucose levels are normal
Abnormal chest radiographs; patchy alveolar pattern in lower lobes with or without
interstitial/alveolar hemorrhage
Electrocardiogram
atrioventricular block
abnormalities:
sinus
tachycardia,
myocarditis,
first-degree
A definite diagnosis of leptospirosis is based either on isolation of the organism from the patient
or seroconversion or a rise in antibody titer in the microscopic agglutation test (MAT). In cases
with strong clinical evidence of infection a single antibody titer of 1:200-1:800. Antibodies
generally do not reach detectable levels until the second week of illness. Although not species or
serovar specific, enzyme-liked immunsorbent assay (ELISA) kits to detect immunoglobulin M
(IgM) antibodies enable diagnosis during the first week of illness.
Influenza
Malaria
Rickettsioses
Enteric fever
Viral hepatitis
Hantavirus infections
Other acute febrile illnesses
THERAPY
Antibiotic treatment is most beneficial when started within 4 days of illness.
Doxycycline 100 mg orally twice daily for 7 days started within 48 hours of illness,
decreased the duration of illness by 2 days in one study.
Severe infection requiring hospitalization: Penicilin, 6 milion U iv qd or Ceftriaxone,

1gIV/IM qd.
Supportive care and treatment of the hypotension, renal failure(including dialysis), and
hemorrhage than can complicate leptospirosis are crucial for a good outcome.
After penetrating intact mucous membranes or abraded skin, leptospires enter the blood stream
and are rapidly carried to all parts of the body , including the cerebrospinal fluid (CSF) and eye.
Jaundice, which occurs in the severe cases, is due primarily to hepatocellular dysfunction,
usually without necrosis. Hepatic damage is apparently subcellular , and leptospires are rarely
seen in the liver. Renal functional abnormalities may be profound and out of proportion to
histologic changes seen in the kidney. Renal failure is primarily a result of tubular lumen.
During the first week of infection, leptospires may be readily found in the CSE but meningeal
signs are absent. Later,when serum antibody appears, meningitis may develop.
134
RABIES
Carmen Chiriac
Rabies is an acute viral infection of the central nervous system, with terminal evolution. Humans
are infected by the bite of an ill animal or which is in the period of incubation.
-
Lyssa (gr.) craziness
Rabiaes, rabere (lat.) violence
Rabhas (Sanskrit) violence
Louis Pasteur created the anti-rabies vaccine in 1884
Victor Babe - proved the prophylactic efficiency of the anti-rabies serum (1889)
Etiology
The virus of rabies forms part of Lyssavirus genus, Rhabdoviridae family also including other
viruses: the vesicular stomatitis virus (VSV). The rabies virus is a virus of large size 180 mm,
having a long shape of a bullet.
The nucleocapsid is formed by monocatenary RNA. The lipoprotein cover presents external
projections with the function of attaching the virus to the host receivers.
The rabies virus is destroyed by ethers, soap, quaternary derivates of ammonium but it lasts for
years if frozen at -70C.
Epidemiology
Rabies is a zoonotic viral disease, specific to warm blood vertebrates, and accidentally it can be
transmitted to humans. It is spread worldwide, excepting the following geographical areas:
Antarctic, England, New Zeeland, Hawaii, Cyprus.
The rabies virus is kept in circulation by means of three natural cycles:
1) The sylvatic reservoir of rabies virus is represented by some salvage animals,
reservoirs of rabies virus: in Europe foxes, wolves (in the areas where they still
exist), badgers, otters, rats, mice, rabbits; in USA coyotes, skunks
2) Urban, canine rabies the rabies virus reservoir is represented by dogs, cats, rarely
horses, bovines, pigs.
3) Chiroptera virus (vampires, bats) which can be healthy carriers of rabies virus,
United States, Spain, Portugal.
The transmission to humans is done by the saliva of contaminated animals: bites or epidermalmucous with the spit of ill animals. There have also been reported cases by airborne transmission
(exposure to aerosols in labs or caves where thousands of bats survive) or post-transplant. The
cornea transplant represented the rabies source in eight cases. Exceptionally, the virus can be
transmitted by inhalation in the caverns populated by bats. The handling of death animals is also
dangerous.
The receptivity is general. The death is mortal. The virus is excreted by spit 5-7 days before the
appearance of clinical signs, during the period of disease, till death. The virus does not penetrate
the healthy skin. The inoculation of mucous membranes by smeary hands is possible.
135
Pathogeny
The rabies virus penetrates the organism by a solution of teguments continuity: animal bite, by
mucous membranes, respiratory tract.
The rabies virus is multiplied at local level, mostly in the corrugated muscular cells. It crosses neuralmuscular junctions, attaches to acetylcholine receptors (their blocking restrains the attaching of the
rabies virus). The penetration of the rabies virus into the sensitive and motor neurons is followed by
an ascendant, centripetal migration along the axons of peripheral nerves with a speed of 100-400
mm/day towards the spinal cord, brain stem, central nervous system (CNS).
In the CNS, the rabies virus is multiplied exclusively within the gray substance where it causes more
neuronal malfunctions and less neuronal destruction. From the level of the CNS, the virus spreads
centrifugally along the peripheral nerves towards other tissues: salivary glands, lungs, liver, kidneys,
adrenal glands, muscles, teguments, heart. The rabies virus is multiplied in the acinar cells of the
salivary glands and excreted by saliva. The histopathological modifications are specific: minimal
mononuclear inflammatory infiltrates in leptomeninges, perivascular, microglial nodules (Babe
nodules). The parenchyma reveals intracytoplasmic eosinophil inclusions containing viral
nucleocapsids denominated Negri corpuscles (more spread in the Purkinje cells from the
cerebellum).
Clinical frame
The medium incubation period is between 20 and 90 days. The shortest incubation periods have
been described in case of multiple bites on face, scalp, neck and the longest incubation periods
have exceeded 1 year.
Two clinical forms of rabies at humans have been described: furious rabies and paralytic rabies.
Furious rabies
Prodrome: the period of invasion (prodromal) with the duration of 2-4 days reveals: asthenia,
anorexia, fever, psychomotor excitation with anxiety, agitation, irritability, insomnia, a
depressive state.
The ill person complains about paresthesias/pain at the place of the bite, progressively a state of
epidermal, diffuse hyperesthesia.
State of disease: it begins with hyperexcitability, defined agitation, the patient becomes hoarse,
shouts, talks a lot, is disoriented, has hallucinations. Hydrophobia and aerophobia determined by
the glottic spasm are frequent, pain during the attempt to swallow liquids (or when hearing
flowing water) or when an air current passes over the face of the patient. Dysphagia also occurs,
the patient salivates excessively, cannot swallow the saliva which creeps through the
commissures. Other symptoms are also present: fever, muscular fasciculations, mydriasis,
hypersudoration, localized or generalized convulsions. After the appearance of furious crises,
patients die in maximum 1-2 weeks.
Paralytic rabies
It begins with rachialgias, pareses, soft paralyses, initially in the region of the bite, they extend
afterwards, ascending similarly to the Landry ascendant paralytic syndrome. Intense pains of the
limbs, or muscular volumes are common, the mental status is progressively degraded. Unlike the
furious type, aerophobia, hydrophobia are not present. The cephalorachidian fluid (CRF) is
hypertensive, normal biochemical parameters, moderate pleocytosis (lymphocytes).
The paralytic form also evolves to death in about 6-30 days from the installation of coma.
136
Evolution: Rabies is a fatal disease, although recently there have been communicated also cases
of cure.
Diagnosis
Epidemiological data: animal bite
Clinical data: pain / paresthesias at the level of the bitten canker, hydrophobia/aerophobia
neurological signs
Etiologic diagnosis: isolation of the rabies virus from tissues, saliva, cornea, mucous membranes
intracerebral inoculation in mice.
The virus detection by immunofluorescence (2 hour result) from: saliva, CRF, corneal imprint,
fragment of teguments. Specific neutralizing antibodies into serum can be detected a few days
after the release of symptoms. Some patients do not create antibodies. The specific antibodies in
CRF suggest rabies, no matter the immune status of the patient.
The detection of viral RNA into the saliva, CRF, tissues, by the technique RT-PCR is very
specific and sensitive. Post mortem, the highlight of Babe Negri corpuscles in AMMONs
horn cells.
During the precocious phases of disease, rabies, having a sporadic progress, is difficult to be
distinguished by other encephalitides: herpetic encephalitis, and it benefits of a specific
treatment.
Warm season encephalitides determined by enteroviruses, arboviruses could determine problems
of differential diagnosis with rabies. The epidemiologic data, the identification of specific
viruses using the PCR technique in LRC, blood make a difference with respect to the diagnosis.
Paralytic rabies may give the impression of the Guillain-Barre syndrome, it must be
distinguished from poliomyelitis, encephalomyelitis anti-rabies tetanus post vaccination
(trismus), botulism (symmetrical paralyses, without sensorial disorders)
The rabies phobia exaggerated fear of rabies may cause similar symptoms to rabies, agitation,
hypersialorrhea. Persons affected by rabies phobia may give the impression of hydrophobia but
they cannot imitate aerophobia.
Treatment
At the present time there is no etiologic specific treatment. Triggered rabies: special measures
are necessary for the maintenance of vital functions, prevention and control of complications.
Recently, there have been a few attempts for antiviral treatment: Amantadin, Ribavirin,
Interferon, which failed.
Post-exposal prophylaxis
The plague with rabies potential:
-
Prolonged abundant wash with water and soap

Rinse with water
Disinfection using 70 alcohol, iodine
There is no scientific, infectious argument for the postponement of the plague
stitch
137
The biting animal should be supervised by a veterinarian for 14 days

In case the aggressor animal dies spontaneously/killed its head should be taken to
a vet laboratory for virology investigations
Post-exposal specific prophylaxis:

-
Anti-rabies serum and anti-rabies vaccine

Anti-rabies immunoglobulins indicated without time limit after the aggression
A part of the immunoglobulins are injected at the level of plague
Anti-tetanus prophylaxis
Antibiotics
Prophylaxis
1. The existence or absence of rabies in the zone where the animal comes from; 2. The
deepness and the extension of lesions (face, neck, extremities, most dangerous mucous
membranes rich in nervous fillets); 3. The known/unknown aggressor animal, signals of
rabies in the aggressor animal. All bat bites or plagues smeared by the saliva of a suspect
animal: immediate anti-rabies treatment.
Post-exposure anti-rabies treatment (World Health Organization WHO)
Category
Type of exposure, state of the Recommended treatment

animal in the moment of the
exposure
Contact with animal saliva on recent NO

excoriations
Domestic animal, healthy, supervised
II
Bites, excoriations, contact with Immediate vaccination

saliva on excoriations, superficial Interruption of vaccination after
bites
10 days of observation (5 days),
healthy animal, suspicion of
rabies, unknown animal, complete
vaccination
III
Bites,
deep vaccination (face, Anti-rabies
serum
neck, genital organs, other parts of (immunoglobulins + vaccine)
body)
Healthy animal interruption of
vaccination after 5/10 days
Wild animals
Serum + complete vaccination
138
Lyme borreliosis
Brndua ilea
Definition
It is defined as a natural focal infectious disease transmitted by ticks from the Ixodes class
produced by bacteria of the Borrelia type, clinically characterized by multisystem manifestations
with evolving stage and polymorphous clinical picture.
Etiology
Lyme borreliosis (LB) has a universal spread with endemic avolution or in small
outbreaks.
It belongs to Borrelia spirochetes, the species Borrelia burgdorferi (Bb). Taxonomically

Borrelia is classified in the Spirochaetaceae family, Spirochaetales order. Spirochete was
identified by Willy Burgdorfer in 1982 from Ixodes dammini tick gut, being isolated
from patients from blood, CSF, skin, liver, spleen, muscle, bone, myocardium.
Based on the diversity of antigen surface protein (Ospa) seven kinds of antigens or
serotypes have been described. Bb sensu lato is classified into eight subspecies and two
genomic groups.
Using genetic and immunological criteria, three human pathogenic subspecies have been
identified as pathogenic for human beings:
Borrelia burgdorferi sensu stricto or OspA1 serotype strain 212 in Europe and B31 in the
U.S.
Borrelia garinii or OspA3-7 serotype, strain 2004 in Europe.
Borrelia afzelii or OspA2 serotype, strain VS 461 in Europe.
Spirochete Borrelia burgdorferi is a Gram-negative germ, with sizes between 4-30 metri
an average of 7 to 11 flagella at each end, mobile, microaerophilic, catalase negative,
which multiplies slowly at 30-37 C. Like all spirochetes it possess a cytoplasmic
membrane surrounded by protoplasmic cylinder, then the flagella and outer membrane.
Borrelia is longer and less coiled than other spirochetes. The external membrane has a
trilaminar structure and it is fluid.
Growth media used for spirochetes culture is liquid, complex, after the BarbourStoenner-Kelly (BSK) formula.
Epidemiology
Borrelia burgdorferi was isolated from 24 different species of mammals or birds.
The potential reservoir of infection are the animals that may be act as hosts for the vector
agent. It is a vast reservoir (for Ixodes persulcatus 240 different species and for Ixodes
ricinus over 300 species of animals: wild mammals, domestic birds, reptiles).
Borrelia burgdorferi transmission between animals and accidentally from these to

humans takes place via ticks at different life stages (larva, nymph and adult form). The
Ixodes tick remains infected throughout her life, without transmitting the causative agent
to the offspring.
139
Various species of tick transmit spirochete Bb: primary (rodent - rodent, rodent domestic animal) and secondary (rodent - domestic animal - human accidental infection).
To transmit Bb infection more bites of infected arthropods are necessary, especially in the
case of the larval stage or the connection by arthropod bite and the host should be
extended at least of 24 hours.
In Romania Ixodine species are found in the following genres: hyalloma Ixodes,
Rhipicephalus, Dermacentor, Haemaphysalis, margaropus.
The most widespread species is the Ixodes ricinus. (Fig. 72)
The main risk factor for Lyme borreliosis is permanent or temporary human presence in
areas with high tick infection with the spirochete Bb.
Given the nature of the reservoir of germs and vectors of Lyme borreliosis, people who
are at risk are forestry workers, staff working in agriculture, forestry, hunters,
veterinarians, hikers, people who visit nature where they meet both the source infection
as well as the specific vectors.
Borrelia burgdorferi antigenic structure
major external surface proteins - OSPA and OspB, specific but only rarely detected and
only in the tardive stage of infection (more than six months of evolution).
other cell-surface proteins identified are represented by a group of proteins of molecular

weight 20-25 kDa. These include protein C (PC), 22 to 25 kDa, identified in Europe and
21 to 25 kDa detected in some strains isolated in North America.
Pathogenesis
Once it goes beyond the skin, Bb penetrates in the blood stream and invades various
tissue compartments, thus generating systemic infection. Spirochete can migrate and at
derm level. The difficulty in isolating blood spirochete suggests that spirochetemia is
transient and low.
Experimental studies have shown that the BB is able to adhere to a variety of human
cells, such as endothelial cells, cells of the central nervous system (microglial cells,
Schwann cells) cardiac cells, synovium.
Spirochete attachment to host tissue cells is the step that initiates infection, this
attachment involves an interaction between glucosamin structures on the surface of host
cells and the three proteins: 67 kDa, 62 kDa and 41 kDa (flagelina).
Spirochetes multiply and disseminate in blood, causing damage to the ECM, representing
the clinical manifestation of early stage I being thus the primary stage of the disease.
Stage II occurs with the hematogenous dissemination of spirochete (spirochetemia). At

this stage, spirochetes can be seen in blood or CSF. The duration of this stage may be
between 1-6-12 months.
Stage III, tardive, or tertiary, covers a period of months or years, if appropriate therapy is
not initiated. A persistent infection occurs which may affect: CNS osteoarticular,
cardiovascular system.
Spirochete adheres to endothelial cells, causing vascular lesions, large areas of localized
cerebral vasculitis and perivasculitis, heart, joints and skin.
140
Bb induces the production of cytokines (IL-1 - TNF-), which potentiates the intensity
of inflammation.
Immune mechanisms are involved as well circulating immune complexes and

cryoglobulins being present.
Impairment occurs only late to persons showing major histocompatibility complex HLA
DR4.
The clinical manifestations are polymorphic, but the most common manifestations are cutaneous,
neurological, cardiac, joint, which fall into three stages illustrated below:
Early infection
Primary Stage
Tardive infection
The secondary
Multiple ECM
Benign
limphocitom
Tertiary stage
Acrodermatitis
atrophicans
cutaneous
chronical
Chronic
Early
neuroborreliosis Tardive neuroborreliosis
erythema
(radiculitis,
meningitis,
(chronic
progressive
migrans (ECM) encephalitis, myelitis)
encephalomyelitis,
delayed
polyneuropathy)
Charditis
Arthritis
Chronic Arthritis
Table I - Lyme borreliosis stages

Chronic erythema migrans
Chronic erythema migrans (erythema migrans cronicum ECM) occurs early, usually at
1-30 days after the bite of the infected tick with spirochete Bb. At skin macula or Papillary
element occurs and then it extends gradually showing a clear zone in the center and the
periphery, clearly defined, is darker, sometimes having a ring-shape hence the name of eryhtema
annulare centrifugum (fig. 1). ECM may have a purplish-red color with thickened vesicular or
necrotic tegument, without producing tenderness. ECM constitutes the typical cutaneous
impairment the clinical diagnosis of Bb can be established by proper identification of this lesion.
The most common locations in adults are the legs (popliteal, groin, thighs) and trunk in 50%
cases, while in children the most common location is the cephalic extremity (25% of cases) and
lower limbs. ECM lesions are usually asymptomatic but they may be pruritic or painful as well.
Cutaneous manifestations of ECM take about 3-4 weeks and then gradually subside.
141
During spirochetemia patients may show: general systemic manifestations (mild fever up to
38C, chills, myalgia, arthralgia, coryza, without local acute inflammatory phenomena) that
occur as a result of acute or subacute damage to vital organs (arthralgia , headache, dysphagia,
fatigue,
stiffness,
transient
meningeal
irritation
syndrome),
lymphadenopathy,
hepatosplenomegaly, cardiac arrhythmias, myositis, hepatitis, transient impairment of CNS
outside any determinations.
Cardiac manifestations
Cardithis due to BL shows conduction abnormalities, various degrees of atrioventricular
block, these being the most common.
AVB I, II, III
Conduction abnormalities
Major branch blocks

Minor branch blocks or
Intraventricular
Ventricular: rare due to myocarditis
Tachyarrhythmias
Fibrillation: due to pericarditis
Miopericarditis
ST-T segment changes
Light myocardial dysfunction

Chronic
Cardiomyopathy
Congestive
Table II - Cardiac Manifestations

Osteoarticular manifestations
Joint damage was in the U.S. at the origin of the description of this disease that was
initially called "Lyme arthritis" (fig. 74). Involvement of the osteoarticular apparatus in the BL
can occur at any age but it is found with higher frequency in children, it can occur both at an
early stage and the late stage of the disease.
Ophthalmic Manifestations
Keratitis is one of the most common ocular manifestations occurring in the months or
years following the onset of the disease.
In addition, several cases have been described of uveitis, chorioretinitis under Bb

infection.
Neurological manifestations - Lyme neuroborreliosis
Infection of the central nervous system (CNS) and the peripheral nervous system (PNS)
caused by spirochete Bb has been defined as Lyme neuroborreliosis - NBL. Spirochete
142
was detected in the central nervous structures both in the acute and sub-acute stage of the
disease as well as in later stage, which is why a distinction between accute subacute
neuroborreliosis occuring in weeks or months (6-12 months) after contact with infected
arthropods and chronic neuroborreliosis affection occurring after a period of over 12
months, even years later after infection is necessary.
The pathogenesis of NBL proves to be complex, involving the following:

-
Bb penetrates directly into the CNS, involving a combination between direct

action of spirochetes and indirect immune reactions.
spirochaete penetrate the blood-brain barrier during infection subsequent to the

interaction with the intraluminal surface and then it is located in areas with
possible vascular lesions via astrocytes, causing a process of focal vasculitic with
mononuclear cell infiltrates (especially T cells - helper) leading to focal
leptomeningeal changes with a release of inflammatory mediators;
a decrease in cerebral blood perfusion has been noted particularly in the white
matter as demonstrated by functional neuroimaging techniques;
research studies in laboratories have shown many times that the spirochetes have a
preference share for oligodendrocytes;
in CNS disease vascular direct modifications, localized mainly at the SAC level
have been identified;
it has been demonstrated in patients with NBL, in both stages of the disease, the
aspect of toxic metabolic encephalopathy induced by lymphokines;
involvement ofother immunological factors such as IL-6, interferon and matrix

metalproteic (MMP) has been noted;
Early Lyme Neuroborreliosis - Acute Stage
Acute lymphocytic meningitis or Lyme is the most common manifestation of NBL. It

occurs most frequently in the secondary stage of the disease being more common in
children and adolescents with less manifest clinical symptoms. The CSF pressure is
usually normal, moderate pleocytosis, from tens to hundreds of items, mononuclear.
Albuminorachia is slightly increased, normal glicorachia.
Meningitis is often associated with cranial neuritis (facial nerve VII) and with
radiculoneuritis, Bannwarth syndrome.
Acute Lyme encephalomyelitis. Cerebral parenchymal abnormalities are found in 2050% of North American patients with Lyme meningitis. The frequency of CNS
manifestations is generally low in Europe and almost always accompanied by pleocytosis
in CSF and peripheral cranial neuritis. Central lesions may occur alone or may be
associated with meningeal peripherals damage, representing clinical picture of acute
meningoencephalitis, meningoencephalomielitis, encephalomielo polyradiculoneuritis.
Cranial nerve lesions. The most common is peripheral nerve VII palsy unilateral or
bilateral. Other nerves may be involved, especially the trigeminal and oculumotor one.
Optic neuritis. It may occur in isolation, requiring differentiation of idiopathic optic

neuritis or that of MS.
Radicular lesions with sensory predominance. Radiculoneuritis occurs in approximately

one third of patients with neurologic impairment, accompanied by pleocytosis in CSF.
The first symptom is the radicular pain, numbness and / or hyperaesthesia starting on
143
average 30 days after the tick bite, the most common locations being the lower limbs,
upper cephalic extremity.
Peripheral motor injuries. Motor impairment is rare, being responsible for asymmetric
paralysis, most commonly proximal, located at the level of certain muscles responsible
for muscular atrophy. Prolonged evolution, sequelae are possible.
Tardive Lyme Neuroborreliosis - chronic

Current research shows that the time of occurrence of delayed neurological manifestations, after
inoculation, varies from 12 months to 17 years with an average of 5 years. The physiopathogeny
of these lesions is not well known, but it is considered as in syphilis that the impairment of
neuraxis is partly due to vascular lesions.
Chronic lymphocytic meningitis. It is discovered incidentally, often being associated to

encephalitis in the tardive stage. CSF: 80-400 cells / mm 3, albumino-cytological
dissociation being noted.
Borrelia encephalomyelitis is the most well-defined progressive tardive neurological

NBL, the clinical evolution can simulate an MS relapse or stroke. Risk of confusion with
MS is higher due to CSF abnormalities CT and / or MRI of the brain being almost
identical. (Fig. 2)
Lyme encephalopathy refers to a cognitive disorder of average or moderate severity

affecting first of all memory and learning. It is accompanied by primary psychiatric
symptoms or mild drowsiness, but unaccompanied by neurological signs or pathological
changes in the MRI exam of the brain. The SPECT (single-photon emission CT and
positron) demonstrated a reduction in cerebral perfusion in the frontal cortical and
subcortical areas.
Polyneuropathy and neuropathic tardive sclerotic lesions. The most common symptoms
are called paresthesia, often intermittent, asymmetric, focal involving the upper and lower
limbs. A quarter of patients had carpal tunnel syndrome.
Psychiatric disorders in Lyme borreliosis. Psychiatric aspects have been described more
frequently in children and adolescents with spectacular remission subsequent to
antibacterial therapy. The most common mental disorder observed (70%) is depression.
Other possible problems: short-term memory loss, anxiety, panic attacks, personality
changes, paranoia, mood swings, psychotic episodes, etc..
Diagnosis
BL accurate diagnosis remains problematic at the moment until a diagnostic test "gold standard"
will be developed. BL and NBL diagnosis is currently based on serological methods, which are
far from being satisfactory, both in terms of sensitivity and specificity. Serological tests need to
be interpreted with caution, taking into account the epidemiological and clinical context. Various
methods currently used in the diagnosis of BL are summarized in the table below:
Direct detection methods
Indirect detection methods
Microscopic examination
Serological methods
Culture
THAI indirect hemagglutination test,

RFC
144
Immunohistology
IFI indirect immunofluorescence

ELISA technique
Methods of capturing antigens

Detection of bacterial DNA by PCR
Western blotting
T lymphocyte
method
proliferation
study
Table III - Methods of diagnosis of Lyme borreliosis

In conclusion, serology for BL has 3 major limitations:
1. low sensitivity in the diagnosis of early infection due to slow antibody response
2. low specificity of available tests because many cross-reactions
3. inability to delineate recent infections and tardive ones due to the persistence of
antibodies both in the treated forms and in the untreated ones.
CSF-based assays in acute NBL demonstrate:

-
lymphocytic pleocytosis;
blood-brain barrier dysfunction;
predominance of intrathecal production of IgM, detection of activated B cells

containing all three classes of immunoglobulin (Ig) with IgM predominance.
The differential diagnosis of ECM considers other erythema, such as cellulite, tinea, candidiasis,
erythema multiforme, urticaria, etc.. Lyme arthritis can be distinguished from other lesions, as
follows: RAA, meningococcal arthritis, gonococcal, LED, psoriatic arthritis, gout, etc..
Neuroborreliosis can be distinguished from other meningitis, aseptic encephalitis with trenant
evolution.
Optic neuritis requires differentiation of idiopathic optic neuritis but also from that of multiple
sclerosis.
Lyme encephalopathy needs to be differentiated from other types of encephalopathy (toxic,
metabolic), tertiary syphilis, HIV encephalopathy, LED.
Treatment
There are different therapeutic strategies based on the staging, as follows:
Antibiotic
Dose / day
Administration Duration (days)
Amoxicillin
3x500 or 2x1000 mg mg
po
10 to 21
Azithromycin
500 mg
po
5-7
Doxycycline
2x100 mg
po
10 to 21
Cefuroxime axetil
2x500 mg
po
10 to 21
145
Penicillin V
3x1000 U
po
10 to 21
Table IV - Treatment ECM

Antibiotic
Dose / day
Ceftriaxone
2g
iv
14 to 21
Cefotaxime
3x2 g
iv
14 to 21
Penicillin G
3x3 MU
iv
14 to 21
Table V - Treatment of carditis

Antibiotic
Dose / day
Amoxicillin
3x500 mg (child) or 3x1000

po
mg (adult)
14 to 30
Doxycycline
2x100 mg
po
14 to 21
Ceftriaxone
2g
iv
14 to 21
Cefotaxime
3x2 g
iv
14 to 21
Table VI - Lyme arthritis treatment

Clinical
form
NBL early
Tardive
NBL
Antibiotic
Dose
Administration
Duration (days)
Ceftriaxone
2g
iv
14 to 21
Cefotaxime
2g
iv
14 to 21
Penicillin G
3x3 MU
iv
14 to 21
Doxycycline
2x200 mg
po
14 to 21
Amoxicillin
/
2g
clavulanic acid
po
14 to 21
Ceftriaxone
2g
iv
30
Cefotaxime
2g
iv
30
Penicillin G
3x3 MU
iv
30
Doxycycline
2x200 mg
po
30
po
30
Amoxicillin
/
2g
clavulanic acid
Table VII - Treatment of Lyme neuroborreliosis
In case of pregnant women treatment of firmly diagnosed cases and suspicions as well, is
recommended. Treatment with Aminopenicillin, macrolides (azithromycin) is recommended in
cases of infection localized to the tegument and in cases with neurological determination
Ceftriaxone is advisable.
146
Duration of therapy in both BL and NBL is variable between 14-30 days, but it can be extended
up to six weeks, even months in trenant or relapsed cases.
Complications and prognosis in Lyme borreliosis
The risk of acute complications in BL and NBL is more reduced if antibacterial therapy is
instituted early to avoid progression from acute stage to the tardive stage of the disease.
In cases of early NBL with severe CNS SNP impairment in about 10% of cases were
notified motor sequelae, residual neurological clinical symptoms such as headache,
dizziness, paresthesia, myalgia, arthralgia, anxiety.
Prophylaxis
Doctors who have to decide on the therapeutic approach in case of patient stung by ticks
have three alternatives:
-
to treat the patient;
to monitor the patient and to establish therapy if signs or symptoms of disease

occur;
to appreciate the dynamics of serology (blood, CSF) immediately and then after 36 weeks, treating only if there are clinical signs of a serological infection.
Prophylactic therapy is recommended for all persons who are stung and from endemic areas of
BL. The most commonly used antibiotics are: Amoxicillin, Amoxicillin / clavulanic acid,
azithromycin both in children and adults.
Cyclins (Doxycycline) is the recommended antibiotic in ECM prophylaxis and impaired adult
with SNP. Prophylactic therapy duration is between 14-21 days.
Nonspecific prophylactic measures
Physical measures
physical measures refer to avoiding areas with high density of ticks, using appropriate
clothing to avoid skin-fixing of the tick, regular monitoring of the presence and removal
of any tick.
Chemical Control
It is made using:
-
acaricides sprayed powder in endemic areas, but they present limitations, namely:
environmental pollution, side effects, duration of action limited in time, high cost,
inability to use them for wildlife;
Vaccination with DNA

-
Recent advances in molecular biology have led to the development of new

techniques for induction of immune response by using plasmids. The vaccine
consisted of plasmids encoding a surface protein Ospa Bb using a eukaryotic
promoter and / or virus or the bacteria itself.
147
The vaccine approved by the ACIP (Advisory Committee on Immunization

Practices) Center for Disease Control (CDC, Atlanta, USA) and currently used in
the U.S., is called Lymerix. It is a recombined vaccine, made using genetic
engineering techniques.
Fig. 1 - Ixodes ricinus, different stages
Fig. 2 - Chronic erythema migrans
(Larva, nymph and adult tick)
Fig. 3 - Lyme Arthritis
Fig. 4 - Lyme Encephalitis (MRI image)
References:
1. Cifecu C, Hristea A. Borrelioza Lyme. Ed. Briliant, Bucureti, 1999; 100-125.
2. Cohen J, Opal SM, Powderly WG. Infectious Diseases, 3rd Edition, vol I, 2010,
464-474
3. Pilly E. Maladies Infectieuses et Tropicales, 19e ed. 2004; 402-417, 422-450.
4. ilea B. Borrelioza Lyme. Ed. University Press, Tg. Mure, 2008; 40-80.
5. ilea B. Patologie Infecioas. Fundamente de licen n medicin. . Ed.
University Press, Tg. Mure, 2009, 111-119
6. Wilske B. Microbiological Diagnosis in Lyme Borreliosis. J Med Int Microbiol,
2002; 33:114-119.
148
ANTHRAX
Iringo Kezdi
The disease anthrax is produced by the sporulating bacterium Bacillus anthracis, found in the soil
in many parts of the world. The spores from the infected animal carcasses can contaminate the
pasture for many decades and lead to sporadic outbreaks.
It is believed that the fifth and sixth plagues of Egypt, described in the Old Testament, were
probably caused by anthrax, and also the description of the black bane, which caused an
estimated 60.000 deaths in cattle in Europe in the 1600s, indicate that this was anthrax.
Two microbiologists, Robert Koch and Louis Pasteur both studied anthrax in the 1870s. Koch
demonstrated that the disease could be produced by the transfer of infected material from one
animal to another. He also demonstrated the ability of the bacillus to produce heat- resistant
spores, which had the ability to germinate and infect animals.
Pasteur, confirmed the germ theory of the disease and he also demonstrated in 1881, in a
famous public experiment, that cows, goats and sheep could be vaccinated by use of a live
attenuated skin. The current vaccine is a live vaccine made from an unencapsulated, avirulent but
toxigenic strain.
The common name is derived from the Greek name anthrakis, or coal, so named from the
black cutaneous lesions produced.
Epidemiology
The disease is naturally one of animals, particularly herbivores, who ingest spores on the grass
and from the environment. Until the advent of an effective vaccine, the disease was common in
cattle, sheep, goats, horses and pigs, but is now far rarer. Infections in humans were most
oftenassociated with the handing of an infected animal carcasses or hides. Wool sorter`s
disease was contracted by those handling infected fleeces or hides, often from inhaling spores
released in the processing of the fleeces or hides. Anthrax is still endemic in some parts of the
world, notably Africa, the Middle East, Asia and some parts of the US and Australia. Inhalation
anthrax is extremely rare under normal conditions.
As has been illustrated so clearly in the US recently, anthrax can be used as a weapon of terror. It
is one of the favored species for germ warfare, or bioterrorism, but in not necessarily an ideal
one. It is not highly pathogenic, requiring a large number of spores to produce infection by any
route. It is not transmitted from person-to-person other than in exceptional circumstances. The
spores need to be transmitted in a very fine aerosol to be highly effective. Resistance can be
developed experimentally to most of the current agents of choice, and it remains to be seen
whether widespread use of ciprofloxacin and doxycicline will create a selective pressure on the
organism.
Etiology
B. anthracis is a large (1-3mm), gram-positive, aerobic, rod-shaped, non-motile, sporulating
bacillus. The spores are thermostable. Like many other members of the genus Bacillus, the
spores are remarkably resistant and long-lived in the environment. The organism grows rapidly
on normal laboratory media (nutrient or blood agars) not needing any special cultural techniques,
but does not grow on Mac-Conkey agar. There are a number of mop=rphological distinguishing
149
characteristics; white-grey, flat or slightly convex, irregular round colonies with a ground-glass
appearance. A Medusa head colony is characteristic for B.anthracis. culture are not or very
slightly haemolytic, but not -haemolytic. In smears from infections, long chains may be formed
and a capsule is present. The capsule can be seen clearly using India Ink. The lack of motility
distinguishes B.anthracis from many other Bacillus species. Modern molecular techniques can be
used to confirm strains of B. anthracis. Multiplex PCR has been used in recent outbreaks and
immunohistochemical staining can be valuable. MIC determination showed recently the
following results: Susceptible strain to: Doxycycline, Ciprofloxacin, Amoxicillin, Penicillin G,
Rifampicin, Clarithromycin, Clindamycin, Vancomycin, Chloramphenicol.
Intermediate to: Erythromycin, Azithromycin, Ceftriaxone
Preliminary studies report the presence of a Class B cephalosporinase( constitutive) and the
possibility of an inducible penicillinase.
Pathogenesis
Naturally acquired anthrax in humans is generally due to contact with infected animals or their
carcasses. Although fatal human disease may occur, B. anthracis is not highly virulent, and in
spite of its previous prevalence in the environment and in animals, human infections were not
common and are now rare. Virulence is associated with encapsulated strains and death is caused
by toxins, that produce massive haemorrhagia and shock. The most common form of the disease
is cutaneous, which is frequently self-limiting. To produce the serious form of inhalation
anthrax, a large number of spores, greater than 2000, and possibly 5-10.000, are necessary to
establish an infection. The organisms do not multiply in the lungs but are carried by alveolar
macrophages to the mediastinal lymph nodes where the spore germinate and multiply. From this
focus they are able to spread rapidly throughout the body. Three toxins are produced by
B.anthracis all thermolabile proteins; a protective antigen (PA), an oedema factor (OF), a lethal
factor (LF). The individual toxins have no adverse effects, they need to combine to produce the
characteristic toxicity seen in the disease. They target the macrophages and have little effect on
other cells. The protective antigen binds to receptors to the macrophage cell-surface protease.
This produces a cell-bound C-terminal 63kDa protein (PA63). This cleaved portion, A63, has
high affinity binding sites for the other two toxins. The bound complex enters the cell by
receptors mediated endocytosis. The OF toxin has calcium and calmodulin-dependent
adenylatecyclase activity. The LF toxin is a protease that interferes with the protein kinase signal
transduction pathway. The assembled toxin has powerful proteolytic activity, which causes the
eventual death of the macrophage. The release of cytokines, including IL-1 and TNF, from the
damaged macrophages is believed to cause the damage to the blood clotting system and to
contribute to the septic shock and oedema. The genome of B.anthracis has been sequenced
recently and considerable advances have also been made in understanding the mode of of action
of toxins. The plasmids coding for toxins (pX01) and the capsule-associated plasmids (pX02)
have also been identified and sequenced.
Cutaneous form is the commonest form of the disease, occurring in up to 95% of cases.
Incubation period is 3-10 days. It is seen most often on the face, hands, forearms and
neck since infection is generally from handling infected material. The organisms, usually
spores, invade from a skin abrasion or cut. After germination of the spores, the vegetative
bacilli multiply locally and a small, visible papule, appears. Several days later a vesicle or
ring of vesicles develops (4-6 cm). This discharges clear with surrounding oedema. In
most cases cutaneous anthrax is self-limited, the lesion resolving within 10 days. In some
150
cases systemic anthrax may develop (malignant edema), but unless therapy is initiated
very late, by which time extensive toxin production has occurred, the disease responds
very well to chemotherapy. Painful, regional adenopathy may persist even after
successful therapy. In untreated cases the death rate can reach 20%, but is less than 1%
when treated.
Inhalation anthrax is rarer, compromising only approximately 5% of all cases. Once
established, this is a far more serious disease with a high death rate. Incubation period is
3-5 days. Initial symptoms are insidious and flu-like, generally mild and non-specific. In
the second phase there is acute respiratory distress, sepsis and an acute
haemorrhagicmediastinal widening. X-ray symptoms can be confused with those of
tuberculosis. Blood culture may be positive at this stage, and if the disease has progressed
to this stage, it is frequently fatal as toxin production has already advanced and therapy
can thus be ineffective.
Gastro-intestinal anthrax is even rarer and is contracted by consuming large number of
spores, which infect the intestinal tract or the oesophagus. The illness may present as an
acute abdomen, bloody diarrhea or cholera-like syndrome.
Meningitis is a rare complication of any form of anthrax, and is generally fatal since, by
the time it is diagnosed, toxin production is well advanced. It evolves with hemorrhagic
CSF.
-
Gram stain examination of vesicle fluid, CSF, blood;

Culture of vesicle fluid, CSF, blood;
Immunofluorescence;
In those with negative blood cultures, PCR, immunohistochemical staining or a four0fold
rise in IgG can confirm anthrax;
Electrophoretic immune-transblot test;
Termoprecipitating reaction (Ascoli-Cornelson-Toma) (formation of an opalescent ring at
the interface between the mixture containing crust and anti-anthrax serum);
Abnormal radiographs/mediastinal widening in inhalation anthrax;
Total WBC normal or only slightly elevated;
Increases % of neutrophils or band forms;
-
Cutaneous anthrax: staphylococcal lesions, cutaneous leishmaniasis, herpes zoster, herpes

simplex lesion, erysipelas, inflammatory edema of the face
Gastrointestinal anthrax: food poisoning, acute abdomen, shigellosis, yersiniosis
Inhalation anthrax: other pneumopathies
Anthrax meningitis: Listeria meningitis, tuberculous meningitis meningeal hemorrhage
Treatment
Most strains of B.anthracis are susceptible to a wide range of antibacterial agents. The organism
was traditionally highly susceptible to penicillin and, until recently, this was the drug of choice.
Wild-type strains often produce a constitutive cephalosporinase. Penicillin-resistance has been
noted, albeit rarely, in wild-type strains and, in addition, strains with resistance to penicillin are
believed to have been engineered durong the cold war era. For these reasons, the first choice is
now generally a fluoroquinolone, (ciprofloxacin), although other FQ are probably also effective.
Most authorities still recommend that therapy be switched to a penicillin (penicillin G, penicillin
151
V, ampicillin, amoxicillin) if antibacterial susceptibility is confirmed. Alternative drugs include

doxyxycline, minocycline, erythromycin, clindamycine, vancomycin and chloramphenicol.
Cotrimoxazol is not active and 3rd generation cephalosporins are not recommended. Therapy of
current inhalation cases: combination intravenous treatment with Ciprofloxacin and Rifampicin
plus Clindamycin/Vancomycin/Penicillin.
Current dosages recommended:
Penicillin G (procaine)- 600.000 U im. Every 6 or 8 hours
Penicillin V- 500 mg orally 3 times a day
Doxycycline- 100 mg orally 3 times a day
Ciprofloxacin- 500 mg twice a day
For localized or uncomplicated cutaneous anthrax these doses are normally given for 7 days.
The therapy is recommended to continue for 60 days suspected or known inhalation anthrax to
protect against the possibility of delayed germination of spores.
Systemic anthrax: high intravenous doses are recommended. Penicillin + Streptomycin is often
suggested. FQ and tetracyclines are not normally recommended therapy for children and should
thus be used with caution. Therapy should be switched to penicillin or alternatives as soon as
possible.
Patients need to be hospitalized and isolated until clinical recovery and the elimination of the
crust.
Prevention
An adsorbed culture filtrate vaccine became available for humans some four decades ago and is
generally used for those at high risk of exposure including veterinarians, and military personnel.
Repeat vaccination is advised. A live, toxigenic unencapsulatedavirulent vaccine is available for
animals, but this is not regarded as sufficiently safe to give to humans, although a live vaccine is
apparently in use in Russia. Those known to have been exposed can be protected by immediate
chemoprophylaxis. Vaccination is not viable option currently for large numbers of people and
supplies are not plentiful. In addition, the strain employed in the bioterrorist attacks is the US is
thought to be the Ames strain, used originally in the US and the UK for their germ warfare
programmes. Vaccination is not though to give full protection against the strain. Better methods
of protection from the lethal effects of the toxins are required and various recent approaches may
hold out some promise. A DNA-based vaccine has proved itself to be of value in experimental
work in mice. Plasmids coding for the PA and LF toxins were used by Galloway et al. to
immunize mice who were able to survive over five times the usual lethal dose of anthax.
152
Tetanus
Iringo Kezdi
Tetanus is a disease of the nervous system characterized by persistent tonic spasm, with violent
brief exacerbations. The onset is acute and the spasm almost always commences in the muscles
of the neck and jaw, causing trismus, and involves the muscles of the trunk more than those of
the limbs.
Etiology
Clostridium tetani is an obligate anaerobic rod that in young culture stains is gram positive, but
after 24 hours of incubation Grams stain is negative. The organism is found commonly in soil
samples around the world, especially in warmer climates. It is isolated from the intestinal tract of
animals and from human excrement. The mature C.tetani organism develops a terminal round
spore creating a tennis racket appearance and producing tolerance to extremes of
environmental conditions. Two exotoxins, tetanospasmin and tetanolysin, are released by some
strains of the organism while it is actively dividing. The role of tetanolysin is unknown ( it is
presumed that can disrupt cell membranes). Tetanospasmin disseminates from the infected site of
entry, to neuromuscular junctions, by intraaxonal transport, in the central nervous system. The
organism remains localized in the anaerobic tissue environment.
Pathophysiology
Tetanospasmin act at three levels: central motor control, autonomic function and neuromuscular
junction.
The 150 kD peptide tetanospasmin inhibits release of inhibitory neurotransmitters gaminobutyric acid (GABA) and glycine. The resulting imbalance in the central nervous system
predisposes the patient to reflex spasms. The process involves three steps:
-binding to the presynaptic membrane
-translation of the toxin to the active site
-induction of paralysis
Tetanospasmin disinhibits sympathetic reflexes at the spinal level, so the hyperadrenergic
findings do not depend on hypothalamic or brain stem dysfunction. The clinical effects of
tetanospasmin may persist for 4-6 weeks.
Tetanus can occur in patients with gangrene, burns, decubitus ulcers, septic abortions,
intramuscular injections, dental infections, penetrating eye injuries, and umbilical stump
infections.
The incubation period range from 3 to 30 days (11 days). The disease has four forms:
1. Generalized tetanus is the most frequent form of the disease.
a. The most commonly presenting sign is trismus (inability to open the mouth) caused
by the rigidity of the masseter muscles. Among the first symptoms are also the
stiffness in the neck, or jaw, difficulties in swallowing and back or shoulder stiffness.
153
The initial symptoms of generalized tetanus tend to descend from the head to the
skeletal muscles of the trunk and extremities.
b. Risussardonicus is another characteristic sign
c. The typical generalized spasm resembles decorticate posturing, consisting of: sudden
tonic contraction of muscles causing opisthotonus, flexion and adduction of the arms
and extension of the lower extremities. Other positions are orthotonus and
pleurosthotonus
d. Generalized spasms can involve abdominal, diaphragmatic, and laryngeal muscles,
causing apnea and necessitating endotracheal intubation. During these spasms
patients do not lose consciousness, and sustained skeletal muscle contractions are
extremely painful. Tetanic contractions are powerful enough to cause fractures of the
spine and long bones.
e. Autonomic dysfunction is the leading cause of death in tetanus patients. This
syndrome includes: labile hypertension, tachycardia, irregularities of cardiac rhythm,
peripheral vascular constriction, profuse sweating, pyrexia, and sometimes
development of hypotension (signs which are present toward the end of the first
week, or during the second). The disease may continue to increase in intensity for 1014 days, recovery requiring about 4 weeks.
2. Localized tetanus may develop in persons who are partially immunized to tetanospasmin.
Muscle rigidity depends on the location of injury, which could involve agonists,
antagonists and fixators. The muscles are painful, and deep tendon reflexes are enhanced.
3. Cephalic tetanus: -facial paresis is usually present
-ophtalmoplegic tetanus when there is a paresis of the IIIrd, IVth, and VIth
cranial nerves
4. Neonatal tetanus occurs when the mother lacks immunity; usually follows an infection of
the umbilical stump. Infant is unable tu suck, typical opisthotonic posture occurring later.
Rating scales for tetanus severity
Table 1.Veronesi scale
Veronesi scale
Incubation period < 7 days
Period of onset* < 48 hours
High-risk portal of entry (surgical, abortion, etc)
Generalized tetanus
Core temperature above 40C
Tachycardia (heart rate>120 in adults, >150 in neonates
Score one point for each
*period from the first symptom to the first reflex spasm
Table 2. Severity and prognosis
Score*
Severity
Mortality
154
0-1
Mild
< 10%
2-3
Moderate
10-20%
Severe
20-40%
5-6
Very severe
>50%
*cephalic tetanus is always scored as severe or very severe

Neonatal tetanus is always scored as very severe
Table 3. Modified Ablett scale of severity
Group
Symptoms
Mild
Mild rigidity and spasms
Moderate
More intense spasms and rigidity, accompanied by disphagia
Severe
Marked rigidity,
compromise/apnea
frequent
generalized
spasms,
disphagia,
respiratory
Diagnosis
The average annual incidence of tetanus in the world is about 1 million cases. Due to its rarity,
the initial clinical symptoms may be missed and the diagnosis may not be made until a
generalized tetanic spasm occurs. Diagnosis is established in the presence of a portal of entry,
trismus, tonic contraction, sudden spasms and a descending manner of contraction progression.
Wounds are classified as clean or tetanus prone. The latter are more than 6 hours old;
contaminated with dirt, feces, soil or saliva; or involve tissue with poor vasculature. Diabetic
foot infections are commonly polymicrobial and contain necrotic tissue classifying them as
tetanus prone. The diagnosis of tetanus cannot depend on wound cultures because cultures are
positive for c.tetani in only 32-50% of cases. In addition, isolation of C. tetani is inconsequential
in immune patients. The lack of a defined wound does not exclude the diagnosis of tetnus. A
protective titer antitetanus antibodies may help to exclude diagnosis, but only in retrospect.
Trismus in tetanus must be distinguished by: alveolar ridge abscess, temporomandibular
joint arthritis, tonsillitis;
Spasms and rigidity must be distinguished by: generalized convulsive status epilepticus,
strychnine intoxication, tetany precipitated by hipocalcemia, meningitis, encephalitis,
brain hemorrhage;
Local tetanus- with transverse myelitis
Complications
1. Respiratory dysfunction: atelectasias, apnea (phrenic and laryngeal neuropathy),
pneumonia
2. Cardiovascular complications: cardiomiopathy
155
3. Urinary tract infections and acute renal failure caused by rhabdomyolysis

4. Vertebral compression, fractures, hyperostosis
5. CNS and systemic consequences of hypoxia
Management
Management of tetanus involves:
A.
B.
C.
D.
E.
Neutralizing wound and circulating toxin

Eradicating the source of toxin
Standard supportive care
Treating related complications
Treatment of the portal entry
A. Neutralizing Clostridium toxins may require administration of tetanus toxoid (active

immunization) and HTIG (human tetanus immune globulin).
Concomitant administration of HTIG and tetanus diphtheria toxoids (Td) is
recommended in the care of some wounds because tetanus toxoid alone does not provoke
a sufficient, prompt immune response to remove the toxins. Tetanus immune globulin,
used for passive tetanus immunization in patients with tetanus toxoid hypersensitivity,
contains antibodies specific to tetanus toxin, expediting toxin removal. Both HTIG and
Td should be administered at separate sites due to the possibility of interference with
active immunization. Of importance HTIG is limited by the lack of penetration into the
central nervous system and the need for intramuscular injection. The minimum effective
dose of TIG has not been established; however, 500 IU appears to be as effective as
3000-5000 IU. Injection of TIG around the site of Clostridium infection does not have
significant benefit. With immunization histories being frequently unreliable or
unavailable in emergency departments, liberal use of tetanus toxoid and tetanus
immune globulin was recommended for patients with an incomplete or unknown
immunization history. Booster injections beyond treatment guidelines are potentially
harmful. Patients with tetanus antitoxin titers greater than 5U/ml are likely to have an
adverse reaction to tetanus toxoid.
B. Eradicating the source of toxin
Despite the resistant nature of C.tetani spores, in vitro activity occurs with penicillins,
cephalosporins, macrolides, tetracyclines, imipenem, and metronuidazole. A study
comparing oral metronidazole with intramuscular penicillin reported a lower mortality
rate, shorter hospitalization, and less progression of disease in patients receiving
metronidazole. Poor results with penicillin corresponded to its known GABA
antagonistic effects as well as adverse effects caused by intramuscular injections.
Effective eradication of the bacterium is not correlated with immediate improvement in
symptoms because antibiotics do not affect preexisting tetanospasmin. Antibiotic
regimens should contain metronidazole.
C. Standard supportive care of generalized tetanus in the past required:
- Neuromuscular blockade: diazepam dose of 20 mg/hour, vecuronium/pancuronium
- Mechanical ventilation
- GABA agonists: labetalol, morphine 5 mg
D. Treating related complications
Because of extended hospital stay, long-term mechanical ventilation, and several
intravenous access sites, these patients are prone to nosocomial infections. Routine care
such as intramuscular injections and patient stimulation trigger spasms. Extra measures
should be taken to avoid patient stimulation caused by the intensive care unit
environment.
156
E. Therapy of the portal of entry

Debridement should be performed after administration of benzodiazepines
Mortality
Even with todays advanced level of care, during 1995-1997 the case fatality ratio of tetanus was
11%.
157
CHAPTER 5
ENTEROVIRUS INFECTIONS
Nina incu
Etiologic agents
Enteroviruses = single-stranded RNA viruses, which belong to the Enterovirus genus in the
Picornaviridae family. Their denomination came from their ability to replicate inside the human
digestive tract, but they are responsible for a wide variety of diseases apart from infectious
gastroenteritis: herpangina, hand-foot-and-mouth disease, exanthem, acute hemorrhagic
conjunctivitis, pneumonia, pleurodinia, central nervous system infections (meningitis /
encephalitis, paralysis), myocarditis / pericarditis.
65 human serotypes have been identified so far:
-
Poliovirus 3 serotypes
Coxsackievirus - group A 23 serotypes induce flaccid paralysis in suckling

mice
- group B 6 serotypes induce spastic paralysis in suckling mice
Echovirus (enteric cytopatic human orphan = ECHO) 29 serotypes (1-34).
Their name was given by their cytopathic effect in primate cell cultures, usually
without any pathogenic effects in suckling mice
Enterovirus 68-71 4 serotypes. Enterovirus 70 was associated with outbreaks
of acute hemorrhagic conjunctivitis, enterovirus 71 with paralysis.
Enteroviruses lack a lipidic envelope - structural feature which confers them stability in acidic
environment, including human stomach, and facilitates replication within the digestive tract.
Epidemiology
Distribution: worldwide. Enterovirus infections evolve in endemic or epidemic patterns.
Seasonality: summer - early autumn in temperate climate regions, all year round in tropical
areas. cases appear in children, but adults can be subject of enteroviral infection as well.
Overcrowding, poor hygiene favour the transmission of enterovirus infections, especially in
groups of children. Nosocomial transmission of enterovirus has been documented.
Infection reservoir: human, patients with clinically manifest infections, as well as those with
subclinical forms (50% all enterovirus infections, 90% poliovirus infections asymptomatic).
Contagiousness: several days before and after the onset of the disease, patients shed the virus
through their faeces as well as in the pharyngeal secretions.
Transmission route: direct route: faecal-oral (contaminated hands), or airborne, via respiratory
droplets, as enterovirus can be found in the patients stool and pharynx. Indirect route via
contaminated objects or water (swimming pools) has also been incriminated. Enterovirus can
also be detected in the vesicular fluid from hand-foot-and-mouth disease skin lesions. Mother-tochild transmission during pregnancy has been reported, as enteroviruses cross the placenta.
Direct inoculation of conjunctival mucosa with enterovirus via contaminated hands or fomites
has been reported in cases of acute hemorrhagic conjunctivitis.
158
Susceptibility: general
Immunity: serotype-specific humoral immunity IgM antibodies appear 1-3 days after contact
with the virus and last for 2-3 months, IgG antibodies initially appear about 10 days after contact
with the virus and persist for life, but are targeted against the specific serotype which caused the
infection. Infection with other viral serotypes is possible.
Pathogenesis
Enteroviruses penetrate into the human body via the digestive or upper respiratory tract
(pharynx). Following replication at the entrance gate, in submucosal lymphatic tissues,
enteroviruses penetrate into the bloodstream and cause minor viremia, which results in the
infection of the reticulo-endotelial system, where the virus continues to replicate (liver, spleen,
bone marrow). From these sites, virions are again discharged into the bloodstream, causing a
second, clinically manifest, major viremia. In most cases, immune mechanisms are able to
contain the infection before the second phase of major viremia, which leads to subclinical
forms of infection.
Clinical entities
Enterovirus infections may cause a wide range of clinical manifestations. Disregarding
poliovirus, for which a distinct chapter is reserved, Coxsackievirus and Echovirus infections may
involve the gastro-intestinal and respiratory tracts, the central nervous system, eyes, kidney,
myocardium and pericardium. Clinical entities characterised by fever and exanthema may also
be the result of enterovirus infections.
The incubation period for most cases of enterovirus infections range between 2-14 days, with an
average duration of incubation beneath 7 days.
Herpangina. It is usually caused by group A coxsackievirus, particularly serotypes 1-10, 16, 22.
Rare etiologic agents could be group B coxsackievirus serotypes 1-5 and echoviruses and
enterovirus 71. Clinical manifestations include acute onset, fever, sore throat, odynophagia,
possibly associated with vomiting, myalgia, headache. The characteristic enanthem consists of 24 mm vesicles on erythematous base, distributed on the soft palate, uvula, tonsilary pillars,
sometimes on the posterior pharyngeal wall, with subsequent ulcerations. Acute lymphonodular
pharyngitis, caused by group A coxsackievirus serotype 10, is regarded as a clinical variant of
herpangina, with small yellowish nodules (formed by lymphocytes) situated on the soft palate
and uvula, without consecutive ulceration.
Pleurodinia (Bornholm disease). It is actually o myositis usually caused by group B
coxsackievirus, serotypes 1-6, less often by group A coxsackivirus or echoviruses. Clinical
manifestations consist of acute, knifelike spasmodic pain in the chest (adults) or upper abdomen
(children), with 15-30 minutes duration, accompanied by fever peaks, which resolve along with
the pain. Physical examination reveals pleural rub and local tenderness to palpation of the
involved muscles, but chest X-ray is negative.
Pneumonia more frequent in children, it can be caused by echovirus serotypes 6, 7, 9, 11, 12,
19, enterovirus 71, but also group A or B coxsackievirus. Respiratory symptoms concur to
interstitial or patchy bronchopneumonia features on chest X-ray.
Other respiratory diseases caused by enteroviruses are: choryza, laringo-tracheo-bronchitis,
croup and bronchiolitis.
159
Nonspecific febrile illness (summer grippe) the most frequent enterovirus-associated clinical
entity, with flu-like symptoms fever, coryza, sore throat, cough; it occurs during the summer
early autumn warm season. It resolves spontaneously, within 3-7 days.
Exanthems. Enteroviruses produce a broad range of exanthems, accompanied by fever,
resembling those encountered in rubella, measles, scarlet fever, roseola infantum, herpetic or
allergic rash and even petechial exanthema.
Hand-foot-and-mouth disease is most often caused by coxsackievirus A16, although other
serotypes of coxsackievirus group A 4-7, 9-10, group B 2-5, echovirus 18 and enterovirus 71 are
also known to produce the disease. Clinical manifestations include fever, vesicles and ulcerations
in the oral cavity and skin lesions, consisting of erythematous papules and clear vesicles
surrounded by erythema distributed characteristically on the hand, feet and sometimes gluteal
regions. The etiologic agent can be isolated from the vesicular fluid.
Aseptic meningitis most frequently caused by group B coxsackievirus serotypes 1-5 and
echovirus serotypes 4, 6, 7, 9, 11, 13, 16, 18, 19, 30, 33, less often by group A coxsackievirus
type 2, 4, 7, 9 and 10. Enteroviruses are reported as the most frequent cause of aseptic meningitis
in children and young adults, evolving especially during the warm season. Clinical
manifestations include fever, chills, headache, vomiting, photophobia, neck stiffness and other
meningeal sings, sometimes accompanied by other clinical symptoms that indicate an
enterovirus infection: herpangina, diarrhea, rash, myocaditis. CSF analysis reveals pleocytosis:
initially polymorphonuclears prevale (differential diagnosis with bacterial meningitis), but
lymphocytes become dominant usually after 24 hours. Total CSF cell count is usually below
1000 cells/L, glucose CSF levels are normal, protein CSF levels are slightly elevated. Prognosis
is usually good, with clinical recovery after one week.
Encephalitis enteroviral infection account for about 10-20% cases of viral encephalitis. Most
cases appear in children and young adults, during the warm season. Coxsackievirus B2, B5, A9,
echovirus serotypes 6, 9 and enterovirus 71 have been incriminated more frequently. Mental
status impairment, ranging from disorientation to coma, seizures, cerebellar ataxia and
sometimes paresis are present. A severe form brainstem encephalitis, caused more frequently
by enterovirus 71 implies cardio-respiratory malfunction of central origin. CSF alterations
resemble those from enteroviral aseptic meningitis. Imaging and electroencephalogram may
reveal various generalized or localized abnormalities. Prognosis is good in most cases, although
fatal outcome and lifelong sequelae have been reported as well.
Other central nervous system infections. Paralysis (poliomyelitis-like flaccid motor paralysis)
may be the result of enterovirus 71 or coxsackievirus A7. Less frequent etiologic agents could be
coxsackievirus A4, A9, B1-B5, echovirus serotypes 6, 9. The course of the disease is less severe
than in poliomyelitis. Guillain-Barre syndrome has also been depicted associated to
coxsackievirus A2, A5, A9 and echovirus 6, 22. Chronic meningitis or encephalitis has been
reported in patients with hypo- or agammaglobulinemia infected with enterovirus.
Acute hemorrhagic conjunctivitis. It is usually caused by enterovirus 70, which evolves in
epidemic outbreaks, but coxsackievirus A24 has also been reported as etiologic agent. The most
common route of transmission is direct inoculation of mucosa via contaminated hands or fomites
(towels, handkerchiefs). Clinical manifestations include pain, foreign body sensation in the eye,
eyelid oedema, serous or seromucoid discharge, subconjunctival haemorrhages, with 7-10 days
duration. Upon physical examination, small follicles are found on the tarsal conjunctiva. Corneal
erosions and punctuate keratitis may sometimes be seen. Signs initially manifest unilaterally, but
they rapidly involve the contralateral eye. Fever and malaise appear in about 20% cases.
Myocarditis and pericarditis most commonly encountered as a unitary entity
myopericarditis. Enteroviruses are responsible for > 50% cases of viral myopericarditis.
Coxsackievirus A4, A9 and A16, B1-B5 and echovirus serotypes 6, 9, 11, 22 are most frequently
160
involved. The virus reaches the myocardium via bloodstream and induces an inflammatory local
immune response, which may persist for months. Myocyte destruction is a consequence of both
the virus and the inflammation. Myopericarditis is more frequent among adolescents and young
adults. Clinical signs and symptoms imply fever, malaise, chest pain, cardiac arrhythmias
(tachyarrhytmias, various degrees of cardiac block), dyspnea and, in case of pericardial
involvement sharp pain in the precordial area, exacerbated by recumbent position, pericardial
friction rub on cardiac auscultation. Cardiomegaly and congestive heart failure may appear.
Serum myocardial enzymes are increased. Electrocardiogram reveals ST-segment and T-wave
abnormalities, while echocardiography may depict dilation of cardiac cavities or reduction of
ejection fraction. Recovery implies interstitial fibrosis and myocyte loss. Long-term sequelae are
present in 1/3 adult patients, including cardiomegaly, chronic congestive heart failure and
persistent echocardiographic changes. Dilated cardiomyopathy and chronic constrictive
pericarditis may occur.
Gastro-enteritis. Both coxsackie and echovirus, especially echovirus serotypes 11, 14, 18 have
been incriminated in cases of non-bacterial gastro-enteritis, characterised by fever, vomiting and
diarrheic stools.
Generalized neonatal disease. It may be the result of vertical transmission of enterovirus in the
perinatal period (maternal infection during the last week of pregnancy) or infection acquired
during the first month of life (either from an infected mother or during nosocomial outbreaks in
nurseries). Although many enterovirus serotypes produce the same clinical manifestations in
newborns as in older patients, some serotypes cause a severe, generalized disease of the
newborn, particularly coxsackievirus group B serotypes 1-5, echovirus saerotype 11. Group A
coxsackievirus serotypes 3, 9, 16 and echovirus serotypes 4-6, 7, 9, 12, 14, 16, 18, 19-21, 31 are
less frequently encountered. Generalized disease of the newborn includes myocarditis, hepatitis,
encephalitis and respiratory distress syndrome, sometimes with fatal outcome.
Other clinical entities have also been depicted in association with enterovirus infections: acute
nephritis, acute arthritis, parotitis, orchitis, polymyositis. Group B Coxsackievirus has been
isolated from the pancreas of several children diagnosed with type 1 diabetes mellitus, but, so
far, there is no confirmed correlation between enteroviruses and this metabolic condition.
However, acute pancreatitis has been depicted in association with group B coxsackievirus type
1-5 and echovirus serotypes 6, 11, 22 and 30.
Positive diagnosis
Epidemiologic and clinical data are rarely suggestive for enterovirus infections. Clinically
distrinct entities, such as hand-foot-and-mouth disease or herpangina are exceptions. Enterovirus
infections may be suspected in case of epidemic outbreaks, by contact with other confirmed
cases.
Laboratory findings
Serologic tests detect the presence of anti-enterovirus IgM antibodies after 1-3 days from contact
with enterovirus, which last for 1-3 months, and of IgG antibodies, which appear > 10 days from
the infective contact with lifelong duration. Anti-enterovirus antibodies are serotype-specific.
Neutralizing and complement-fixating titers of antibodies can be determined. Dynamic
serological tests should be performed, detecting antibody titers at 4 weeks-distance.
Enteroviruses can be isolated in cell cultures (monkey kidney cell lines, human embryonic
fibroblasts, human rhabdomyosarcoma cell lines), by characteristic cytopathic effect, or into
suckling mice. Thus, enteroviruses can be isolated from the throat, faeces, CSF or blood.
PCR (polymerase chain reaction) detects the presence of enteroviral RNA genome in blood,
CSF, stool, naso-pharyngeal samples or from tissues.
161
Treatment
So far, no antiviral medication has been licensed for enterovirus infections. Iv administration of
immunoglobulin containing high anti-enterovirus antibodies titers can be used in
agammaglobulinemic patients, newborns with severe generalized neonatal disease or in other
patients with severe forms of illness, including central nervous system infections.
Treatment is supportive: symptomatic, anti-inflammatory medication, bed rest. Meningitis
encephalitis requires corticosteroids, depletion, neuronal trophic medication, group B vitamins.
Patient isolation can be performed either at home in mild cases or by hospitalization in severe
forms of illness.
Prophylaxis
Apart from poliovirus, there is no vaccination against other enterovirus infections. Good
hygiene, hand washing, use of gloves and masks help prevent enterovirus transmission
(especially nosocomially). Enteric precautions should be maintained for about 1 week after the
onset of the disease. Overcrowding should be avoided.
162
POLIOMYELITIS
Nina incu
Definition
Acute infectious and contagious systemic disease caused by poliovirus (an enterovirus), with
diverse clinical manifestations, ranging from asymptomatic infection to paralyitic poliomyelitis
and even death.
polios = gray, myelos = marrow (Greek): involves gray matter neurons (especially the
anterior horns of the spinal cord).
Etiology
Poliovirus genus Enterovirus, family Picornaviridae. It has single stranded RNA structure,
proteic capside and no lipidic envelope, which makes it resistant in acidic environments, such as
the human stomach. It may resist for several days at room temperature, several weeks at 4C and
is not destroyed by alcohol, ether, chloroform and usual detergents. It is inactivated by
formaldehyde, ionizing radiations and phenol.
Poliovirus can be cultivated in HeLa cell lines or monkey kidney cell cultures.
Poliovirus has 3 known serotypes:
- Type 1 (Brunhilde) most frequently involved in severe, paralytic forms of
disease
- Type 2 (Lansing) usually causing asymptomatic infections
- Type 3 (Leon) rarely encountered
Epidemiology
In 1988, World Health Organisation (WHO) set poliomyelitis eradication until the year 2000 as
major goal. The introduction of anti-poliovirus vaccination significantly decreased the number of
cases of poliomyelitis. However, in spite of general availability of anti-poliovirus vaccination,
the disease is not yet eradicated worldwide, as cases are still reported, especially in the subSaharan region and south-east Asia. In Romania, poliomyelitis is considered eradicated illness,
although the possibility of import cases in travellers returning from endemic areas cannot be
excluded.
Reservoir: human. It consists of patients infected with poliovirus, either developing a clinical
manifest disease or apparently healthy carriers of virus. Persons recently vaccinated with oral
live-attenuated vaccine (OPV) shed the virus through their faeces and may be source of infection
for unimmunized contacts.
Contagiousness: high. The period of contagiousness begins from the last ( 5) days of
incubation and last for about 8 weeks after the clinical onset of the disease. Poliovirus can be
isolated from the oropharynx for about 3 weeks and from the faeces for about 8-12 weeks after
the onset of the disease.
Transmission route: both airborne, through naso-pharyngeal droplets, and via faecal-oral route,
by contact with faeces, contaminated hands, food and / or water. About 1 million infective doses
are eliminated within 1 gram of faeces.
163
Susceptibility: general, among unimmunized contacts. However, only a minority develop the
paralytic form of disease, asymptomatic infection and minor illness are more frequent.
Immunity: Infection with one poliovirus serotype confers type-specific lifelong immunity, but
does not protect against infections with different serotypes. Immunity following vaccination with
trivalent vaccine lasts for about 5 years. Secretory IgA antibodies appear in the oropharynx and
intestinal tract after 1-3 weeks from OPV. IgG serum antibodies develop after OPV or IPV.
Breastfed infants born to immune mothers benefit of protection against poliovirus infection due
to the passage of mothers antibodies during their first 3-4 months of life.
Pathogenesis
Poliovirus penetrates into the organism via the oropharynx or digestive tract. After infecting the
epithelial cells of the digestive mucosa, it replicates inside local lymphoid structures: tonsils and
Peyers patches (the intestinal stage of infection). It subsequently disseminates to the
reticuloendothelial system via minor viremia and, in most patients, infection is limited at this
stage by antibody formation (asymptomatic disease). Bloodstream dissemination follows
replication inside the reticuloendothelial system (major viremia), corresponding to clinical
phenomena characterising the minor illness. If infection is contained at this stage, without
involving the central nervous system (CNS), the patient develops a form of abortive
poliomyelitis (4-8% cases of infection).
CNS impairment (CNS invasion stage), resulting in paralytic poliomyelitis, may be the result of
dissemination via neuronal pathways or from bloodstream; occurs in 1-2% cases. The poliovirus
receptor is found at the site of neuromuscular junctions, which suggested that poliovirus reaching
the junction during viremia may travel from muscles to the anterior horns of the spinal cord via
long axons composing the peripheral nerve fibres.
Poliovirus affects the motor and autonomic neurons from the gray matter of the spinal cord
(especially the anterior horns), but also from cranial nerves nuclei from the brainstem,
(especially medulla oblongata and pons). Apart from neuronal destruction, inflammatory lesions
were depicted, consisting of leukocyte infiltrates, oedema and vasculitis, that persist for months.
Muscle denervation and atrophy are the result of neuronal degeneration, with the formation of
glial scars in the place of destroyed neurons.
Several factors may influence the development of paralytic poliomyelitis, apart from strain
virulence: age, immune status, pregnancy, trauma. Tonsillectomy predisposes to bulbar paralytic
poliomyelitis and reduces the duration of the incubation period. Intramuscular injections are
prohibited as they favour the onset of muscle paralysis.
About 95% cases of infection are asymptomatic. 4-8% cases are abortive forms of poliomyelitis.
1-2% cases involve CNS.
The classic evolution of poliomyelitis is biphasic and includes several stages:
Incubation: average: 9-12 days (ranging from 5 to 35 days). Incubation period is shortened in
case of tonsillectomy (< 1 week).
Minor illness: duration: 2-3 days. The patient complains of fever, headache, vomiting,
abdominal pain, sore throat, respiratory symptoms, without any neurological signs. It resembles
flu and may be misdiagnosed. In abortive poliomyelitis, the course of infection ends at this
stage.
Latency period: a 3-5 day symptom-free period.
164
Major illness: temperature raise, followed by a pre-paralytic phase, which lasts for 1-2 days,
resembling aseptic meningitis: headache, vomiting, neck stiffness, pleocytosis of the CSF, with
minimum elevation of CSF protein levels (cyto-albuminologic dissociation). Pronounced
myalgias, hyperesthesia, paresthesia, muscle spasms and fasciculations precede the onset of the
paralytic stage by 1-2 days. Signs and symptoms are characteristic for the peripheral motor
neuron syndrome. Flaccid paralysis occurs, with asymmetrical distribution. Lower limb muscles
are more frequently interested than upper limb muscles and proximal muscles of the limbs are
more frequently affected that distal muscle groups. Deep tendon reflexes are hyperactive at the
beginning, than become absent. Abdominal and thoracic muscle paralysis may occur as well.
Paralysis of the respiratory muscles intercostals and diaphragm may cause respiratory arrest..
Paralysis progression extends during hours or days and stops after fever remission.
Lesions of autonomic neurons translate into circulatory troubles, cold extremities, perspiration,
urinary retention due to urinary bladder paralysis.
In bulbar forms, the involvement of neurons belonging to cranial nerves (especially IX and X)
leads to dysphonia, dysphagia, sometimes dyspnea. Facial palsy is possible. Alteration of the
cardio-circulatory brainstem centres may be fatal.
Consciousness troubles are uncommon, except for polioencephalitis. Sensory deficits are not
characteristic for poliomyelitis; they impose differential diagnosis with Guillain-Barre syndrome.
Recovery stage: begins 10-14 days after the onset of the disease and lasts for months or years,
though most reversible lesions disappear in one month. Partial recovery of the motor functions
may take place in various amounts. About two thirds of patients remain with lifelong sequelae.
Stage of sequelae: lifelong; it is characterised by definitive limb paralysis and muscle atrophies
due to denervation. Deformations of the limbs, pelvis or spine are common, especially since
paralysis is asymmetrical and involves either only the extensors or only the flexors of one limb.
Since the opposite muscle group maintains its tone, various vicious positions may be acquired.
Equinovarus foot, valgus deformity, scoliosis may occur. Failure to grow of one limb, while the
controlateral limb develops normally leads to the apparent shortening of one limb.
Postpoliomyelitis syndrome: appears 20-40 years after the initial episode of poliomyelitis. It s
characterised by newly established weakness, muscle atrophy, fatigue, pain, usually in the same
muscle groups involved in the initial episode of disease, rarely extending to previously healthy
muscle groups. The cause is considered to be the progressive loss of motor units innerving
muscle groups already impaired during the initial course of the disease (motor units that had
taken over the function of previously destroyed neurons) and not an infection reactivation. It
affects 20-30% patients. Disease severity and rate of progression is not comparable to those from
the initial episode of poliomyelitis.
Clinical forms
Non-paralytic forms:
- Asymptomatic forms 90-95% cases
- Abortive poliomyelitis includes only minor disease 4-8% cases
- Polio meningitis aseptic meningitis (initial cyto-albuminological dissociation in
the CSF, followed by albumin-cytological dissociation)
Paralytic forms:
- Spinal paralytic poliomyelitis the most frequent paralytic form paralysis of the
limb muscles (monoplegia, hemiplegia, paraplegia, quadriplegia), of the abdominal
or thoracic muscles, including respiratory muscles, paralysis of neck muscles
165
- Bulbar paralytic poliomyelitis paralysis of muscle groups inervated by cranial

nerves, especially IX and X: dysphonia, dysphagia, accumulation of secretions in
the airways, dyspnea. It may involve the cardio-respiratory centres from the
brainstem, with usually fatal outcome.
- Polioencephalitis alteration of consciousness, confusion, sometimes seizures. It
resembles viral encephalitis of different etiologies. Unlike other forms of
poliomyelitis, spastic paralysis occur, as in central motor neuron syndrome. It is
more frequent in infants.
- Mixed forms: spino-bulbar,
intertwined symptoms
spino-encephalitic,
bulbo-encephalitic,
with
According to the age of patients: infants may develop polioencephalitis or severe forms more
often than adults.
Vaccine-associated poliomyelitis follows OPV
Positive diagnosis
-
Epidemiologic data:
vaccination history.
Clinical data: infectious syndrome, neurological suggestive signs and symptoms
Laboratory findings: Poliovirus can be isolated from the oropharynx, faeces and
CSF by PCR technique or cultivated on HeLa / monkey kidney cell cultures. For
epidemiologic purpose, it is important to identify the viral strain as wild-type, OPV
or vaccine-derived poliovirus. Serological tests, performed 4 weeks apart, detect an
increase in neutralizing or complement-fixation titres of IgM antibodies. CSF is
clear, characteristic for aseptic meningitis, with lymphocytic pleocytosis, but
slightly elevated or normal protein levels (cyto-albuminological dissociation), with
normal glucose levels. Poliovirus can be identified from the CSF by PCR or
cultivation on cell lines. However, lumbar puncture should be avoided, as it may
exacerbate the course of illness.
infective contact, poliomyelitis epidemics outbreaks,
Differential diagnosis (DDx)

-
Minor disease: DDx with flu and other respiratory virus infections
Major disease pre-paralytic stage: DDx with aseptic meningitis
Major disease paralytic stage: DDx with other enterovirus infections (enterovirus
71), West-Nile infection, vaccine-associated myelitis, brain haemorrhage, botulism,
post-dyphteric paralysis, spinal cord compression, Guillain-Barre syndrome
(symmetrical, bilateral, ascending paralysis, sensation impairment, albumincytological dissociation in the CSF: elevated CSF albumin level without significant
pleocytosis)
Complications
-
Pulmonary complications: pulmonary oedema, respiratory failure (paralysis of

respiratory muscles, airways obstruction with secretions in bulbar forms,
impairment of respiratory neurological centres), bacterial pneumonia (due to
superinfection)
166
Cardiac complications: myocarditis, elevated blood pressure
Gastro-intestinal complications: paralytic ileus, digestive tract bleeding, gastric

dilation.
Urinary complications: urinary tract infections (in-dwelling catheters required by

urinary retention)
Treatment
No etiologic antiviral treatment has been discovered so far. Case management implies supportive
methods. Hospitalization and careful monitoring is required during the acute phase of paralytic
poliomyelitis. Severe forms of disease require hospitalisation in an intensive care unit. Bed rest
is compulsory during this stage, with no exercise. Intramuscular injections are prohibited, as they
may exacerbate neurological symptoms. Hot moist packs are applied to involved muscle groups.
Pain relievers, sedatives, group B vitamins may be of help.
Mechanical ventilation is necessary in case of paralysis of respiratory muscles: tracheal
intubation and positive pressure ventilation. Postural drainage and secretion aspiration is useful
in patients with bulbar forms of poliomyelitis, with accumulation of secretions in their airways.
Physical therapy begins in the recovery phase and may last for years. Sometimes surgery is
necessary to correct vicious positions or limb abnormalities.
Prognosis
Mortality in paralytic forms of poliomyelitis was reported to be of 5-10% during polio epidemics
and even more increased in bulbar forms of disease. Lifelong sequelae are frequent in paralytic
forms, characterised by limb paralysis and muscle atrophy, usually accompanied by vicious
positions of the limbs due to asymmetric muscle involvement.
Prophylaxis
Two types of anti-polio vaccine have been available.
Live-attenuated oral poliovirus vaccine (Sabin) OPV contains strains of poliovirus attenuated
by multiple successive passages in monkey kidney cell cultures and selection of mutant strains
with low virulence. It is administered orally and induces local, gastro-intestinal immunity,
reflected by local appearance of IgA anti-poliovirus antibodies after 1-3 weeks from vaccination.
IgG antibodies appear as well. Trivalent vaccine is used (effective against all 3 serotypes of
poliovirus). However, as it contains a live-attenuated viral strain, one must bear in mind the risk
of developing vaccine-associated poliomyelitis following administration of oral (live-attenuated)
vaccine. It is about 1 case/2.5 million doses among immunocompetent subjects and 2000 times
higher among immunosuppressed individuals, disease occurring both in vaccinated persons and
their contacts, as vaccinated persons shed poliovirus through their faeces (up to 6 weeks) and
naso-pharingeal secretions (up to 3 weeks). The replication of the live-attenuated viral strain
inside the digestive tract may lead to mutations and transformation into a virulent strain that may
cause disease. Intramuscular injections are prohibited during the first months following OPV
vaccination as these manoeuvres increase the risk of vaccine-associated poliomyelitis.
Intercurrent diarrheal diseases reduce the efficacy of OPV. Like other live-attenuated vaccines,
OPV is prohibited in immunocompromised hosts.
Inactivated poliovirus vaccine (Salk) IPV is obtained by formalin-inactivation of viral strains.
It does not cause vaccine-associated poliomyelitis. It induces IgG antibody formation.
167
While industrialized countries mostly use IPV, OPV is administered at large scale in less
developed regions. Nowadays, IPV is used in Romania. Four doses are recommended in children
at the age of 2 months, 4 months, 6-18 months and 4-6 years.
168
ACUTE INFECTIOUS DIARRHEAL DISEASES

Andrea Incze
Introduction
Acute infectious diarrheal diseases are the second worldwide regarding their frequency,
following the acute respiratory illnesses. In children under 5 years diarrhea appears 2-3 times per
year in developed countries, whereas in developing countries in can have a frequency of 10-18
episodes per year. In Asia, Africa, and Latin America diarrhea is a leading cause of morbidity
and mortality in children.
Definition
Diarrhea is defined as passing 3 or more watery stools, or one or more bloody stools per day.
The average stool weight is 100 g per day, whereas diarrhea is defined as at least 200 g of stool
output per day.
Severe diarrhea is characterized by one or more of the following: volume depletion, fever, 6 or
more stools per day, the illness lasting above 48 hours, and immunosuppression.
Classification
Classification regarding the duration of diarrhea
Regarding its duration diarrhea can be classified as:
-
acute (lasts up to 14 days)
persistent (lasts 14-30 days)
chronic (lasts above 30 days)
Classification based on the etiologic agent of diarrhea

Infectious diarrhea is caused by:
-
viruses
bacteria
parasites
fungi
Classification regarding the pathogenic mechanism of diarrhea

-
noninflammatory diarrhea (enterotoxigenic):

o the proximal small bowel is affected
o the stools are watery
o stool findings: no fecal leukocytes, mild or no increase in fecal lactoferrin
o examples: Vibrio cholerae, enterotoxigenic and enteroaggregative Escherichia
coli, Clostridium perfringens, Bacillus cereus, Staphylococcus aureus,
169
Aeromonas hydrophyla, Plesiomonas shigelloides, rotavirus, norovirus,

adenovirus, Giardia lamblia, Cryptosporidium spp., Cyclospora spp.,
microsporidia
-
inflammatory (invasive or cytotoxic) mechanism:

o distal small bowel or the colon is affected
o diarrhea is dysenteric (bloody mucopurulent) or inflammatory
o stool findings: fecal polymorphonuclear leukocytes, important increase in
fecal lactoferrin
o examples: Shigella spp., Salmonella spp., Campylobacter jejuni,
enterohemorrhagic and enteroinvasive Escherichia coli, Yersinia
enterocolitica, Vibrio parahaemolyticus, Aeromonas hydrophyla, Plesiomonas
shigelloides, Clostridium difficile, Entamoeba histolytica
penetrating mechanism:
o distal small bowel is affected
o the microorganisms penetrate the epithelial layer via the phagocytes, and
disseminate throughout the body, causing enteric fever
o
stool findings: fecal mononuclear leukocytes
o examples: Salmonella typhi, Yersinia enterocolitica, Campylobacter fetus

Epidemiology
The source of infection is human (ill persons or healthy carriers), or animal (in some cases, for
example Salmonella).
The infection is either transmitted through direct contact with the source of infection, or through
contaminated objects (food, personal articles, water). Dirty hands play an important role in the
transmission of diarrhea. Vectors such as flies or rodents can transmit the enteric pathogens.
Toxins that are preformed in the food might cause diarrhea this is the case of food poisoning.
Receptivity is general, although children under 5 are more exposed.
There is no immunity following the infection in most of the cases, a new infection is possible.
Most cases of diarrhea are sporadic, but it can occur in epidemics, pandemics (for example
cholera) also, or it can be endemic.
Diarrhea can be related to travel to undeveloped areas, and produced through the ingestion of
contaminated water or food. The most frequent etiologic agent of the travelers diarrhea is E. coli
(enterotoxigenic and enteroaggregative).
There are certain sites where cases of diarrhea can accumulate: day care centers (rotavirus),
hospitals (rotavirus in pediatric wards, Clostridium difficile among adults), nurseries for
newborns (enteropathogenic E. coli) and chronic care institutions for elderly (Clostridium
difficile).
Pathogenesis
Host factors
170
A great number of microorganisms are ingested with every meal, neutralized by the defense
mechanisms of the normal host. The elements of the host defense are:
Gastric acid
The acidic pH (<4) of the stomach destroys the majority of enteric pathogens. Neutralization of
this barrier by antiacid medication might conduct to enteric bacterial and parasitic infections.
In order to pass this barrier a great inoculum of pathogens is needed (for example: 108 organisms
of Vibrio cholerae).
Some microorganisms can survive gastric acidity such as rotavirus, which is stable in acid
environment, and some parasites, their process of excystation is facilitated by the low pH.
Personal hygiene
The acquisition of an enteric infection depends on the number of pathogens ingested. The
exception is Shigella, which can be transmitted with only 10-100 organisms, and cysts of certain
parasites.
The route of transmission of enteric pathogens is oral in most of the cases. Therefore the supply
of uncontaminated water and appropriate sanitary facilities play an important role in the
prevention of diarrhea.
Normal flora
The intestine is inhabited by a large number of bacteria, 99% of which is anaerobic (1011
organisms per gram of normal feces Bacteroides, Clostridium, peptostreptococci, peptococci
and others). These bacteria produce volatile fatty acids and provide acidic pH, which prevents
colonization of the bowels by enteric pathogens.
Infants who have not developed yet their normal flora, or persons receiving antibiotics that cause
a loss of normal flora, are more likely to have infections with enteric pathogens. A single dose of
antibiotic can eradicate the protective effect of normal flora.
Intestinal motility
Gut motility and diarrhea helps the host to get rid of the intestinal pathogens. Antimotility drugs
administered in bacterial diarrhea might worsen the outcome, and conduct to bacteremia in some
cases.
Immunity
Cellular and humoral immunity play an important role in protection from enteric infections.
Humoral immunity consists of systemic IgM and IgG, and local secretory IgA.
The first line defense is the mucosal immune system. Bacterial antigens are bound to the luminal
surface of the M cells in the distal small bowel and they are presented to the subepithelial
lymphoid cells. As a result sensitized lymphocytes (plasma cells) are produced, these spread
throughout the mucosa, and produce secretory IgA.
Breast-feeding has a protective role through the antibody, lactoferrin, lysozyme, phagocyte,
lactose, low pH, low protein, low phosphate and oligosaccharide-fraction content of the human
milk.
Host genotype and age
Host genotype and age influence the susceptibility to colonization with enteric pathogens. For
example persons with blood group O are more susceptible to cholera, shigellosis, and norovirus
infection, whereas those with blood group A to giardiasis. Infections with enteroaggregative E.
coli are associated with a polymorphism in the interleukin 8 gene.
171
Rotavirus and enteropathogenic E. coli infections affect young children especially. This is
related to age-specific changes of intestinal mucosa, cell surface factors, microbial flora,
environmental exposure, and specific immune factors.
Microbial factors
Inoculum size
There is a certain number of microorganisms that has to be ingested in order to cause disease.
This number can be low (10-1000 bacteria or cysts) for Shigella, enterohemorrhagic E. coli,
Giardia lamblia and Entamoeba, or high (105-108) in the case of Vibrio cholerae.
Adherence
By adhering to the intestinal walls microorganisms can avoid the effect of peristaltism, they can
colonize the mucosa.
Microorganisms adhere to the specific receptors of the intestinal cells through specific surface
structures, such as pili, fimbiriae, or other adherence factors (adhesins). Examples of
microorganisms using adherence factors: Vibrio cholerae, enterotoxigenic and enteropathogenic
and enterohemorrhagic E. coli.
Enterotoxin production
The enterotoxins act on the secretory mechanisms of the mucosa. They activate the adenilate or
guanilate-cyclase enzymes of the eneterocytes, which results in cyclic AMP or GMP formation.
These cyclic nucleotides activate the water and electrolyte secretion, which conducts to watery
diarrhea. Examples of enterotoxin-producing microorganisms: Vibrio cholerae, enterotoxigenic
E. coli.
Cytotoxin production
Cytotoxins inhibit the protein synthesis of intestinal epithelial cells, which conducts to cell
destruction. As a result of this disentery syndrome appears, characterized by bloody stools with
inflammatory cells (frequent low quantities of mucous-purulent-bloody stools associated with
abdominal cramps and tenesmus). Examples of cytotoxin-producing microorganisms:
Clostridium difficile, Vibrio parahaemolyticus, Enteropathogenic E. coli, some types of
Salmonella, Shigella dysenteriae type 1, and Shiga-toxin producing E. coli. The last two produce
a verotoxin, which conducts to hemolytic-uremic syndrome and hemorrhagic colitis.
Neurotoxins are produced by microorganisms outside the host, which are ingested. This is the
case of food poisoning. For example the staphylococcal and Bacillus cereus toxins act on the
central nervous system, and produce vomiting.
Invasion
Many microorganisms can adhere to and invade the intestinal epithelial cells. This conducts to
the destruction of the epithelial cells and dysentery syndrome. The bacteria multiply in the cells,
destroy the cells and spread to adjacent cells. An important local inflammatory reaction appears.
The subsequent systemic invasion is rare however it might appear in the immunocompromised
patients. Examples of invasive microorganisms: Shigella, enteroinvasive E. coli, Salmonella.
172
Penetration
Some microorganisms can penetrate the intact intestinal mucosa, without local destruction. They
multiply in the phagocytes found in Peyers patches or intestinal lymph nodes. Afterwards they
produce systemic invasion, manifested as enteric fever syndrome, characterized by fever,
headache, relative bradycardia, abdominal pain, splenomegaly, and leukopenia. Examples of
penetrating microorganisms: Salmonella typhi and paratyphi, Salmonella cholerae suis, Yersinia
enterocolitica.
Mature epithelial cell destruction
Mature epithelial cells are infected and destroyed in viral intestinal infections. However
destruction does not affect the cells of the intestinal cryptae. As a result the structure of intestinal
vili is destroyed, and the absorption of the fluids altered. Water and electrolyte loss occurs
therefore the stools are watery, although rarely they might be also bloody.
Diarrhea can be easily recognized based on the presence of frequent soft stools associated or not
with abdominal cramps, tenesmus. However, it is not easy to establish the etiology of diarrhea.
Complications
Dehydration and electrolyte loss are frequent acute complications of diarrhea.
Chronic complications can follow an acute episode of diarrhea. Chronic diarrhea can be caused
by: lactase deficiency, small bowel bacterial overgrowth, malabsorbtion syndromes.
Inflammatory bowel disease can be exacerbated by an acute infectious diarrhea.
Reactive arthritis (Reiters syindrome) can appear following infection with invasive
microorganisms (Salmonella, Shigella, Campylobacter).
Hemolytic-uremic syndrome, manifested with hemolytic anemia, thrombocytopenia and renal
failure can appear in case of verotoxin producing microorganisms (Shigella dysenteriae type 1,
enterohemorrhagic E. coli).
Diagnosis
History
Historical data has to be obtained about:
-
the duration of diarrhea
the presence / absence of fever (fever means either invasive disease, or it can result
from an infection outside the intestinal tract)
the appearance of stool:

o bloody mucous stools: ulceration of the large bowel
o bloody stool without leukocytes: shiga-toxin producing enterohemorrhagic E.
coli
o white stools: small intestinal process, malabsorption
o profuse rice-water stools: cholera, or other toxigenic process
173
frequency of stools and vomiting: can appoint towards dehydration
abdominal pain:
o severe in inflammatory processes (Shigella, Campylobacter)
o painful cramps caused by electrolyte loss: in cholera
o bloating: lambliasis
o appendicitis-like syndrome: Yersinis enterocolitica
tenesmus (painful rectal spasms with the sensation of defecation, but little passage of
stool): proctitis (shigellosis, amebiasis)
vomiting:
o toxin-mediated illness
o food poisoning
o systemic illness
o bowel obstruction
contacts presenting the same symptoms: food poisoning, the food can be examined
previously consumed food
current or recent antibiotic therapy: Clostridium difficile diarrhea (antibiotic should

be stopped, tests for Clostridium difficile should be performed)
travel: travelers diarrhea
Physical examination
Severe disease has to be identified: high fever, toxic syndrome, dehydration.
Dehydration can be mild, moderate or severe:
-
mild dehydration: thirst, dry mouth, decreased urine output, decreased axillary sweat,
slight weight loss (5%)
moderate dehydration: orthostatic fall of blood presure, decreased skin turgor, sunken
eyes, sunken fontanelle (in infants), moderate weight loss (5-10 %)
severe dehydration: hypotension, tachycardia, confusion, shock, severe weight loss

(10%)
Laboratory evaluation
Test for fecal leukocytes
A thin smear of stool is prepared on a glass slide, a drop of methylene blue is added, and it is
examined. Fecal lactoferrin is a marker of the fecal leukocytes. Its evaluation is more sensitive,
and avalilable in latex agglutination and ELISA formats.
The presence of neutrophils suggests an invasive or cytotoxic mechanism, although it can be
present in ulcerative colitis and Crohns disease, also.
The absence of leukocytes suggests noninflammatory diarrhea, which can be either infectious
(enterotoxin-produced, viral, parasitic) or noninfectious (tumors, immunosuppression).
Gram stained smear from stool
It is useful in case of staphylococcal diarrhea and cholera. It cannot be used to distinguish the
Gram negative microorganisms.
174
Cultures
Stool culture: The stool sample has to be obtained before the initiation of antibiotic therapy.
Negative stool culture does not exclude the bacterial etiology of an acute diarrhea. Indications to
perform stool cultures are: dysenteric syndrome, feverish diarrhea lasting > 3 days, diarrhea
outbreaks, travelers diarrhea, diarrhea following antibiotic therapy, immunosuppressed patients.
In case of food poisoning cultures have to be made from vomiting and the food also.
Blood cultures are useful in the case of typhoid fever, and invasive diarrhea (Salmonella,
Yersinia enterocolitica, Campylobacter spp.)
Detection of specific pathogens
The useful tests to detect viruses as the cause of diarrhea are: latex agglutination (rotavirus),
ELISA tests and PCR (norovirus).
Parasites can be detected by performing native and coloured smears, either from stool or from
the duodenal fluid, or from intestinal biopsy. At least three specimens should be examined.
If there is a suspicion of cholera, stool should be cultured on TCBS (thiosulfate-citrate-bile saltssucrose) agar.
In case of Clostridium difficile: the toxins A and B have to be detected in stool, by latex
agglutination, or ELISA tests.
Acute infectious diarrhea has to be differentiated from:
-
toxic diarrhea (intoxication with mushrooms, ciguatoxin and scombrotoxin from fish
or seafood, heavy metals such as lead, mercury)
diarrhea caused by drugs (purgatives, immunosuppressive agents)
food allergy
diarrhea caused by endocrine diseases
psychogenic diarrhea
chronic inflammatory diseases (Crohns disease, ulcerative colitis)
neoplasms
acute abdominal diseases (intestinal occlusion, mesenteric infarction, appendicitis,

diverticulitis)
disaccharidase deficiency (lactose intolerance)
Treatment
In most cases of infectious diarrhea an etiologic diagnosis is not necessary or available, due to
the time consuming diagnostic approaches, therefore the therapy is empirical. It is focused on
adequate rehydration, diet, symptomatic therapy. Most of acute infectious diarrheas are self
limited and do not require antimicrobial therapy.
Most of the patients with diarrhea are treated at home. Hospital admission is necessary in cases
of severe dehydration and certain diseases with epidemiologic risk (dysentery, cholera, typhoid
fever).
175
The diet is rich in liquids (tea, rice soup, vegetable soup with salt and glucose, plain water).
Boiled rice, boiled pasta, followed by boiled meat and vegetables, toast, non fermented cheese
can be consumed, in small, frequently administered quantities. It is advisable to avoid milk,
juices, alcohol, coffee, vegetables with high cellulose content (beans, peas), potatoes, fruits,
sweets, other foods that are not easily digested.
Breast-feeding should be maintained in infants, however in case of formula fed infants lactosefree formulas have to be used.
Rehydration is the most important therapeutic action. Oral rehydration solutions are effective in
mild and moderate dehydration. The World Health Organization recommends oral rehydration
solutions that contain 3.5 g sodium chloride, 2.5 g sodium bicarbonate, 1.5 g potassium chloride
and 20 g glucose per liter of water.
In case of vomiting or in severe dehydration intravenous rehydration is necessary. Physiological
saline, 5% glucose, Ringers lactate solutions can be used.
Antidiarrheic therapy such as loperamide is recommended only in watery diarrhea. It is
contraindicated in invasive diarrhea, dysentery syndrome, due to its lowering effect on the bowel
movements. This facilitates the invasion of microorganisms, and their entrance into the systemic
circulation.
Intestinal adsorbents such as Bismuth subsalicylate, Pectin, Kaolin and Diosmectite can be
used.
Probiotics facilitate the recolonization of intestines with lactobacilli, which modify the local pH,
and create unfavorable conditions for pathogenic microorganisms.
Antimicrobial therapy is recommended in enteric fever, dysentery, diarrhea caused by
Clostridium difficile, cholera. The recommendation is debated in case of diarrhea produced by
Campylobacter, Yersinia, Aeromonas, and E. coli.
Antimicrobial therapy can be either empirical or specific. Many antibiotics can be used:
fluoroquinolones (ciprofloxacin, levofloxacin), 2nd and 3rd generation cephalosporins,
azithromycin, erythromycin, trimethoprim-sulfamethoxazole, rifaximin (not recommended in
dysentery), furazolidone, doxycycline. The duration of antimicrobial therapy is 3-5 days.
Examples of antimicrobial therapy according to specific agents:
-
Campylobacter spp.: erythromycin
Clostridium difficile: vancomycin, metronidazole
E. coli: trimethoprim-sulfamethoxazole, 2nd and 3rd generation cephalosporins
Salmonella spp.: trimethoprim-sulfamethoxazole, 3rd generation cephalosporins (in

case of non-typhi salmonella antibiotics are recommended only at the extreme ages
and in immunosuppressed)
Shigella spp.: trimethoprim-sulfamethoxazole, 3rd generation cephalosporins, new

quinolones
V. cholerae: doxycycline, macrolide
Yersinia spp.: trimethoprim-sulfamethoxazole, 3rd generation cephalosporins
Prophylaxis
Individual and comunitary hygiene has to be improved in order to reduce the fecal-oral
transmission of enteric microorganisms.
176
Travelers should eat only cooked food, avoid raw vegetables, salads and unpeeled fruit, drink
only boiled or treated water, and avoid ice. Prophylactic antimicrobial therapy is recommended
for travelers only if they are immunosuppressed (rifaximine, trimethoprim-sulfamethoxazole,
quinolones).
Rotaviral infections can be prevented by vaccination. A live attenuated oral vaccine is available,
that has to be administered in 2 doses to infants aged between 6-24 months.
References
4. Gantz NM, Brown RB, Berk SL, Myers JW Manual of clinical problems in infectious
disease, 5th Edition, 2006, Lippincott, Williams & Wilkins
5. Szalka A, Timr L, Ludwig E, Mszner Zs Infektolgia, 2005, Medicina Knyvkiad,
Budapest
6. Chiotan M Boli infecioase, 2002, editura Medical Naional, Bucureti
7. http://www.fda.gov/downloads/biologicsbloodvaccines/vaccines/approvedproducts/ucm13353
9.pdf
177
SALMONELLOSIS AND TYPHOID FEVER

Andrea Incze
Bacteria of the genus Salmonella are divided in many species and subspecies. They can infect
humans and animals also. The typhoid Salmonellae (typhi and paratyphi) infect humans only,
causing enteric fever. The non-typhoidal Salmonellae have a wide range of animal hosts. More
than 200 serotypes are pathogenic to humans, causing gastroenteritis bacteremia.
Etiologic agent
Salmonellae are gram-negative, facultatively anaerobic, non sporulated bacilli, which are part of
the Enterobacteriaceae family. Salmonella genus has 2 species: Salmonella bongori and
Salmonella enterica. The latter was divided to 6 subspecies.
Salmonella subspecies are classified based on the somatic O antigen (lipopolysaccharide, cell
wall component), surface Vi antigen (restricted to Salmonella typhi and paratyphi C) and
flagellar H antigen in > 2400 serotypes, according to the Kauffmann-White scheme. O-antigen
serogroups are designated A, B, C1, C2, D and E. These can be detected through agglutination
reaction. Strains of these 6 serogroups cause 99% of salmonella infections in humans. This
classification is useful in epidemiologic studies.
Epidemiology
In case of non-typhoidal Salmonallae the sources of infection are ill persons, chronic carriers,
and animals, whereas the only source of Salmonella typhi is human.
The route of transmission is fecal-oral, and through contaminated food.
Non-typhoidal Salmonella infections can be sporadic, or appear in outbreaks. These are linked to
certain food consumption, such as milk, eggs, poultry, or inadequately washed raw vegetables,
undercooked ground meat, dairy products, the lack of hygiene, inadequate food preparation.
Contact with animals, especially reptiles might conduct to sporadic cases of salmonellosis.
Rates of morbidity and mortality are higher in the immunosuppressed patients and at extreme
ages.
Antibiotic resistance has increased in non-typhoidal Salmonellae, due to the widespread use of
antibiotics in food animals, and in animal feed.
Pathogenesis
The inoculum producing infection in case of Salmonellae is 103-106 bacteria. This number
lowers in case of hypoclorhidria or antacid therapy. Intestinal surgery, inflammatory bowel
disease, and alteration of the normal intestinal flora through antibiotic therapy are facilitating
Salmonella infections.
At the level of small intestine Salmonallae traverse the intestinal layer through the M cells
(phagocytes found in Peyers patches). As a result of non-typhoidal Salmonella colonization
interleukin 8 is secreted, that is a strong neutrophil chemotactic factor. This conducts to massive
polymorphonuclear infiltration in the mucosa of small bowel and colon. Neutrophils degranulate
and release toxic substances, which damage the intestinal mucosa, and cause inflammatory
diarrhea.
178
In some cases there is no sign of disease, only a transient carrier state. If the process is not
limited to the intestines, bacteria can pass into the lymphatic and systemic circulation. Metastatic
foci can appear in case of bacteremia.
Gastroenteritis is characterized by nausea, vomiting, diarrhea, with an incubation of 6-48 hours.
Abdominal cramps, fever can also occur. The stools are of moderate volume, loose, nonbloody,
but they might be bloody, dysenteric or watery. Symptoms mimicking appendicitis might appear.
Diarrhea is self limited, antimicrobial treatment is recommended only in the immunosuppressed
patients and extreme ages. The carriage state lasts 4-5 weeks, or > 1 year in case of chronic
carriage.
Bacteremia appears in 5% of diarrheal diseases, and 5% of these develop septic metastases.
These are more common in S. choleraesuis and S. Dublin infection, and at extreme ages or
immunosuppression. Endocarditis, arteritis can occur as a result of bacteremia.
Non-typhoidal Salmonellae can cause intraabdominal infections, such as hepatic, splenic
abscesses, cholecystitis. These are facilitated by gallstones, hepatobiliary tract abnormalities,
abdominal neoplasms, and sickle cell anemia.
Other infections:
-
CNS infections: meningitis (in infants below 4 months), ventriculitis, subdural

empyema, brain abscess
pulmonary infections: lobar pneumonia, lung abscess, empyema, bronchopleural

fistula (facilitated by lung cancer, sickle cell disease, glucocorticoid use)
urogenital infections: cystitis, pyelonephritis, ovarian and testicular abscesses,

prostatitis, epididymitis (facilitated by malignancies, urolithiasis, structural
abnormalities, HIV infection, renal transplantation)
bone, joint and soft tissue infections: osteomyelitis, septic arthritis (facilitated by
sickle cell disease, hemoglobinopathies, preexisting bone disease)
Reactive arthritis (Reiters syndrome) can follow non-typhoidal Salmonella gastroenteritis.

Diagnosis
Non-typhoidal Salmonellae can be isolated from stool, blood, or another body fluid (joint fluid,
abscess drainage, CSF).
In case of localized infection echocardiography, computed tomography are used.
Treatment
Antibiotics should not be used to treat non-typhoidal Salmonella gastroenteritis in
immunocompetent patients. In case of dehydration fluid replacement is necessary.
Certain categories have to receive antibiotics: neonates up to 3 months, persons older than 50
years, immunosuppressed patients, patients with cardiac valvular or endovascular abnormalities,
vascular grafts, prosthetic joints, hemoglobinopathy, bacteremic, or hospitalized with severe
diarrhea and fever.
179
Antimicrobial agents used in therapy are: ciprofloxacin (2x500 mg/day), levofloxacin (500
mg/day once daily), azithromycin (500 mg/day once daily), trimethoprim-sulfamethoxazole,
amoxicillin, ceftriaxone, ampicillin.
There are resistant strains to trimethoprim-sulfamethoxazole, chloramphenicol, ceftriaxone,
fluoroquinolones.
The duration of antimicrobial therapy of gastroenteritis is 48-72 hours-7-10 days, or in case of
immunosuppression 7-14 days. In AIDS patients with Salmonella bacteremia the duration of
therapy is longer, 1-2 weeks iv therapy followed by 4 weeks of oral fluoroquinolones. Those
who relapse should receive long term suppressive therapy. In case of endocarditis or arteritis the
duration of therapy is 6 weeks. In case of extraintestinal nonvascular infections the duration of
therapy is 2-4 weeks. Surgical treatment is required in some cases.
Chronic carriers should receive a prolonged antibiotic course.
Prophylaxis
Every step of food production should be monitored. Contaminated food has to be pasteurized,
irradiated or cooked properly.
The infections have to be reported to the Public Health Authority to prevent larger outbreaks.
Limited usage of antibiotics in humans and animals might prevent the emergence of multidrogresistant Salmonella.
180
TYPHOID (ENTERIC) FEVER
Typhoid fever is a human systemic disease caused by Salmonella typhi or paratyphi serotypes A,
B, or C, characterized by fever, splenomegaly, typhoid state, and rose spots, with severe,
potentially fatal evolution.
Etiologic agent
Salmonella typhi has a somatic antigen (O), flagellar antigen (H induces specific antibodies,
which are determined by the Widal reation), virulence (Vi) antigen, with antiphagocytic
characteristics.
The microorganism is resistant in the environment, can survive at low temperatures for long
periods of time. Salmonella typhi is destroyed by common disinfectants.
Epidemiology
The hosts of Salmonella typhi and paratyphi A, B, and C are exclusively human. The source of
infection is the ill person or healthy carrier.
The disease is transmitted through fecal-oral route, directly, or indirectly, through contaminated
food, water or objects. Sexual transmission is possible between homosexuals. The infection of
health care workers is possible through contact with ill persons or processing clinical specimens
or cultures.
Receptivity is general, the immunity is relative, does not provide protection in case of massive
reinfection.
Outbreaks of enteric fever are related to poor sanitation and lack of clean drinking water.
Sporadic cases may appear in travelers.
Multidrug-resistant strains of Salmonella typhi have emerged, which are resistant to
chloramphenicol, ampicillin, trimethoprim, ciprofloxacin.
Pathogenesis
Salmonella typhi and paratyphi passes the intestinal epithelium through the M cells within
Peyers patches at ileocecal level. Subsequently they are phagocytosed by macrophages,
however they survive within macrophages. Then they disseminate throughout the body in
macrophages via the lymphatics. This is the first, transient bacteremia. They colonize the
reticuloendothelial tissues such as liver, spleen, lymph nodes, bone marrow. The patient has no
fever and few symptoms in this phase (incubation).
Salmonellae are taken up by the tissular macrophages, multiply within them, and in 1-3 weeks a
secondary bacteremia occurs, with the spread of infection to another organs, such as the
gallbladder, biliary tract, and reinfect the Peyers patches of the ileon. The secondary bacteremia
is continuous, low quantities of microorganisms are continuously released into circulation. As a
consequence intestinal lesions appear such as necrosis of Peyers patches, followed by
ulceration. The symptoms of the disease start in parallel with the secondary bacteremia.
The endotoxin of Salmonella typhi plays a major role also, it enhances the inflammatory
response at the microbial multiplication sites, pyrogenic molecules and inflammatory cytokines
181
are produced. The delirious attitude called typhoid state, myocarditis, and leucopenia are caused
by the endotoxin.
Incubation lasts for 10-14 days.
The initial symptoms appear progressively, the fever increases progressively during 5-7 days,
there is severe, persistent headache, insomnia, fatigue, myalgias, anorexia. Rarely starts the
disease abruptly with high fever.
Prolonged fever is the most important symptom, which lasts up to 4 weeks.
Typhoid state appears, called muttering delirium or coma vigil, which is characterized by a
delirious attitude, dreaming, the patient touches imaginary objects, rarely insomnia, psychosis.
At the end of first week a rash appears, rose spots, pink maculae situated on the abdomen, basis
of the chest, it resolves in 2-5 days. Salmonella can be cultured from these lesions.
Digestive syndrome is characterized by anorexia, nausea, vomiting, and coated, dry tongue
(parrot tongue). Ulcerative angina (Duguet angina) may be present. The abdomen is
meteoristic, with diffuse pain, especially in the right iliac fossa, where bowel movements can be
observed. The stool can be diarrheic (yellow-green stool), or can be normal, or constipation may
be present.
Hepatosplenomegaly may be present.
Cardio-vascular symptoms: relative bradycardia (discordant with fever), hypotension.
Other symptoms: bronchitis, oliguria, albuminuria, cylindruria, hematuria, encephalitis, coma.
In the absence of treatment this phase lasts 2-3 weeks. After this fever lowers progressively,
during a weeks period.
Convalescence lasts 2-4 weeks, but relapse is possible during this period.
Clinical forms
There are mild, moderate, atypical and severe forms.
Other clinical forms:
-
encephalytic form
hemorrhagic form
cholera-like form
Complications
Neurological complications are encephalitis, meningitis, polyradiculoneuritis.
Digestive complications are:
-
intestinal bleeding
bowel perforation
Both are life threatening, require rapid fluid replacement and surgical intervention.
Cardiovascular complications: myocarditis, thrombophlebitis, arteritis
182
Bacterial superinfection can occur (pneumonia, stomatitis, otitis)

Osteitis, osteomyelitis can appear at a distance of many years from the disease.
Diagnosis
Epidemiological data: infectious contact, travel.
Clinical data: prolonged fever, typhoid state, rose spots, digestive syndrome, splenomegaly,
relative bradycardia.
Non-specific findings:
-
leucopenia, lymphocytosis
leukocytosis appears in children or in intestinal perforation and subsequent infection
moderately elevated liver function tests and muscle enzyme levels
Specific findings:
-
isolation of Salmonella typhi from: blood cultures (1st week), bone marrow cultures,
stool cultures, urine cultures, cultures from the rose spots, cultures from bile,
intestinal secretions (obtained by non-invasive duodenal string test), abscesses
serologic tests: paired sera (acute and convalescent) are sampled to evaluate the antiO anti-H (Widals test) and anti-Vi antibodies
PCR: detects salmonella typhi in blood
Other diseases that cause prolonged fever have to be differentiated: sepsis, endocarditis,
brucellosis, tuberculosis, malaria, mononucleosis, leptospirosis, neoplasias, malignant
hemopathies, chronic inflammatory diseases
Diseases with typhoid state: exanthematic typhus, recurrent fever, meningoencephalitis have to
be differentiated.
Treatment
In typhoid fever prompt antibiotic therapy is mandatory. Ciprofloxacin (2x200 mg IV/day 7-10
days), levofloxacin (750 mg PO or IV/day 7-10 days) Ceftriaxone (2 gram IV/day 7-14
days), azithromycin (1 gram PO 1st dose, than 500 mg PO/day for 5-7 days), chloramphenicol
4x500 mg PO or IV/day 14 days), amoxicillin, trimethoprim-sulfamethoxazole can be used.
The patient has to be admitted to the hospital. Complete bed rest is recommended.
In severe forms with neurologic manifestation or shock corticosteroid therapy (Dexamethasone)
is recommended.
Cholecystectomy and antimicrobial therapy for 10-14 days is recommended in case of gallstone
in chronic carriers. In case of normal gallbladder the antimicrobial therapy lasts for 4-6 weeks in
chronic carriers. Amoxicillin, ciprofloxacin or trimethoprim-sulphametoxazole can be used.
Prophylaxis
183
Ill patients are isolated in hospital. They can be released after 21 days of normal body
temperature, but only after 3 negative stool cultures were obtained.
Persons working in risky areas such as public alimentation, day care centers are allowed to return
to work only after 3 months. The carriers must not be employed in risky areas.
It is important to provide adequate sewage disposal and water supplies.
Three vaccines are available, an oral live attenuated, a parenteral, that contains purified Vi
polysaccharide, and a killed whole cell vaccine. The travelers vaccination is recommended.
Persons who have intimate or household contact with carriers, or laboratory workers who
frequently deal with Salmonella typhi, should be vaccinated.
References:
Budapest
4. Rebedea I Boli infecioase, 2000, Editura Medical Bucureti
5. Gilbert DN, Moellering RC, Eliopoulos GM, Chambers HF, Saag MS The Sanford
Guide to Antimicrobial Therapy, 41st Edition, 2011, Antimicrobial Therapy Inc., USA
184
PARATYPHOID FEVER
The etiologic agents of paratyphoid fever are Salmonella paratyphi A, B or C. The disease
resembles typhoid fever, with slight differences according to each etiologic agent.
In paratyphoid fever A the intestinal lesions are rare and superficial therefore the digestive
complications are rare.
In paratyphoid fever B the incubation period is shorter than in typhoid fever, the onset is rapid,
the rose spots appear in greater numbers, and diarrhea is more prominent. The course of disease
is shorter, with fewer complications.
In paratyphoid fever C the clinical manifestations are severe, and the patients might have
jaundice and encephalitis. However there are no intestinal lesions.
Diagnosis and therapy are similar as in typhoid fever. The Widal reaction shows the presence of
anti-Salmonella paratyphi A, B, respective C antibodies.
185
SHIGELLOSIS
Andrea Incze
Definition
Shigellosis or dysentery is an acute infectious diarrheal disease caused by Shigella spp.,
characterized by fever, tenesmus and bloody mucopurulent stools.
Etiologic agent
Shigellae are non-spore forming, imobile gram-negative bacteria. They are members of the
Enterobacteraiceae, and genetically related to E. coli.
There are 4 serogroups of Shigella:
-
A Shigella dysenteriae (10 serotypes)
B Shigella flexneri (6 serotypes)
C Shigella boydii (15 serotypes)
D Shigella sonnei (1 serotype)
Epidemiology
Dysentery is present worldwide.
The reservoir of infection is represented by persons with acute or chronic infection, and healthy
carriers. Higher primates can also be reservoirs of infection.
The transmission is by fecal-oral route, via unwashed hands. Contaminated water, food, or flies
can play a role in the transmission. Shigella can survive in food, causing food-borne infections.
Sexual transmission is also possible among homosexual men.
The receptivity is general. Morbidity and mortality rates are higher among children below 10
years. Infants may be protected during breastfeeding.
Shigellae are resistant to the low pH of the stomach, therefore the inoculum required to produce
infection is low (10-100 bacilli).
Pathogenesis
Shigella invades the mucosa of distal ileon and colon. The microorganism spreads from cell to
cell after crossing the epithelial barrier through M cells (specialized translocating epithelial
cells). This conducts to inflammation and necrosis, focal ulcerations that can reach the
submucosal layer.
Shigella dysenteriae type 1 produces a neurotoxin (Shiga toxin), which increases the severity of
the disease. Other shigellae produce enterotoxins which alter the hydro-electrolyte transport, and
conduct to intraluminal fluid accumulation.
Systemic invasion is rare, it occurs only in infants, in case of immunodepression, and
malnutrition.
186
The incubation period lasts 1-8 days.
The initial manifestations are high fever, diffuse or lower abdominal pain, watery diarrhea,
malaise, anorexia, tenesmus. At this stage the small intestine is affected.
The manifestations of dysentery follow: small volumes of bloody mucopurulent stools with
tenesmus and abdominal cramps. In this stage the distal colon and rectum is affected.
The disease is self-limited in most of the cases, and resolves within 1 week.
Complications
Dysentery can be life-threatening in malnourished children below 5 years.
Bacteremia can occur in malnourished and immunosuppressed patients.
Dehydration can be present, it can be severe also. However dehydration is not a major feature in
dysentery. Other metabolic complications such as hyponatremia, hyopglycemia can occur.
Neurologic symptoms may appear in young children: meningism, seizures, confusion, delirium,
coma, and headache. Very rare complications: meningitis, toxic encephalopathy.
Hemolytic uremic syndrome is characterized by hemolytic anemia (hemoglobin <8g/dl),
thrombocytopenia (<60000/ l) and acute renal failure leukemoid reactions (leukocyte number
50000/l).
Local complications are rectal prolapse, intussusception, toxic megacolon (the inflammation
reaches the colonic smooth-muscle layer and causes paralysis, dilatation peritonitis), and
intestinal perforations.
Reiters syndrome can appear as postinfectious immunologic complication, manifested as a
reactive arthritis weeks or months after shigellosis. It appears especially in patients with
histocompatibility antigen HLA-B27, and only following Shigella flexneri infection. The
arthritis can be associated with conjunctivitis and urethritis.
Diagnosis
Epidemiological data can reveal contact with ill persons or healthy carriers.
Clinical data consist of the presence of dysentery syndrome, although shigellosis can evolve
without dysentery syndrome also.
-
Non-specific findings:
o test for fecal leukocytes: neutrophil predominance
o blood leukocyte count: can be normal, low or elevated (leukemoid reactions
occur in infections with Shigella dysenteriae type 1)
Specific findings:
o isolation and identification of Shigella from stool
Shigella is fragile, can be destroyed by temperature and pH changes,

therefore Cary Blair holding medium is used before inoculation).
The parts of stool containing bloody mucopurulent material should be

sampled.
187
o rectal sawbs can also be used to isolate the microorganism

o blood cultures are rarely positive, they should be performed only in case of
sepsis
o Serny test: conjunctival inoculation of guinea
keratoconjuctivitis in case of invasive microorganisms
pigs
conducts
to
o PCR: high sensitivity test that can detect Shigella from stool
The following diseases should be differentiated from shigellosis:
-
Infectious diarrhea with dysentery syndrome caused by Salmonella enteritidis,

enterohemorrhagic and enteroinvasive E. coli, Campylobacter jejuni, Clostridium
difficile, Yersinia enterocolitica, Vibrio parahemolyticus, or Entamoeba histolytica.
Noninfectious bloody diarrhea: appears in inflammatory bowel disease (Crohns

disease, ulcerative colitis), neoplasms of the colon, intussusception, food allergy,
hemorrhoids, anal fissure.
Treatment
The patients with dysentery have to be admitted to hospital. Diet, rehydration and symptomatic
therapy should be applied. Antimotility agents have to be avoided. Although mild cases respond
well to this therapy, antimicrobial therapy shortens the course of disease, and facilitates the
sterilization of the intestine.
Antimicrobial therapy:
-
Ciprofloxacin 2x15 mg/kg/day or 2x500-750 mg/day PO
Levofloxacin 500 mg/day once daily
Ceftriaxone 50-100 mg/kg, once daily, IV or IM
Azithromycin 6-20 mg/kg, or 500-1500 mg/day once daily PO
Rifaximin 3x200 mg/day PO
The duration of treatment is 3-5 days, or 7-10 days in immunosuppressed patients.

Other antibiotics such as trimethoprim-sulfamethoxazole, nalidixic acid, tetracycline, ampicillin
can be used, however there are resistant strains.
Evolution
The mild and moderate diseases resolve spontaneously in one week, although the patient might
remain healthy carrier. The healthy carrier state can last above 2 months, especially in
malnourished patients.
5% of the untreated cases can chronicize.
The mortality rate is < 0.1% in adults, and 6-7% in infants and young children.
188
Prophylaxis
Patients with shigellosis have to be isolated in hospital, and the cases are reported to the Public
Health Authorities. Patients can be released from hospital only after obtaining 3 negative
cultures form stool. Stool cultures have to be repeated in the following 3 months.
Hand washing before handling food, after defecation and after handling childrens feces is
important.
References:
Budapest
5. Bannister B, Gillespie S, Jones J Infection Microbiology and Management 3rd Edition,
2006, Blackwell Publishing, London
189
CHOLERA
Andrea Incze
Definition
Cholera is an acute infectious diarrheal disease, caused by Vibrio cholerae, characterized by high
quantities of watery diarrhea, vomiting, subsequent severe dehydration, muscle cramps, and
possibly death.
Etiologic agent
Vibrio cholerae has 200 serogroups, classified based on the structure of the lipopolysaccharide O
antigen. They are divided into 2 groups: those with O1 antigen, and without O1 antigen (non-O1
Vibrio cholerae). Non O1 serogroups cause only sporadic outbreaks, serogroup O1 causes
epidemics. Serogroup O139 can also cause epidemics.
Serogroup O1 is divided into 2 biotypes: classical and El Tor. These biotypes are divided into 3
serotypes: Inaba, Ogawa and Hikojima.
The disease can be produced only by toxin-producing strains from groups O1 and O139.
A specific medium, TCBS (thiosulfate-citrate-bile salts-sucrose) agar is used for inoculation.
Vibrio cholerae is destroyed by heat, gastric acid, and disinfectants. Biotype El Tor is more
resistant in the environment than the classical biotype.
Epidemiology
The natural habitat of V. cholerae is coastal salt waters. Humans become infected incidentally.
After being infected they spread the infection. Ill persons with symptomatic or oligosymptomatic
disease, convalescent and healthy carriers can be sources of infection. The carrier phase is longer
(3-4 months) in case of biotype El Tor.
The route of transmission is fecal-oral, especially through the consumption of contaminated
water or food.
The infectious dose is high (108-1011 bacteria) however it decreases in case of hypochlorhydria or
antiacid consumption (106 bacteria).
The receptivity is general, higher in children, although they can have asymptomatic forms more
frequently.
Secretory IgA seems to be responsible for immunity. Breastfed children have a passive
immunity, through secretory IgA from milk, and do not develop severe cholera. There is no
cross-immunity between groups O1 and O139.
Cholera is either endemic, or appears in epidemics, or pandemics. Since 1817 seven global
pandemics were noted. Biotype El Tor caused the last one. It was believed that V. cholerae O139
was the cause of the 8th pandemic, however, it did not spread outside Asia. War or other
circumstances that conduct to the breakdown of public health measures facilitate the spread of
cholera.
Many geographic areas are affected in the present, such as: the Indian subcontinent, Asia, Africa,
Latin America.
190
Pathogenesis
A large inoculum dose is needed in order to pass the gastric barrier. Subsequently Vibrio
cholerae traverses the intestinal mucous layer with the help of proteases. It colonizes the small
intestine, adheres through a pilus, and produces a toxin. The diarrhea is toxin-mediated.
The toxin has 2 components: subunit A (enzymatic activity) and subunit B (binding activity).
Subunit A activates the adenylate cyclase, and as a result intracellular cyclic AMP concentration
increases, conducting to intraluminal sodium and chloride secretion. Water moves passively
along. When the quantity of secreted water exceeds the resorbtive capacity of the intestine,
diarrhea appears.
The quantity of diarrhea is high, about 1 liter per hour, that conducts to severe dehydration,
acidosis, shock.
Incubation may last 1-5 days.
The initial symptoms have sudden onset, with painless watery diarrhea and vomiting.
The volume of the stools increases rapidly, they are frequent, 20-50 per day, watery, profuse, the
aspect resembles rice-water, with sweet, inoffensive odor.
Fever usually is absent.
Muscular cramps appear due to electrolyte loss.
The signs of mild, moderate or severe dehydration are present. (Table 1.)
Finding
Mild dehydration
Moderate
dehydration
Severe dehydration
Loss of fluid
<5% of body weight
5-10% of body weight
>10% of body weight
Thirst
Moderate
Intense
Very intense
Mental status
Normal
Normal
Normal
or
somnolence, coma
Pulse rate
Moderate tachycardia
Rapid pulse rate
Very rapid
Radial pulse intensity
Normal
Weak
Feeble or impalpable
Respiration
Normal
Deep
Deep and rapid
Blood pressure
Normal
Orthostatic
hypotension
Very low
Skin elasticity
Retracts rapidly
Retracts slowly
Retracts very slowly
Eyes
Normal
Sunken
Very sunken
Voice
Normal
Hoarse
Not audible
Urine quantity
Normal
Oliguria
Oligoanuria, anuria
Table 1. Clinical findings according to degree of dehydration
191
Clinical forms
There are mild, moderate and severe forms of cholera.
Cholera may have the form of a common gastroenteritis.
Cholera sicca is a very severe form characterized by important fluid loss and paralytic ileus. The
fluids may not be eliminated through diarrhea or vomiting, and the patient dies within hours.
Another severe form is the typhoidic form, with high fever and rapidly lethal evolution.
Complications
The complications that can occur in cholera are:
-
shock
acute renal failure (due to acute tubular necrosis)
acidosis
hypoglycemia
bacterial superinfections
Diagnosis
Epidemiological data reveal residence or travel in endemic or epidemic geographical areas, or
contact with ill persons or cholera carriers.
Clinical data show afebrile abundant watery diarrhea with rice-water aspect and rapid
dehydration.
Non-specific findings
-
elevated hematocrit
mild neutrophilic leukocytosis
elevated serum urea and creatinine levels
reduced bicarbonate level (<15 mmol/l)
elevated anion gap (increased serum lactate, protein, phosphate)
low arterial pH (7.2)
Specific findings
-
identification of V.cholerae in stool or vomiting fluid:

o the samples have to be taken on peptone water
o detection with dark-field microscopy (mobile bacilli with flagellum)
o the serotype is detected through immobilization with specific antiserum
isolation on TCBS (thiosulfate-citrate-bile salts-sucrose) agar

o identification based on biochemical testing, monoclonal antibodies, PCR
detection of the toxin in stool: latex agglutination, ELISA tests
serologic tests: antibodies appear in the 4th-6th day, the titer lowers in 2-3 months,
except in the healthy carriers
192
Cholera can be differentiated from other acute infectious diarrheas, toxic diarrheas, meningitis
(in children).
Treatment
The patient has to be admitted to the hospital.
The most important is to replace rapidly the fluid, electrolyte, and base losses.
Rehydration with oral rehydration solutions (ORS) can be used. If they are not available, WHO
recommends a substitute made of teaspoon salt and 6 level teaspoons of sugar dissolved in a
liter of potable water.
In case of severe vomiting or severe dehydration intravenous rehydration is needed. The total
fluid deficit can be replaced in 4 hours, half within the first hour. Ringers lactate is
recommended. Potassium replacement is needed.
Antimicrobial therapy:
-
tetracycline 2g once, or 4x500 mg/day for 3 days
doxycycline 300 mg once
ciprofloxacin: single dose of 30 mg/kg-1g, or 3 days course 15 mg/kg bid (not to

exceed 1g/day)
erythromycin: 4x500 mg /day for 3 days in adults or 40 mg/kg/day tid, for 3 days in
children
azithromycin 1g single dose or 20 mg/kg/day single dose in children
trimethoprim-sulfamethoxazole 2x2 tablets/day
furazolidone (5-10 mg/kg/day), trimethoprim-sulfamethoxazole (5-7 mg/kg/day)

these can be used in children
Resistant strains to ciprofloxacin, sulphonamides and furazolidone have emerged.

Azithromycin and erythromycin are recommended in the treatment of pregnant women with
cholera.
Prophylaxis
In Romania all of the cases of cholera, their direct contacts and the carriers have to be admitted
to hospital, and declared immediately to the Public Health Authorities. Direct contacts receive
prophylactic antimicrobial therapy with tetracycline 2g/day for 3 days.
It is important to provide safe water and appropriate facilities for disposal of feces, to prepare
and store food in an adequate way.
There are two types of cholera vaccines: a killed whole-cell vaccine, and a live attenuated
vaccine. Neither of them provides sufficient protection. Travelers should be vaccinated only if
this is required by the visited countries.
193
References:
Budapest
5. Rebedea I Boli infecioase, 2000, Editura Medical Bucureti
194
Botulism
Iringo Kezdi
Botulism is a paralytic illness caused by the neurotoxin produced by the bacterium C.botulinum.
Botulism begins with cranial nerve paralysis, including diplopia, dilated and fixed pupils,
dysarthria, dysphagia, and dry throat. Paralysis first affects the cranial nerves, then the skeletal
muscles; untreated intoxications can lead to dense flaccid paralysis, respiratory failure, and
death.
Etiology
Members of genus Clostridium are gram-positive, anaerobic bacilli. C.botulinum and closely
related organisms produce toxins designated as types A, B, C, D, E, F and G. Human botulism is
most commonly caused by types A, B and E. Type E is associated with foods of marine or
freshwater origin. The toxins causing this disease are among the most potent bioactive
substances known (the oral lethal dose for humans is 0.05-0.5 microgrames). C.botulinum spores
are ubiquitous. Safe food preservation methods destroy spores or inhibit their germination and
growth. Conditions that promote germination and growth of C.botulinum spores include absence
of oxygen (anaerobic conditions), low acidity (pH>4.6), temperatures>39F, and high moisture
content.
Pathogenesis
There is four clinical type of botulism:
1.Foodborne botulism- characterizes infection in adults and older children and is caused
by the ingestion of food contaminated with preformed botulinum toxin. From the upper
small intestine the toxin pass into the bloodstream and binds irreversibly to the following
sites:
Receptors on cholinergic nerve fibers at a neuromuscular junction
Postganglionic parasympathetic nerve endings
Autonomic ganglia
The toxins enter the nerve endings and irreversibly interfere with the release of acetylcoline.
2. Wound botulism results from spore germination and toxin production in contaminated
wounds with subsequent systemic absorption of toxin.
3. Infant botulism results from the ingestion of spores that germinate and produce toxin in
the infants gastrointestinal tract.
4. Infectious botulism develops after ingestion of spores, followed by toxin production
in gastrointestinal tract.
The latent period is typically 12-36 hours, but can range from 6 hours to 10 days. Pacients are
afebrile in the absence of complications. The symptoms are:
Gastrointestinal: nausea, vomiting, abdominal cramps, diarrhea/constipation, dryness of

mucous membranes
195
Neurologic: which are manifestations of cranial nerve dysfunction: blurred vision,

diplopia, dysartria, dysphagia, dysphonia, ptosis, facial muscle weakness, tongue
weakness
Dizziness, fatigue
Muscle weakness progresses in a descending manner (is typically symmetrical); in severe
cases, flaccid upper and lower extremity weakness and dyspnea are present
Manifestations of parasympathetic nervous system dysfunction: dryness of the mouth and
paralytic ileus, orthostatic hypotension
Pupils may be dilated or nonreactive
In wound botulism gastrointestinal signs usually do not occur. Muscle tone permits
differentiation from tetanus.
Infant botulism is manifested with lethargy, weak cry, decreased sucking, ptosis and
constipation.
Symptoms and signs of botulism are reversible, but cranial nerve dysfunction and mild
autonomic dysfunction may persist for more than a year.
Complications include otitis media, aspiration pneumonia, respiratory distress syndrome.
Detection and identification of botulinum toxin in blood, feces and in the food
consumed before onset of illness. Mouse bioassay consist on intraperitoneally
inoculation of above mentioned extracts (positive test:death within 24-48 hours of all
mice except those protected by the polyvalent and type-specific antisera and those
receiving inocula that have been heat-treated).
Isolation of C.botulinum from the stool
CSF is normal
The disease that may be confused with botulism are: tick-borne encephalitis, diphtheria,
poliomyelitis, Guillain-Barre syndrome, myasthenia gravis, food poisoning or other etiology.
For infant botulism differential diagnosis includes: sepsis, dehydration, pneumonia, Epstein-Barr
infection, diphtheria, congenital myasthenia gravis, muscular dystrophy, hypothyroidism,
metabolic and toxic conditions which may produce weakness and hypotonia.
Therapy
1. Supportive care, nutritional support
2. Prevention of nosocomial pulmonary and urinary tract infection
3. Trivalent botulinum antitoxin (neutralize only circulating toxin) must be administrated
as early as possible, with a test for the hypersensitivity.
-for cutaneous testing: 0.1 ml antitoxin in 1/100 physiologic saline dilution,
intracutaneously
- for ocular testing: one drop of antitoxin in a 1/10 dilution of physiologic saline (PS) is
instilled in one eye with a control drop of PS in the other eye (lacrimation and
conjunctivitis occurred after 10-30 minutes is evidence of hypersensitivity)
- anaphylaxis should be treated with epinephrine hydrochloride, steroids or ACTH
196
Antitoxin must be give intravenously, in one vial (if there are no signs of hypersensitivity).
Hypersensitivity reactions must be averted through the use of human botulism immune globulin.
Botulism antitoxin desensitization: with serial subcutaneous injections of antitoxin in 20 minute
intervals
0.05 ml of 1/20 dilution PS

0.1 ml undiluted
0.2 ml undiluted
0.5 ml undiluted
Therapeutic does intramuscularly
4.
5.
6.
7.
Guanidine hydropchloride
High-dose penicillin therapy is generally given
Antibiotics if there are complications
Debridement of the wound
When foodborne botulism is suspected, clinicians and public health investigators should inquire
about the preparation and eating of foods preserved by any home method (e.g., canning, pickling,
curing and fermenting). C.botulinum spores are not killed by boiling at 100C. The toxin is heatlabile, so it may be inactivated by boiling of foods before consumption. Mortality rate is 25-30%.
197
CHAPTER 6
Acute Viral Hepatitis
Anca Georgescu
Generalities
Acute viral hepatitiss are systemic infections that affect mainly the liver through inflammation.
They are still a major public health problem due to high morbidity and mortality rates in spite of
the existence of efficient vaccines against the two most frequent etiologic agents: Hepatitis A
Virus (HAV) and Hepatitis B Virus (HBV); the resulting health costs are high and the treatment
resources are limited.
Five different viruses are accounting for more than 90% of the hepatitis infections: HAV, HBV,
Hepatitis C Virus (HCV), Hepatitis D Virus (HDV) and Hepatitis E Virus (HEV). While HBV is
a DNA virus, the rest of these are RNA viruses.
This etiologic diversity leads to complex antigenic properties, diverse pathologies, different
evolutions; the clinical picture is however similar for all types of hepatitis. The clinical specter
spans from asymptomatic infections to extremely severe and rapid evolutions but the main public
health burden is due to the possibility of evolution towards chronic infections with B, C and D
viruses and the risk of developing hepatocellular carcinoma.
Etiology
HAV is belongs to the Hepatovirus genus of the Picornaviridae family; it was initially classified
as an Enterovirus to which it however displays differences of structure, it has a slower
replication and does not induce cytopathic effects.
It is a RNA non-enveloped virus with icosahedric symmetry. The capsid has 4 polypeptidic
units, VP1 to VP4 that are bearing the antigenic determinants. The viral genome is a single
stranded positive RNA molecule with a single open reading frame (ORF) and 3 coding regions
(P1, P2, P3). Although there are 7 genotypes HAV cross-reacts antigenically: it displays a single
serotype and a single major epitope: (Ag HAV).
HAV does not induce cytopathic effect, is slowly replicating on cell lines; although it can be
cultivated in vitro, this technique is not of diagnostic use; in vivo, it replicates strictly in the
liver; it can be detected in the liver, bile and the feces by the end of the incubation period.
HAV is thermostable and resistant to acids and organic solvents; it remains viable in the feces
several hours at room temperature. It is inactivated by boiling for one minute, intense
chlorination, autoclaving, UV exposure and formaldehyde.
HBV is a type 1 hepadnavirus that belongs to the Hepadnaviridae family alongside distinct
genera that induce hepatitis in mammals and birds.
HBV has three morphologic forms that circulate in the serum of infected patients:
-
Spheric 22 nm or 20 nm phylamentous particles; they consist of the surface protein (Ag

HBs) to which they are antigenically identical; they predominate, do not include
nucleocapsidic material and are not infective
198
42 nm spheric particles, 100-1000 times less frequent, that represent the complete virions
(Dane particles).
The complete virion consists of a lipid envelope and the core (nucleocapsid)
The envelope embeds the surface antigen HBsAg that has three forms: Large, Medium and
Small. The Large peptide displays several epitopes: a (which is present in all strains) d/y and w/r,
respectively; their combination defines the 8 subtypes and 8 genotypes (A-H) that have distinct
geographical distribution and differ in terms of chronic evolution vs. clearance of the virus. The
A (adw) and D (ayw) genotypes predominate in Europe.
The viral nucleocapsid (core) is 27 nm large, is localized in the nucleus of the hepatocyte and
consists of:
-
HBc AG: it is located strictly in the hepatocyte and cannot be detected in the blood, it
is highly immunogenic, eliciting anti-HBc Ac
HBe Ag: it is the soluble form of HBc Ag. It is a replication marker, its presence
indicates high infectivity; it is transiently present early in the infection; its clearance
indicates recovery but its persistence for more than 3 months is predictive for chronic
evolution.
HBV DNA: its presence in blood accounts for the contamination risk; it is small
(3200 ntd), asymmetric, closed and circular, partially double stranded. The negative
strands codes for 4 overlapping ORFs (Fig. 1):
o S: it codes for the major surface protein (HBs) that mediates the attachment of
the virion on the hepatocyte and the penetration and other 2 surface proteins
(Medium: pre-S2+S, Large: preS1+preS2+S)
o P codes for the DNA polymerase
o C codes for HBcAg and HBeAg (pre-C segment)
o X codes the HBxAg
The DNA polymerase intervenes in the viral replication that occurs in the liver and in the
lymph nodes. HBV and the other hepadnaviruses are unique among DNA viruses because
this enzyme mediates a replication process that includes reverse transcription of the RNA
very much like it is performed by retroviruses.
The HBxAg is a protein involved in the hepatocyte apoptosis induces activation of

cytolytic T cells and is associated with liver ontogenesis.
HCV is the only member of the Hepacavirus genus of the Flaviviridae family. Prior to its
identification it was known as posttransfusional hepatitis virus and the disease as non-A nonB hepatitis.
It is a single stranded positive RNA virus, with a diameter of 55 nm. A single ORF coding for
structural (C, E1, E2, p7) and nonstructural (NS2-NS5) proteins is flanked by 5 and 3
untranslated regions (UTR). The viral genome does not integrate in the host genome.
The viral envelope is lypoproteic and it embeds two proteins, E1 and E2 that have a role in the
attachment of the virus to the cell surface.
Genetic variation is a major characteristic of HCV; there are 6 genotypes, more than 50 subtypes
and all are quasispecies. This diversity is generated by a high mutation rate during viral nucleic
acid replication. The effects of variability are of major consequence:
199
Circumventing the immune response through generation of escape mutants that

are not recognized by a thus inefficient humoral immune response. Neutralizing
antibodies are detected early during HCV infection (preceding hepatic cytolysis)
but are transitory, and do not protect against infection with other strains and not
even the homologous strain. Third generation ELISA tests detect specific
antibodies during acute infection.
The apparition of resistance against antiviral treatment
Evolution towards chronic infection
Lack of protection by vaccination (so far)
The most accurate diagnostic test is detection of HCV RNA by molecular techniques (PCR). The
Simmonds classification of HCV by sequencing the 5 UTR and NS5 describes 6 genotypes (16) and 12 subtypes. This classification correlates with the response to interferon (IFN) treatment
and with evolution; the 1b genotype is associated with high levels of viremia, higher rate of
chronic infections and liver carcinoma and poor to average response to IFN; in contrast, the
genotypes 2a and 3a have a 100% response rate to treatment.
HDV is a single stranded circular negative RNA virus; it is spherical with a 35-37 nm diameter.
It is defective: the presence of HBV is required for HDV pathogenic effects to be elicited.
It has an envelope that has AgHBs embedded and a core-like structure which associates the viral
genome with HDAg, the only protein coded by the viral RNA.
There are two forms of HDAg: the large P27 inhibits RNA replication and stimulates viral
assembly and export while the small form, P24, initiates the rolling-circle mechanism of the viral
genome replication independently of the HBV replication. These particular replicative
properties alongside the defective character of HDV lead to its classification as a subviral
particle within the Deltavirus genus.
HDV replicates exclusively in the liver cells. It is characterized by a high genetic variability with
effects that are incompletely understood; the major genotypes are IA, IB, II and III.
HEV belongs so the Hepevirus of the Hepeviridae family. It structure and epidemiology are
similar to HAV: a diameter of 32-34 nm, icosahedric symmetry, unenveloped, a single stranded
RNA genome with 5 ORFs: ORF1 codes for the nonstructural proteins that are involved in
replication; ORF2 codes for the structural proteins of the nucleocapsid and ORF3 codes for a
protein with unknown function.
There are one HEV serotype and 5 genotypes, 4 of which are pathogenic in humans and have
distinct geographic distributions. Animal reservoirs are involved in the endemicity of this viral
infection.
The virus is detected in the liver, bile and the feces were it is excreted at the end of the
incubation period. The IgM and IgG responses are very rapid but transient; the viral titers decline
in 9-12 weeks. There are no standardized tests for the routine diagnostic of HEV. The virus is
unstable at cold (-70C) but it resists to acids and alkali.
Epidemiology
Viral hepatitis A
The HAV infection is widely spread through the world with sporadic or endemic/epidemic
evolution, with autumn-winter seasonality and a periodicity of outbursts of about 5 years through
accumulation of receptive population.
200
The proportion of immunize adults has decreased in developed countries as a result of better
sanitation conditions in childhood; the infection is associated with fecal-oral transmission, direct
contact or through contaminated food or water. This route of transmission is still highly
prevalent in poor countries. Intrauterine transmission has not been demonstrated; parenteral
transmission is an exception due to the short period of viremia (10 days before and after the
clinical onset). There have been cited severe epidemics in recipients of coagulation factors.
The source of infection is exclusively the diseased patient weather with or without clinical
symptoms. HAV is detected in the feces starting two weeks after the infective contact until two
weeks after the clinical onset but the infectivity diminishes markedly after the apparition of
icterus; fecal excretion of the virus can last for 8 weeks and even longer in children and
immunocompromised hosts. There is no chronic excretion of HAV.
Humans are universally susceptible to HAV but no more than 40-50% of the infected persons
develop clinical symptoms; these are more frequent and more severe in the elder children and
adults. Anicteric, asymptomatic infections are quite frequent in children. There is solid, lifelong
post infection immunity.
Viral Hepatitis B
Although the HBV infection is globally spread with a human reservoir of more than 350 million
carriers its prevalence varies substantially in different geographic regions. It is only 0.5-1% in
Western Europe and the USA as compared with 5-10-20% in Far East Asia. The prevalence in
Romania is 3-5% with slight zonal variations and a decrease after a vaccination program for the
newborns was introduced.
The source of infection is represented by the patients with acute or chronic disease and the
carriers. HBV is detectable in the blood and in most of the body fluids: saliva, sperm both
sources of infection as well as in milk, genital secretions, tears, CSF.
There are several transmission routes:
-
Parenteral percutaneous or per mucosal, through blood and contaminated blood

products most commonly during:
o Medical interventions :
Transfusions
Use of incorrectly sterilized instruments in stomatology, invasive

investigations, parenteral treatment
Professional accidents: cuts or punctures of the medical staff
o Non-medical interventions
Nail treatment, piercing, shaving, tattooing
Sharing of needles by IV drug users
Exposure of wounds to biological fluids within the family
Non parenteral - sexual (heterosexual or same sex) through genital secretions

and saliva
Vertical perinatal:
o In utero: it accounts for 10% of the vertical transmission cases; the risk
when the pregnant woman is infected during the last three months of
pregnancy; in mothers that are carriers of HBsAg the risk is correlated
201
with the presence of HBeAg (90% risk when it is present vs. 10% when it
is absent).
o Intrapartum the most frequent route of infection
o Postpartum the risk of transmission during breastfeeding has not been
documented enough
The persons at risk of acquiring HBV infection are:
-
Patients on dialysis or with multiple transfusions (transfusion risk: 1/230000)
Intravenous drug addicts
Medical staff
Children born to HBsAg carrying mothers
Sex workers. MSM
Family members of HBV infected patients
Viral Hepatitis C
The HCV infection is universal but unevenly distributed. The human reservoir is increasing
despite the fact that the infecting dose is smaller than for HBV and the blood and blood products
have been controlled rigorously after the 80s.
The reservoir is strictly human, it includes acutely and chronically infected (symptomatic or
asymptomatic) patients; an estimated total of 170 million people carry the virus.
The routes of transmission for HCV are:
-
Parenteral percutaneous transmission through blood and blood products, surgery

instruments, contaminated syringes and needles, unsterilized nonmedical cutting
devices. It occurs most often during:
o Transfusions: HCV accounts for 90% posttransfusional hepatitises. It is
estimated that by testing the donors with latest generation ELISA tests and
by RT-PCR detection of viral RNA the risk of transmitting HCV has been
reduced to 1/23 million transfusions
o IV drug use
o Occupational hazard for staff working mainly in dialysis centers
o Non-parenteral medical procedures
The sexual transmission, although theoretically possible, is rare. It is more often

seen in persons having several partners and in people with sexually transmitted
diseases
The perinatal transmission is extremely rare; it seems that the risk correlates with
the mothers viral load; breastfeeding does not increase the risk of transmission.
The sexual and perinatal transmission routes account for 5% of transmissions which is sensibly
less than the HBV transmission.
There is universal receptivity to HCV. The role of the post infection immunity is unclear: antiHCV antibodies signify history of infection but are not necessarily protective.
202
Viral Hepatitis D
The reservoir of infection for D hepatitis is represented by the persons with double infection
HBV-HDV.
The routes of transmission are identical with those of HBV, most commonly the parenteral route
after multiple transfusions and in IV drug users followed by the sexual transmission. The vertical
transmission is less common.
The receptive population is the HBV receptive population HBV and HBV can be
simultaneously transmitted and persons chronically infected with HBV (HDV superinfections).
The HDV infection can be endemic or sporadic in correlation with the high or low prevalence of
the HBV infection.
Viral Hepatitis E
This form of hepatitis is more common in Asia, India, Africa and Central America where its
prevalence can reach 40 %. The epidemiology is very similar to HAV due to its enteric way of
transmission. The infection is prevalent mainly in young adults although there is general
receptivity and it can propagate by interhuman transmission. The infection is sporadic in
Western countries affecting mainly people travelling in endemic regions; the antibody
prevalence is about 2%.
The source of infection is the infected person whether with manifest or atypical clinical forms;
virus excretion in the feces is short (2 weeks). There is much argument about the existence of an
animal reservoir (pigs, rodents).
Fecal-oral transmission is mediated by food (mainly sea food) or water. There is also vertical
transmission and pregnant women are infected during the last trimester of pregnancy.
The immunity is limited, reinfections are possible.
Pathogenesis
Viral Hepatitis A
HAV is orally ingested and the first round of replication is in the oropharynx, salivary glands
and the bowel where it can be recovered at this time. Multiplication in the epithelial cells of the
small intestine is follow by transport by way of the port vein to the liver where another round of
replication occurs in hepatocytes and Kupfer cells. Transcription of RNA is followed by
synthesis of the viral proteins that are assembled into new capsids then virions in the cytoplasm;
the virions are excreted in the bile ducts without cell destruction HAV lacks cytopathic effect.
HAV is transported through the bile to the feces or can infect new target cells.
The intrahepatic replication is accompanied by viremia that last from week 2 post infection until
week 2 after the onset of symptoms (1 week after the apparition of icterus)
The hepatic lesions are the result of immunologic mechanisms induced by expression of viral
antigens on the surface of hepatocytes; NK (natural Killer) cells and CTL (cytotoxic T cells) are
involved in viral clearance through cytokine and interferon action.
The humoral immunity is limiting the infection and achieves viral clearance; IgM antibodies
appear concomitantly with the clinical onset, during fecal excretion of the virus, and last for 6
months, being thus a marker for current or recent infection; IgG antibodies follow, are
predominant during convalescence and through long life persistence protect against reinfection.
203
Hepatocyte destruction is accompanied by serum increase in lysis specific enzymes and

electrolytes (iron, copper). Hepatic injury affects metabolic processes such as the lipid
metabolism (increase in triglycerides, decrease of cholesterol), protein metabolism (decrease in
albumins and coagulation factors II, V, VII, and IX, increase in globulins), glucidic metabolism
(erratic glycaemia) and hydro electrolytic with a tendency of increase of the extracellular fluid.
Viral Hepatitis B
The hepatocytes are the main site of replication for HBV; the infection has several stages:
Replicative with immune tolerance. It corresponds to the incubation period, lasts for 2-4 weeks,
and is characterized by active viral multiplication with minimal cytolysis, therefore with little if
any hepatic lesions and no symptoms.
Replicative with immunological clearance. The immune system reacts through CTL with the
viral proteins as targets. The markers of viral replication disappear and the HBe antibodies
appear; cytolysis is exacerbated and symptoms of acute hepatitis are prominent. The stage lasts
for 2-4 weeks in patients that clear the virus is indefinite in patients that are becoming chronic
carriers.
The immune clearance and the destruction of infected hepatocytes are followed by remission of
the symptoms and cytolysis and a limited reversion of the histologic modifications: a degree of
fibrosis is present but it does not affect the hepatic architecture although the HBsAg can be shed
for years. If the immune response of the host is very active the integrative stage follows: HBs
seroconversion occurs, the HBsAg disappears, the HBV DNA becomes undetectable in the
serum but still detectable in the liver cell where activation can occur if immunosuppression is
present (HIV infection, immunosuppressive therapy, cytostatic treatment).
The secondary, extrahepatic sites of replication - lymph nodes, circulating lymphocytes, bone
marrow, spleen, pancreas - can act as a virus reservoir although they do not undergo
inflammatory lesions; they can be the origin of extra hepatic syndromes and posttransplant
activation of infection
HBV does not have a direct cytopatic effect; the lesions, the evolution and the symptomatology
are triggered by the immune response of the host. The cytolysis is mediated by cytotoxic CD8
lymphocytes that recognize on the cell surface nucleocapsidic proteins (AgHBc, AgHBe) and by
NK cells. The cytotoxic aggression is associated with inflammatory lesions induced my
macrophages that infiltrate the periportal areas. The type of immune response determines the
clinical picture and possible chronicization.
To some extent, the destruction of the infected hepatocytes is also mediated by early activity of
the inflammatory cytokines and components of the innate immunity.
The humoral immunity does not directly elicit cytolysis. HBc and HBe antibodies mediate the
cytotoxic cellular response. The only protective antibodies are against HBs.
The existence of a direct pathogen effect of the virus is suggested by the association between
certain mutations in the pre-core region and a higher incidence of severe and fulminant
evolutions.
Serologic markers in Viral Hepatitis B (Fig. 1):
HBsAg
Detectable at 1-12 weeks, 2-6 weeks prior to cytolysis and clinical onset
Disappears at 1-2 months after icterus can persist for 6 months
HBsAb
204
Appear after HBsAg clearance; the interval between the two events is
called serologic window
Detectable throughout the rest of the life
Marker of immunity, protective against reinfection
HBcAg: undetectable in the serum, strictly intracellular in hepatocytes

HBc Ab:
early apparition, 1-2 weeks after HBsAg, weeks or months before HBsAb
diagnostic value in the serologic window
IgM persist for 6 months, IgG detectable after 4-6 months
IgG persist indefinitely
HBeAg
Simultaneously or soon after HBsAg
Denotes viral replication, are associated with DNA viral load and Dane
particle
Variant: mutated HBV that does not express HBeAg
disappearance before HBsAg, soon after the cytolytc acme
HBeAc
They appear after HBe Ag disappearance and before HBsAg

disappearance
Marker of low infectivity
Fig. 1. Typical response in acute B hepatitis (months after exposure)

The evolution of HBV hepatitis acquired through vertical transmission is distinct from the
evolution of the hepatitis acquired horizontally at adult age. The neonatal infection is associated
with immune tolerance to HBV which explains the lack of clinical signs of acute infection but
the evolution is constantly towards chronic infection and, eventually, after decades of evolution,
towards cyrosis and hepatocarcinoma. The infection acquired after puberty is accompanied by an
205
active immune response the immune reactive stage, clinically manifest, followed almost
always by healing and clearance of the virus and none of the mentioned complications.
In contrast to this typical evolution of the hepatitis with HBV, the chronic evolution is
announced by the lack of clearance of the HBsAg after 6 months and the lack of HBsAb; only
HBcAb IgG can be detected and HBV DNA is detectable in the serum and in the hepatocytes.
The peak of infectivity is during the replicative stage when virions, viral DNA and HBeAg can
be detected in the serum. The nonreplicative stage follows after the seroconversion in the e
system; at this point the viral DNA is integrated in the hepatocyte genome and only altered
virions are circulating in the periphery; this stage is of inactive carrier. Reversion to the previous
stage is sometimes possible.
Viral Hepatitis C
Infection with HCV is followed after 1-2 weeks by viremia that is at is highest initially then
varies; when the evolution is toward chronic infection the viremia persists after cytolysis
decreases but it correlates with the severity of the hepatic lesions thus indicating poor prognosis.
HCV replication occurs in the hepatocytes with no direct cytopathic effect but also in monocytes
and lymphocytes. The mechanism of the hepatic lesion is by immune response cell mediated
and by cytokines with antiviral effect released by the T lymphocytes. The degree of response by
CD8 cytotoxic lymphocytes correlates with the healing rate, their being present in high titers
indicates favorable prognosis. NK Lymphocytes contribute to controlling the infection. The
effect of these immune mechanisms in controlling the HCV infection is quite often transient;
evolution to persistent infection occurs in 70-85% of the cases. Persistent infection is caused by
suboptimal response of the adaptive immunity as a result of the variability of the virus
(quasispecies) and by the downregulating of the innate immunity (interferon) by the viral
proteins.
The risk of chronicization in HCV hepatitis is influenced by viral factors (genotype 1b high
viremia) and host factors (HIV, HBV coinfections, alcoholism, male gender) and immune
response variations.
Viral Hepatitis D
The hepatic lesions in HDV hepatitis is through direct cytopathic effect through blocking the
host cell protein expression. The immune response is however also playing a role in chronic
infections.
HDV is a defective virus that cannot be transmitted in the absence of HBV. The interaction of
the two viruses leads to higher severity of the hepatitis. There are two types of interaction:
A. HDV-HBV coinfection leading to severe acute hepatitis and biphasic clinical,
biological and histologic pictures; healing is possible but the evolution is more severe
than in hepatitis with HBV only
B. HDV superinfection: severe acute hepatitis occurs in a HBV carrier, liver failure and
fulminant evolution occur in 10% of cases; with chronic evolution, 75% of the
patients progress towards cirrhosis.
206
Viral Hepatitis E
HEV has fecal-oral transmission very much like HAV; ingestion of the virus is followed by
primary replication in the cells of the small intestine and consequently in the liver. The hepatic
lesion is induced by the immune system HEV lacks cytopathic effects.
The humoral immune response is prompt: HEV IgM antibodies are detectable at the onset of the
clinical stage and usually disappear 2-3 months after the acute illness although they can persist
for 2 years and more; the IgG antibodies appear two weeks after the onset of the disease and
persist in small titers for months and up to 10 years without conferring protection against
reinfection.
HEV RNA can be detected in the serum and feces at 4-6 weeks after the onset of the disease.
Clinical picture
The onset of acute hepatitis follows an incubation period that varies according to the etiology. It
is shorter in the forms with fecal-oral transmission: 20-45 days (4 weeks) for HAV, 14-60 days
(5-6 weeks) for HEV; the HBV and HDV hepatitises have an average incubation of 8-12 weeks
(30-180 days at the extremes) and HCV hepatitis has 7 week incubation on average with a very
large variability (15-160 days).
The prodromal (anicteric) stage is polymorphic as symptomatology: it is dominated by systemic
manifestations, unspecific and with varying intensities, that begin 1-2 weeks before icterus and
are often associated with digestive symptoms; the latter are receding with the onset of icterus.
Among the systemic manifestations:
Unspecific digestive syndrome, with anorexia, reduced olfactory and taste
sensitivity, flatulence. When this is the main clinical picture at the beginning it is
a clinical staple of acute hepatitis with digestive onset; the symptoms subside
when icterus appears.
The general infectious symptoms are fever 38-39C (mainly in hepatitis with
enteric transmission), myalgia, asthenia, fatigue, headaches, photophobia.
Common cold syndrome, cough, angina in the pseudoinfluenza syndrome
Small joint arthralgia, nocturnal and symmetric sometime with rash or purpura;
serum sickness-like symptoms occur in 10% of the patients with HBV and 5% of
the patients with HCV and are associated with the infectious syndrome. Pseudorheumatic symptoms occur more frequently in HBV hepatitis (30-70%); Gianotti
syndrome (papular acrodermatitis) is a particular form in children that consists of
papulovesicular skin rash of the face and chest and generalized adenopathy
Neuropsychiatric manifestations: severe asthenia, drowsiness of insomnia,
depression, restlessness, apathy are characteristics of the neuropsychiatric onset
Atypical manifestations: colic, abrupt apparition of icterus can mimic acute
surgical abdomen
Hyper chrome urines and discolored stools appear 2-5 days before icterus.
On clinical examination painful hepatomegaly (10%), and often splenomegaly and adenopathy
(5%) can be detected mainly in children.
The prodrome lasts for 5-7 in HAV hepatitis, 1-4 days in HEV hepatitis and 2-3 weeks in HBV
hepatitis. In HCV hepatitis the symptoms are very faint and are often ignored by the patient.
207
The stasis stage (icteric) is heralded by the attenuation/disappearance of the prodromal

syndromes followed by icterus of skin and mucosa.
The icteric syndrome in viral hepatitises is insidious, varies in intensity and lasts,
on average 3-4 weeks. Acholic stools and hyper chrome urine accompany the
icterus; its intensity is an indicator of the clinical forms severity; if bilirubinemia
does not exceed 2-3 mg/dl the jaundice might not be noticed (mild, anicteric
forms) whereas in cholestatic forms, with longer evolution (3-6 months) and more
characteristic to HAV the jaundice has a striking intensity and can acquire a green
tint.
The hepatosplenomegaly is characterized by tender distension of the liver; its
consistency is soft, the surface is lean and the patients complain of discomfort or
even pain in the right hypochondrium. Fifty percent of the patients have
splenomegaly; cervical adenopathy is less frequent (20%).
The digestive dyspeptic syndrome is unspecific, persists for 1-2 weeks during the
icteric stage and anticipates an evolution that is more severe
Hemorrhagic syndrome: epistaxis, bleeding of the gums, accentuated menstrual
flow or metrorrhagia accompanied in severe forms by liver failure.
Asthenic syndrome: apathy, listlessness, irritability, depression
Extrahepatic symptoms: they are more frequent in HBV (15-20%) and HCV
infections:
o Hypertension, sinus bradicardia,
myocarditis, pericarditis
ECG
late
phase
modifications,
o Pancreatitis, increase in serum amylases in infections with HBV

o Pleurisy
o Interstitial nephritis
o Essential mixed cryoglobulinemia
o Aplastic anemia, agranulocytosis, thrombocytopenia
o Polinevritis, encephalitis
o Antiphospholipidic syndrome, pulmonary fibrosis, thyroiditis in
hepatitis with HCV
The convalescence (post icteric) stage is characterized by onset of systemic symptoms and
persistence of a degree of hepatomegaly and low-level cytolysis. It lasts for 2-12 weeks;
complete remission of the clinical, biological and histological alterations is achieved in 1-2
months in HCV hepatitis and 3-4 months in HBV and HCV hepatitis. The patients must be
monitored clinically and biologically for 6 months because relapses are possible.
Clinical forms
Anicteric acute hepatitis (unapparent, subclinical): the clinical picture is limited to
the preicteric stage; the diagnostic is based on immunological and serologic
alterations; the risk of complications and chronic evolution is the same as in
icteric forms.
o They are more frequent in HAV hepatitis (70%) and HEV hepatitis were it
is endemic (80%)
208
The cholestatic form is characterized by intrahepatic cholestasis and has a clinical

picture of long lasting obstructive jaundice that can be severe; it is frequently
associated with pruritus, sometimes fever and diarrhea; the prognosis is favorable
o 5-10% HBV hepatitis cases and less frequent in HAV hepatitis
The extended uncomplicated form: the stasis stage is longer the serum liver
enzymes decrease more slowly
Persisting forms: characteristic to HBV hepatitis they consist of extension of the
clinical, biochemical and serological alterations characteristic to the acute stage
for 7-8 months; the risk of chronic evolution is higher
The relapsing, recurrent forms: they are extended forms. A first episode and a
convalescence stage of 1-3 months are followed by recurrence of the initial
clinical and biological picture, with an overall evolution of up to 5 months.
o The frequency of this form is 10% in HAV hepatitis
o In HBV hepatitis it may be induced by corticotherapy, concomitant
disease, super infection with HDV
o When occurring with HDV-HBV coinfection it prompts evolution towards
rapid chronic evolution and cirrhosis
The fulminant form or massive liver necrosis is the most severe form of viral
hepatitis that accounts for most of the fatalities; it has a mortality rate of 80%.
Hepatic encephalopathy occurs within the first 8 weeks of disease or 2 weeks after
the onset of jaundice.
o It is not a frequent form but certain patients are at high risk:
Young and adult patients with HBV account for half of the cases of
fulminant hepatitis; the frequency is low, higher when HBV-HDV
confection or chronic hepatitis C are present
In pregnant women with HEV it can reach 20% as compared with

1-2% in the general population
It is rare in patients with HAV; it occurs mainly in elder patients or

in those chronically infected with HBV or HCV
Laboratory diagnostic
The positive diagnosis relies on complex laboratory investigations that reflect the pathology of
the disease:
Hepatic cytolysis:
o The increase in serum transaminases (AST, ALT) is frequently substantial
(20-30 fold), already in the prodromal stage and precedes the jaundice and
reverses gradually during convalescence; their levels do not correlate with the
severity of the hepatic injury
The biliary retention syndrome
o The serum bilirubin (both fractions) increases; jaundice can be observed
when it reaches 4-5 mg/dl
o Higher bilirubin levels (>20 mg/dl) that persist are correlating with severe
forms
209
The cholestatic syndrome is associated with significant increase in serum bilirubin;

the gammaglutamyltranspeptidase (GGT), alkaline phosphatase and cholesterol are
also increased in the serum
The hematologic syndrome:
o Leukopenia, lymphocytosis, neutropenia
The liver failure reflects severe hepatic injury and affects several liver functions:
o Synthesis of the serum proteins: their values decrease:
Prothrombin as reflected by the reduction of the prothrombin index

(PI), increase in INR; it is an early marker for severe prognosis and
anticipates the liver failure
Proconvertin
Christmas factor (IX)
o Detoxification: increase in serum ammonium

o Metabolic: decrease of bilirubin conjugation
Inflammatory syndrome:
o Increase of serum IgG, IgM
o Alteration of the albumin/globulin ratio
o Hipoalbuminemy and hypergammaglobulinemy due to chronic liver injury
The etiologic diagnostic oh viral hepatitis relies on viral markers and serologic tests.
Viral hepatitis A
The etiologic diagnostic is based on serology: IgM antiHAV antibodies are detectable since the
clinical onset and up to 3-6 months later; they signal acute or recent infection.
IgG antibodies signify residual immunity post infection or post vaccination,
HAV antigen can be detected in stools by immune electron microscopy or in serum by ELISA.
The virus can be cultivated and the viral RNA can be detected by RT-PCR but these techniques
are not used for the routine diagnostic.
Viral hepatitis B
(See serologic markers in HBV hepatitis)
Viral hepatitis C
The serologic diagnostic for HCV hepatitis consists of detecting anti-HCV antibodies with
generation I-III ELISA tests. No available serologic tests differentiate between acute and chronic
HCV infection. A significant limitation of these tests is caused by late seroconversion,
approximately 3 months after infection. The more recent generation tests are more sensitive than
the older ones.
HCV RNA in serum can be detected as early as a few days after infection and persists
indefinitely in chronic infections and 3-4 months in limited ones. The positive diagnostic of
HCV infection relies on a positive HCV RNA test and a serologic test (ELISA).
210
Viral hepatitis D
Serology: anti HDV IgM antibodies are detectable after the clinical onset and persist for along
time; they are followed by a serological window and then IgG antibodies.
Virological diagnostic consists of detecting Ag HDV in the serum by immunofluorescence the
second week after infection and during 3 weeks. HDV RNA can be detected in serum by PCR
and signifies viral replication and infectiveness.
Viral hepatitis E
The IgM anti-HEV antibodies appear 4 weeks after infection and persist for 3 month; their
detection signifies acute infection. The same is true for IgE anti-HEV antibodies.
Virological diagnostic is made by detecting HEV antigen in the serum and stools (although
shedding of virus in the stool is limited to a short period); the first viral marker to be detected is
HEV RNA and it persists for approx. 6 weeks.
Prognostic
Viral hepatitis A
The otherwise healthy patients that develop this form of disease recover completely with no
sequels. Elder age, preexisting chronic liver disease and hypo or agammaglobulinaemia are
predisposing factors for more severe evolution, with mortality of 0.1-1%, sometimes through
fulminant evolution.
Viral hepatitis B
The rate of complete recovery after the HBV infection is 95-99% in adults that are otherwise
healthy; it is estimated that only 1% of immune competent people do not eliminate the HBsAg
after an acute infection. Severe forms are more frequent in elderly patients and when other
pathology is associated: alcoholic liver disease, other chronic hepatopathies, and diabetes. The
mortality in HBV acute hepatitis is 1% and severe prognosis is announced by liver failure or
very high hepatic cytolysis.
Viral hepatitis C
The HCV acute hepatitis is milder than HBV hepatitis; asymptomatic and anicteric forms are
much more frequent but the chronic evolution is extremely frequent, 85-90%, and they lead to
cirrhosis in 50% of cases.
HBV-HDV coinfection
The mortality associated to this coinfection is not higher than that of HBV infection (5%) and the
risk of evolution to chronic infection is also low.
211
HDV super infection

As opposed to coinfection, the prognostic is poor due to mortality associated with fulminant
forms (20%) and a high risk of chronic evolution (80%). The evolution of the HBV infection is
more severe regardless of its stage at the time of super infection.
Viral hepatitis E
The prognostic is favorable, the disease is self-limited; pregnant women have, however, high
mortality risk (20%).
Complications
Rare complications:
o Pancreatitis
o Myocarditis
o Atypical pneumonia
o Aplastic anemia
o Transverse myelitis
o Peripheral neuropathy
o Encephalitis
o Vasculitis
o Interstitial nephritis
Bacterial infections, mainly after HAV hepatitis
Porphyria cutanea tarda, lichen planus especially after HCV infection
Chronic evolution
Hepatocellular carcinoma: the risk is high in patients with chronic infection since
childhood that have HBeAg or high viremias as measured by HBV DNA; the risk is
also high in patients with chronic (25-30 years) HCV infection and cirrhosis.
Autoimmune hepatitis with HAV, HBV and HCV hepatitis
Treatment
Acute hepatitis treatment is individualized according to the clinical form and the etiology, to the
associated pathology and possible hepatotoxic factors. Every acute hepatitis must be considered
seriously in the beginning and the treatment must be early; in self-limited forms treatment
consists of general measures and symptomatic and pathogenic therapy.
General measures
Hospitalization and isolation of patients with acute hepatitis during the first 2-3 weeks is
mandatory in Romania due to the complication potential and the transmission risk. Bed rest is
recommended during this time; regular physical activity is progressively introduced
subsequently.
A hypercaloric diet is recommended, ideally fractionate din 4-5 daily meals, and according to the
patients appetite and digestive tolerance; the main meals should be in the morning, during the
212
early stages of disease a diet rich in lacto-vegetarian diet is better tolerated but the diet will
become unrestricted afterwards with the exception of hepatotoxic agents (alcohol); hepatotoxic
drugs and those that are metabolized in the liver or are cholestatic are also to be avoided. The
patients with prolonged gastric intolerance who cannot feed orally most receive parenteral
support glucose and caloric supplements
Etiologic treatment is not generally recommended in acute hepatitis with the exception of cases
that are not selflimited thus being at risk for chronic evolution. There are studies that document
the usefulness of nucleoside analogues of reverse transcriptase in severe hepatitis with HBV and
monotherapy with alfa interferon in HCV hepatitis by inducing a sustained virologic response
and preventing chronic evolution.
The symptomatic medication includes:
Supportive treatment
Treatment of constipation and meteorism
Treatment of insomnia
Antiemetics
Treatment of dislypemia when chronic liver disease is associated
Hepatotropic agents: they have no proven effect on the clinical or virologic
recovery
Treatment of associated diseases (ulcer, gastritis, duodenitis, parasitosis,
nutritional disorders)
Choleretics, muscle relaxants, cholestyramine,
antihistamines in the cholestatic forms
ursodeoxycholic
acid,
Corticotherapy is not recommended during acute viral hepatitis because immune suppression
favors viral multiplication, persistent antigenemia and chronic evolution. It is indicated in
particular cases:
Severe cholestatic forms
Evolution with intense allergic phenomena
Treatment of hematologic complications
Severe, fulminant cases, when the prothrombin index is below 50% (there is no
consensus though)
The treatment of fulminant forms:

The main therapeutic goal is sustaining the vital functions while waiting for the hepatic
regeneration; therapeutic measures include:
Maintaining the hydro electrolyte and acid-base equilibrium
Correction of hypoglycemia
Correction of hiperammoniemia (diet without proteins, evacuator enema, nasal-gastric

aspiration, intestinal decontamination with nonabsorbable antibiotics rifaximine, and
nonabsorbable disaharids lactulose, colic recolonization with lactobacillus)
Control of the hemorrhagic syndrome (fresh plasma transfusion, platelets, K vitamin)
Treatment of the cerebral edema
Management of the renal failure

213
Prophylactic antibiotherapy and the treatment of the associated bacterial infections
Corticotherapy - useful only in the early stages of liver failure
Orthotopic liver transplant with good results
Other radical (and costly) therapeutic measures did not prove their efficacy in improving
the survival rate. Among these, hemoperfusion, extracorporeal circulation,
plasmapheresis
Prophylaxis
Unspecific measures
For enteral hepatitis: improving personal hygiene, correct treatment, transport

and storage of food and water, correct neutralization of waste
For parenteral hepatitis: correct sterilization of surgical and medical

equipment, rigorous control of transfusion blood, the use of single use syringes
and needles, observing the universal protection rules, avoidance medical
maneuvers with infective risk, prophylaxis of the sexual transmission
Specific measures:
Passive prophylaxis with immune globulins

o HAV specific human Ig or standard human Ig for HAV hepatitis prophylaxis in
persons travelling to endemic regions or during the first days after infecting
contact
o HBV specific Ig in newborns with HBV positive mothers or after professional
exposure of the medical personnel
Active prophylaxis:
o HAV vaccination with highly immunogenic inactivated virus
o HBV vaccination recombinant vaccines with very good efficacy; they induce
anti-HBs antibodies
214
CHAPTER 7
Sepsis
Brndua ilea
Definition
Septicemia is a disease caused by various etiologic agents which have an evolution that involves
fever without any tendency to withdraw, while its severity is progressive and the the clinical
manifestation are amplified and complicated, with an important lethal risk.
The classical acception of systemic bacterial infections, the following steps are defining:
1. The entry gate for a pathogen agent (skin, respiratory, digestive, etc..)
2. Establishment of an initial foci - the place, often located near the entrance gate, where
the pathogen multiplies in the body and from where it disseminates in the body with
its exo and endotoxins.
3. Hematogenous dissemination - the germs start from the primary foci and spread in
various other places in the body. It is an essential step and at the same time, the main
manifestation of the disease, being maintained through participation and secondary
foci;
4. Formation of septic metastatic foci secondary to grafting germs involved in
circulation. These secondary foci, originating in the embolized vascular wall will
remain connected with the vessel, in this way they will continue to introduce new
quantities of germs in circulation. The secondary foci maintain and amplify the
presence of germs in the blood.
The existence of septic metastatic foci, differentiates septicemia from bacteremia (simply
discharging the germs from the entry gate or from the primary foci without repercussions in
terms of the illness progress);
5. seriously impairing the patients status by two major consequences:
participation in the clinical manifestations, in addition to systemic

inflammatory response syndrome (SIRS), of signs and symptoms of many
organ systems affected directly (metastatic) or indirectly, with their
characteristic clinical manifestations;
functional impairment of the affected organs and systems due to major

imbalances of homeostasis, which can lead to onset of defense reactions that
can evolve to the stage of shock, disseminated intravascular coagulation
(DIC), MSOF ("Multiple System and Organ Failure" - defined as Multi or
multisystem failure) and death.
The authors tend to simplify the concept, proposing the term "sepsis" for all situations of
uncontrolled infection by defense mechanisms of the body, these carrying the same risk factor in
terms of evolution.
During amplification several developmental stages can be detected:
SIRS (Systemic Inflammatory Response Syndrome) There are four criteria:
215
fever> 38.5 C or hypothermia <35.5 C;
tachycardia> 90 / min.
tachypnea> 20/min.
leukocytosis> 12000/mm 3 or leukopenia <4000/mm 3 or> 10% segmented neutrophils

(fig. 1)
Infection/Trauma (SIRS)
Sepsis
Severe Sepsis
Systemic Inflammatory Response Syndrome which includes more than 2 of following

criteria:
fever> 38.5 C or hypothermia <35.5 C;
tachycardia> 90 / min.
tachypnea> 20/min.
leukocytosis> 12000/mm 3 or leukopenia <4000/mm 3 or> 10% segmented

neutrophils
Fig. 1 - Systemic Inflammatory Response Syndrome (SIRS) definition
Sepsis is defined as SIRS occurred in the context of infection, the defining criteria are valid for
SIRS plus clinical evidence of infection. (Fig. 2)
Infection/Trauma
Sepsis
Severe sepsis
SIRS
SIRS with infection
process confirmed or suspected
Fig. 2 - Sepsis, definition
Severe sepsis is defined as sepsis plus one of the following criteria:
hypoxemia defined as PCO2 / FiO2 <280 intubated patient as PAO2 <75mmHg or the
need to administer an anesthetic gas containing more than 40% O2 artificially ventilated
patient
oliguria - diuresis <480ml/day or <20 ml / h
metabolic acidosis - pH <7.20 or lactic acid ic> 1.5 mmol / l
acute encephalopathy with deteriorating mental status
peripheral vascular resistance <800dyne x sec x cm -5
hypotension with systolic BP <90 mmHg

216
haemostatic disorder as defined by the concentration of PT <30% or a decrease in the

number of platelets under 100.000/mm3 or more than 40% of the value of the previous
day (Fig. 3)
Infection/Trauma
Sepsis
Severe sepsis
SIRS
SEPSIS with one or
more organ impairment:
cardiovascular
renal
respiratory
liver
haematologic
CNS
Metabolic acidosis
SHOCK
Refractory hipotension
Fig. 3 - severe sepsis definition
Septic shock is considered a special case in severe sepsis, having as a criteria for defining
those described above.
The criteria used to define various organ deficiencies are those proposed by Knaus (see
Table XXIV)
Insufficient organ
Criteria for defining
Cardiovascular
AV <55/min
BP <80mmHg
tachycardia or recent atrial fibrillation
pH <7.25 with PaCO2 <50mmHg
Respiratory
respiratory rate <5/min or> 50/min

paCO2> 50/mmHg
alveolar-arterial differences O2 > 350mmHg
ventilator dependence> 24 hours
Renal
creatinine> 3.5 mg%

urea> 120mg%
Diuresis <480ml/zi or <20 ml / h
Hematologic
WBC <1000/mm 3
HT <20%
PLT <20.000/mm 3
217
SNC
GCS <6 in the absence of sedation
Hepatic
HP <15% with factor V <40%

total bilirubin> 6 mg%
Table 1 - Knaus criteria of organ failure
Disseminated intravascular coagulation syndrome - CID (not necessarily enroll in clinical

shock can occur outside or before the phenomena of shock);
Multiple systemic organ failure (MSOF) is interpreted as critical stage consecutive to

major disturbances in circulatory and metabolic shock, and it is defined in the presence
of signs of decompensation of at least three major systems or vital organs:
- cardio, respiratory, excretory, hematopoietic, hepatic, cerebral.
Epidemiology
Although the incidence of severe systemic infections might be expected to decrease due to
improvement of preventive measures and of potentially active therapy in localized infections,
such tendency is not however evident. On the contrary in the U.S. an increase with 39%. in the
incidence of severe sepsis in 2000 compared to 1990. Some of the major causes of this
phenomenon are:
the increase of the capacity of SIRS etiological identification
the increase of immunocompromised persons likely to develop sepsis
increased invasiveness of medical practice through the development of new diagnostic

and therapeutic methods that favor production of bacteremia and sepsis as well.
the acute microbial aggressiveness of parallel to etiological involvement of multiresistant

germs to antibiotics.
Currently in the U.S., are reported over 750,000 cases of sepsis annually, every day 500
patients die from sepsis. The average age is around 58, and considering gender men are more
often affected. (Fig. 4)
Fig. 4 - The incidence of sepsis in the U.S.

group sex
Etiology
The etiological palette is large (fig. 5). Interestingly, not every germ can cause a sepsis. From
this point of view, both in the classical perspective but especially the current view states that
when defense capabilities are normal the fatal septicemic infection are unlikely to occur:
218
the germs with good antigen ability are capable to determine the formation of protective
antibodies (in such a context the development will be self-limiting, even in the presence
of bacteremia stages or in the case of secondary metastasis the case of Salmonellelor
Typhi and Paratyphi that develops typhoid fever).
germs deprived of invasive capacity (Clostridium tetani, botulinum, diphtheria bacillus).
Fig. 5 - etiological agents incriminated in sepsis in the U.S.

Major immunological deficiency eradicates both groups, the first group by the inability to
develop antibodies, and the second one by creating favorable conditions to overcome local
barriers.
Throughout the historical development of therapeutic possibilities, especially recorded in
the last century, a significant change in the etiologic spectrum of sepsis was noted (see table
below).
Germ
Romania
Gram negative bacilli
42%
Enterobacteria
29.5%
Pseudomonas
10.04%
Bacteroides fragilis
0.91%
Other GNB
Gram positive cocci
56%
28.76%
Staphylococcus albus
12.32%
Streptococcus viridans
4.5%
Pneumococcus
4.5%
Enterococci
5.02%
Other Gram-positive cocci
1.76%
Fungi
2%
Polymicrobial infections
Table II - The etiology of systemic bacterial infections in Romania

New ethiopatogenic types are signaled nowadays:
219
"Catheter" sepsis, especially caused by "hospital" germs, pluriresistent to antibiotics

(staphylococci, gram-negative bacilli as Proteus and Pseudomonas, Acinetobacter fungi
etc.).
sepsis in iv drug addicts with opportunistic germs mostly of the saprophyte germs
(Staphylococcus epidermidis, corynebacteria) or intestinal bacteria;
sepsis due to immuno-depressed patients (transplant surgery, cancer, autoimmune

diseases) with an extremely wide range from germs non-pathogenic germs to
pluriresistant selected germs;
sepsis favored by the existence of prothesis or other prosthetic devices, especially

vascular on which germs are grafted as a primary foci that cannot be sterilised - usually
non-pathogenic and conditionally pathogenic germs;
Pathogenesis
Specific key stages in the evolution of sepsis are evident from its definition:
The entry gate of the germ functions as a primary pathogen, its identification therefore,
represents a diagnostic with an indicative value, even retroactively: based on the location and the
conditions in which the infection occurs certain etiologies can be detected. For example, the skin
entry gate suggests the involvement of staphylococci, genitourinary location - aerobic Gramnegative bacilli or enterococci, a genital entry gate especially in the case of a septic abortion,
towards the aerobic and anaerobic germs, etc..
Primary septic sites
Primary infection sites are usually located in close proximity to the entry gate (in case of
soft tissue phlegmon subsequent to infected penetrating wounds of limbs, the case of parametritis
formed after postabortum endometritis etc.) or in its vicinity on the lymph circuit
(adenophlegmon satellites of entry gate ).
Dissemination of germs from the primary septic site is possible in several ways:
by erosion of the walls of small veins trapped in the focus of inflammation, thrombosis at
that level, directly exposed to germs (staphylococci secret coagulase) or by means of
other local mechanisms, infected thrombi detach intermittently and being spread in the
general circulation will embolize distantly usually at the level of vascular bifurcation in
the systemic circulation or in the pulmonary vascular circulation.
primitive lymphatic
adenophlegmons);
through depleted circulating macro-and microphage. These cells incorporate germs for
phagocitosis but they are unable to perform the germs lysis due to the depletion of
lysosomes or the required energy resources so that once entering circulation, they will
end up releasing the viable germs in other places outside the primary infection site
(process revealed in staphylococci).
path
and
subsequently
hematogenous
(in
the
case
of
Secondary metastases formation, marks, as maintained dissemination, completion of

clinical, morphological and functional aspects of sepsis.
Remaining at the predominant model of septic emboli, the place where they stop,
vascular intima is eroding under direct action of germs, they become located at the level of
vascular wall thickness and within hours an adventicial abscess develops, the first form of the
new septic focus. These are quickly formed, maintaining regular contact with drainage vessel
that will discharge, in turn, further amounts of germs.
220
The most affected site in metastasis is the lung (clinically manifest in over 40-60% of
cases) because the alveolar capillary network, is a veritable "filter" in the way of septic thrombi.
The prevalence and dissemination of secondary sites in the body, affecting the viscera including meningocerebral and soft parts of the body the clinical manifestations worsen.
The classic authors maintain that in case of sepsis an important role is played by the defense
capacity of the body. Thus it is stated that:
people with a very good defense capability neutralize infection even in the initial stages;
people with a low capacity for defense evolve to septic shock and death, without clinical
manifestations of sepsis, the fulminant infection evolving rapidly.
The inflammatory syndrome is triggered by a series of mechanisms that are activated in a

cascade, involving as key step, the macrophage system (the current name for reticuloendothelial
system). Mechanisms of the systemic inflammatory response (SIR) are complex and subject to a
good defense capability of the host. (Table XXVI presents the main mediators of inflammation).
MEDIATOR
ORIGINS
EFFECTS
macrophage
TNF
IL 1
IL 2
IL 6
leukotrienes
lipoprotein
inhibitors
T lymphocytes, Nk
hipercatabolism
neutrophils
pyrogenic effect
endothelial cells
antitumor
lymphocyte proliferation
T, B and Nk
receptors stimulate the

production of IL 2
the
most
pyrogenic
Increases the secretion of

antibodies
auto-positive feedback
stimulating macrophage
B and T lymphocyte
stimulation
pyrogenic effect
synthesis of acute phase

reactants
Increased
pulmonary
vascular resistance
involved in the genesis of

acute respiratory distress
lymphocyte
macrophage
T lymphocyte
macrophage
T lymphocyte
arachidonic acid
221
lipase
important
syndrome
PGI2
(Prostacyclin)
TxA2
(Thromboxane)
arachidonic acid
arachidonic acid
PAF
platelets
(Platelet-activating
factor)
macrophages
interferon
T lymphocyte
collagen defect
free radical
granulocytes
vasodilation
antiplatelet
PGI2 antagonist
endothelials
Fibronectin
Endorphins
activation
aggregation
platelet
macrophage activation
increased
permeability
increased
pulmonary
vascular resistance
neutrophil degranulation
Macrophag activation
Nk activation
increases synthesis of IL
1 and TNF-
Low-swelling
toxic bacterial
toxic cell
Increased
permeability
capillary
capillary
Table III - Best known mediators of inflammation

Dinarello managed to create an indicative chart of the stages of these mechanisms. The
essential role is performed by the release - from activated macrophages, of two mediators Interleukin 1 and Tumor Necrosis Factor - alpha, these activate the hypothalamic
thermoregulation center, with the production of fever (and chills, sweating, etc..), which insures
the discharge of young, potent, neutrophils, and stimulate thereafter processes of phagocytosis,
stimulates fibroblasts cells and histiocytic cells towards collagen deposits. Repairing and barrier
is their role, also they develop acidosis - a new resource that provides energy to heart and liver both having a crucial role in defense, they stimulate hepatic release of Acute phase proteins
(different glycoproteins having a role in triggering complement activation via the alternative C3),
they stimulate T and B lymphocytes to release lymphokines and specific antibodies. (Fig. 6)
222
Microorganisms Immune Complexes Bacterial products Tissular lessions Inflammatory

processes Toxines : Macrophage activation syndrome
Interleukina 1 and T.N.F.-alfa
Hypotalamus - fever
Bone marrow leucocitosis with neutrophilia
Neutrophilis - activates phagocytosis
Fibroblasts - collagen deposits
Muscles acidosis
Liver alfa and beta globulines and reactive protein C
Limphocites lymphokines, antibodies
Fig. 6 - Mechanisms involved in sepsis
In addition, especially in severe cases, the following have been identified:
secondary triggering of activation cascade of vasoactive mediators (kinins, serotonin,

protein P) which would determine the evolution towards shock;
triggering the coagulation cascade - by means of factor XII (Hagemann), which may
involve the triggering of DIC;
at the level of vascular endothelium directly assaulted (the action of germs and their
endotoxins) or indirectly, a large amount of nitric oxide will be released (NO) with
negative consequences on circulatory equilibrium (leading to vasoplegia, hiperpermeability leakage of capillary fluid in the tissues) and evolution towards shock.
What is commonly referred to as incubation, considered to be the time spent between the
existence of the entry gate and the first general manifestations, is not precise because sepsis is
not a self-limiting cyclic model of evolution.
Depending on the size of the inoculum and pathogenicity germ, and the ability of the
body's defense, this interval can be of 1-2 days or weeks - months. The shortest incubation were
found in cases with genital entry gate because of septic endometritis postabortion caused
empirically by ingestion of various toxic substances or by the introduction of irritating materials
in the cervix. Extensive local necrosis allows a large area of the entry gate and high
pathogenicity - usually by bacterial association. Meanwhile, the bodies of young women in
question have the capacity to fight the infection so that the inflammatory syndrome is intense and
fast.
The onset is often sudden, with fever, chills, heat curve and may take different aspects
the septic type with large vesperal oscillations, - intermittent type, with unregulated variations
every hour or daily (known as "irregular fever ") can apparently become steady "the plateau
stage "- especially in cases of osteoarthritis or metastatic pleural empyema etc.
Other elements are added to the previous ones:
localized inflammatory events of the metastatic foci - most commonly by hematogenous

bronchopneumonia respiratory syndrome (frequent cough, dyspnea, sometimes stabbing,
cyanosis) or osteoarticular (early for staphylococcal septicemia). The septic emboli or
223
pustular skin aspect or thrombohaemorrhagic, disseminated on the trunk, especially the

limbs (fingers, palms and plants ventral faces) have a high diagnostic relevance.
significant deterioration of general condition - fatigue, indefinite malaise, headache, chest

pain, nausea, loss of appetite, vomiting, restlessness, psychomotor agitation.
Physical examination on appliances, shows the following symptoms:
Skin: various rashes appear on the skin (macules, petechiae, bleeding blisters) of the
embolic type or painless nodules in the extremities (Osler nodes). Often the appearance is
pale or Teros due to vasoconstriction and anemia.
Respiratory tachypnea, nasal wings beat, cyanosis of the extremities, bronchopneumonia

(septic pulmonary metastases).
Cardiovascular: tachycardia, hypotension, cardiorespiratory failure, collapse, forming

part of the picture of endotoxin septic shock, frequently determined by Gram-negative
bacilli; atrio ventricular conduction block, varying degrees of AV block, cardiocirculatory failure.
Sometimes there are local signs of vascular type (superficial thrombophlebitis with
inflammatory edema, rarely large arterial embolism with acute peripheral ischemia syndrome;
Digestive: hepatosplenomegaly, jaundice with toxic hemolysis;
Urinary: dimished urinary secretion, macroscopic hematuria,

glomerulonephritis cilindrurie to acute tubular damage and AKI;
Neurological: may reveal stiff neck or signs of advanced meningeal irritation, inequalities
of tendon reflexes and skin hypotony or isolated paresis, tremor, lack of coordination,
focal neurological signs (microbial embolism) there may be visible signs of encephalitis
(sleepiness or agitation, delirium, etc..).
albuminuria,
Laboratory data usually confirm:
The existence of inflammatory syndrome with accelerated ESR (over 100mm/hour) with
leukocytosis and neutrophilia - but leukopenia with neutropenia combination is common,
either due to lack of reactivity, or due to Gram-negative bacilli, leukopenia being the
expression of a toxic bone marrow inhibition. All other tests for inflammation show
much altered data (C-reactive protein, fibrinemia etc.).
significant anemia by marrow inhibition and therefore hipo-regenerative at recovery

attempts by iron and folic acid or vit. B12;
platelet count is usually very high (infectious thrombocytosis) may exceed

600.000/mmc), but can be much reduced by inhibiting bone marrow toxicity or advanced
cases the DIC;
decompensation of nitrogen balance with constant hyperazotaemia most often by

decreasing renal irrigation and filtration fraction but by nectrotico-inflammatory lesions
and massive release of protein catabolism. When renal impairment is associated the
serum creatinine increases;
constant acid-base decompensation, often towards metabolic acidosis, compensated,

subsequent to diffuse cellular damage with release out of the cell of acid radicals and
deviation of cellular combustion to anaerobic model with release of Tricarboxylic acids lactic and pyruvic.
224
transient hyperglycemia spontaneously reversible by improving biological condition. It

can be explained by releasing additional glucose in the adaptive response (via
glycogenolysis and neoglucogenesis) and by decreasing peripheral consumption rate due
to the fact that the body's cells when pressured (hypoxic, toxic bacterial or endogenous
etc.) can not incorporate glucose and no longer consume it as such; spontaneous
remission of hyperglycemia is the most reliable sign of cellular metabolism remission,
with particular prognostic value;
electrolyte imbalance - sometimes related to fluid retention.
Clinical Forms
From an evolutionary standpoint, there are supraacute forms rapidly evolving to
infectious shock and death within a few days of onset, acute forms (most of them) described
above, and subacute forms, metastatic manifestations being predominant.
Clinical types in terms of etiology and entry gate.
1. Skin sepsis with skin as entry gate is in most cases of staphylococcal etiology (staph
pathogen, aureus, hemolytic coagulase-positive or, more rarely, with pathogenic
staphylococci, coagulase-negative). This type is among the most severe because of
high pathogenicity (rapidly invasive embolizing germ, toxigenic, causing thrombosis,
with tissular destructive-necrotic action) (Fig. 7). It presents two clinical features that
allow etiologic diagnosis:
Early osteoarticular impairment (with osteomyelitis and septic arthritis);
bronchopneumonia with particular radiological aspect (necrotic foci and

pneumonia, "honeycomb radiological aspect").
Fig. 7 Clinical impact of microthrombosis in sepsis

The evolution is severe one of the highest mortality rate and significant risk of endocardial and
osteoarticular sequelae.
2. Sepsis with visceral entry gate
The first are genital sepsis (postabortum, postpartum), often associated with aerobic and
anaerobic bacteria, but also monoetiological type (staphylococci, Gram negative bacilli, isolated
anaerobes). They are considered among the most severe on the grounds already mentioned:
large area of the entry gate;
rapid damage of parameters without surgical drainage conditions of primary infectious

site (simple evacuation of endometrial debris does not solve the issue);
225
local high toxicity (frequently evolving to uterine necrosis) and general toxicity;
high mortality index.
Urinary sepsis (urosepsis) - can be spontaneous, but more often occurs after ureterobladder instrumental explorations. The main cause are - Gram negative bacilli: Escherichia coli,
Enterobacter, Proteus, Pseudomonas. They frequently occur as a complication of diseases
resulting from prolonged immobilization.
Surgical sepsis it is rare, it is a cause of various complications due to digestive, genital
or cardiovascular interventions especially. It is usually monoetiologic with acute or subacute
development due to the normal practice of post-operative prophylactic antibiotic.
A special category is sepsis contracted in ICU services (post intubation maneuvers, vascular or
urinary catheterization, etc..) extremely severe, because of puriresistant germs to antibiotic
treatment.
Evolution and prognosis
In the absence of therapy, fatal sepsis evolves lethally in over 85-90% of cases.
Spontaneous healing is possible, in some cases, but not without sequelae.
Under complex treatment lethality has decreased around 14-17%, and in the personal
research mentioned above, we calculated a mortality rate of only 9.7% in the group of 327 adult
septicemia.
Lethality is higher at extreme ages (over 50-60%), in persons with immune deficiency
and in the cases presented or diagnosed too late. Mortality may also vary depending on the
etiology, it is higher in the case of Gram negative bacilli and sometimes Staph.
Diagnosis
There are two stages of diagnosis:
positive and differential diagnosis of the disease;
etiological diagnosis.
Positive diagnosis is easy when there is a full clinical picture but it may be more difficult
to establish in cases with subacute evolution or in a very early stage, before they show signs of
metastatic impairment.
Differential diagnosis requires the removal:
of other causes of high and persistent fever - typhoid fever, pneumonia, viral diseases
(complicated influenza) system diseases (collagen), lymphocyte and myeloproliferative
syndromes, neoplasms with fever, suppuration (abdominal, perirenal, pelvic), deep pelvic and
cerebral thrombophlebitis etc.
Etiologic diagnosis
It is an absolute must.
Guidance - but with great value in the choice of first-line therapy, the diagnosis has to
consider:
location of the entry gate;
the condition in which the infection was contracted (in the hospital ICU ward, or
community - ie outpatient, home);
226
existence of intensely debilitating diseases;
location of private septic metastases (for staphylococcal osteoarthritis) or suggestive

aspect (in case of hemorrhagic-necrotic cutaneous palmar-plantar, staphylococcal
embolism).
Etiologic diagnosis of certainty is provided by bacteriological investigations.
In order to isolate the causative agent as early as possible and - especially before the introduction
of antibiotic treatment the following procedures are required:
blood cultures (2-4) on aerobic, anaerobic, fungi medium;
cultures (aerobic and anaerobic) from the primary foci and metastatic foci, if possible;
cultures, smears from the entry gate.
Coefficient of certainty is greater if the same germ is isolated from several cultures or if
the isolated germ comes from closed hematogenous foci.
After isolation and identification of the germ, antibiotics will be used for susceptibility to
antibiotics testing, both normal and backup by antibiograms and determination of MICs against
selected preparations.
Rapid methods of diagnosis:
a. capsular antigen determination by agglutination - Latex, counterimunelectrophoresis (for
Meningococcal, Pneumococcal H influenzae, cryptococcal)
b. determination of bacterial DNA by gene amplification methods (PCR)
c. determination of serum levels of procalcitonin, E-selectin, C-reactive protein
d. determining of the level of CD10 -which decreases in bacterial infections.
Treatment
Perhaps more than in other situations, a complex treatment is urgently required (etiologic,
pathogenetic rebalancing, symptomatic and hygienic-dietary treatment).
1. Etiological therapy, involves two steps:
First-line therapy - until etiology is confirmed:

- etiological indicative criteria will be considered;
- complementary and synergic combinations of 2 or 3 antibiotics in terms of the
spectrum;
- the route of administration will be, whenever possible, parenteral- especially IV
bolus - to ensure peak concentrations which will lead to high tissular concentrations.
The choice of antibiotic preparations should consider the following:
- etiological probability;
- statistical probability of the alleged germ sensitivity;
- bioavailability able to ensure effective concentrations in all tissular locations;
- the absence of contraindications due to sensitivity or other circumstances;
- lower toxicity per dose;
- availability for a lasting cure;
227
- few drug incompatibilities;

- affordable price to provide therapy for the duration required.
The entry gate
Germs covered
First-line antibiotics
Cutaneous
Staphylococcus aureus, group Penicillin G+Metronidazole AMG

A streptococci, anaerobic cocci (or Imipenem - cilastatin)
Urinary
BGN (Enterobacteriaceae)
Pulmonary
Pneumoniae, H influenzae, Aminopenicillin / Ceftriaxone

Mycoplasma Legionella
macrolide (or FQN)
Digestive
BGN / anaerobic / enterococci
Tazocilin or Carbapenem AMG
Genital
Streptococcus
B/BGN/anaerobic
Ceftriaxone+AMG+Metronidazole
Ceftriaxone + AMG or FQN

+
Ceftazidime+FQN+Metronidazole
Table IV - empirical therapy in community systemic infections

The entry gate
Germs covered
Cutaneous
Methyl-R
Staphylococcus, Vancomycin and cefepime + AMG
Pseudomonas, other BGN
or FQN
Central
catheter
venous
First-line antibiotics
White Staphylococcus BGN
Vancomycin-4G
Amphotericin B
C3
Digestive Surgery
Tienam (antibiotic antipiocianic +

Enterobacteria / Bacillus fragilis
AMG
+
Metronidazole)
/ Pseudomonas / Candida
Fluconazole
Artificial
ventilation
Pseudomonas, other
Staphylococcus
Urinary
BGN including Pseudomonas /

BL antipiocianic + AMG
enterococcus
BGN,
Carbapenem + Vancomycin
Table V - empirical therapy of nosocomial infections

Affection
Germ covered
First-line antibiotic
Agranulocytosis
Pseudomonas / Staphylococcus C4G + Vancomycin

/ enterococci
Splenectomy
Pneumococcus / H influenzae
Ceftriaxone AMG
Multiple Myeloma
Pneumococcus
Aminopenicillin / Vancomycin
Iv Addiction
Staphylococcus / Pseudomonas Imipenem + fluconazole

/ Candida
Alcoholism
Pneumococcus / Klebsiella
C3G
HIV
Pneumococcus / Salmonella
Carbapenem C4G
228
Table VI - Antibacterial treatment correlated with the context

Etiology
Scheme of choice
Alternative therapeutic
The native valve
Amoxicylin/C3G + AMG
Vancomycin + AMG
The prosthetic
Vancomycin + AMG
AMG + vancomycin + rifampicin
Table VII Treatment of endocardial impairment

Finding germs sensitivity will allow both possible correction formula antibiotics and
possible dose adjustment necessary after MIC determination to selected antibiotics.
Duration of antibiotic administration is adapted to the evolution of each case, between

14-21 days, depending on clinical status and laboratory data but it can be longer in case
of valvular or bone damage (weeks, months).
Control of therapeutic efficacy based on clinical and laboratory arguments.

Clinical arguments :
a)
remission of fever. Persistence of fever over seven days under treatment tested in vitro, for
sensitivity of the germ in question may have several explanations:
the existence of remaining undrained septic foci. Evacuation of pus or serous exudate
will cause significant reduction of fever;
the existence of non-immobilised septic arthritis (fever disappears after immobilization);
b)
remission of general condition and symptoms and of other elements characteristic to
systemic inflammatory response.
Laboratory:
a)
remission of modified biological constants;
b)
checking the inhibitory efficiency level (IEL) or bactericidal level (IEB) in serum under
treatment.
Any amount of IEL of at least 8 offers therapeutical certainty (considering that it will be
able to provide effective concentrations in affected tissues, where the concentration is usually
lower than serum).
2. Pathogenetic therapy involves several aspects:
Ensuring the monitoring of vital functions in an ICU ward, knowing that the patients in a
state of severe sepsis syndrome can easily develop severe septic shock or MSOF
syndrome. Attention will be paid to balance the level of electrolytes, acid-base, and
nitrogen homeostasis;
in the presence of febrile curve of sensitivity or in situations of intense inflammatory

cerebral or pulmonary edema, inflammatory corticosteroid therapy has proven effective
under the protection of antibiotics, short episodes of 4-7 days - as appropriate;
anticoagulation may be used in case of evoluion towards DIC.
3. Other useful therapeutic measures:

229
surgical drainage of primary or secondary purulent collections (including evacuation

serous exudates);
immobilisation of affected joints in manifest inflammatory process;
nonspecific increase resistance by intake of vitamins, calcium therapy, anabolic synthesis

and, especially in children and in cases of immunosuppression, immunoglobulin iv
infusion repeated every 3-5 days (multiple doses).
4. Hygienic-dietary therapy include:
providing bed rest;
ensuring the insulation;
diet will vary according to digestive tolerance, fluid and calories needed, depending on
the patient's age and fever;
control and maintenance of hygiene at the level of skin and mucous membranes, urinary
wells and transcutaneous venous lines etc.
Prophylaxis
The proper treatment of small wounds or infections of the skin and mucous membranes
mean prevention of sepsis. Basically, there are several possibilities:
health education of the population, in schools and youth communities towards:
- Visiting the doctor at the first small signs of local infection or signs of disease in the already
complicated situations;
- Counteracting the tendency to solve empirical localized infections (manual manouvres of
collections);
- Ensure asepsis and antisepsis, especially for people who manage medication (insulin-dependent
diabetes) or iv drug (increasing frequency situation in our country);
- Antibiotic prophylaxis in case of interventions with bleeding risk and bacteremia (dental
uterine curettage), especially in individuals at risk (valvular, cirrhotic, ethylic, splenectomised).
Administration will begin 12 hours before intervention and will be continued at least 2-3 days
afterwards;
References
1. Bartlett J. Pocket Book of Infectious Disease Therapy. Lippincott Williams &
Wilkins, 2007;120-240.
2. Bearden A, Safdar N. Prevention and Management of Health Care-Associated
Infections.Infectious Disease Special Edition. 2009; 12: 67-83.
3. Benea EO, Popescu C, Popescu G. Ghidul Angelescu. Terapie antimicrobian, 2004;
29-133.
4. Cohen J, Opal SM, Powderly WG. Infectious Diseases, 3rd Edition, vol I, 2010,
478-491
5. Chiotan M. Boli infecioase. Ed. Naional, 2002; 149-200.
6. Gilberd D, Moellering R, Eliopoulos G, Sande MA. The Sanford Guide to
Antimicrobial Therapy 37th ed. 2007; 167-190.
230
7. Gopa B Green, Ian S Harris, Grace Lin. Manual de terapeutic medical

WashinghtonTM. Lippincott Williams & Wilkins, Ed. Medical, Ediia 31, 2006; 358399.
8. Popescu C, Popescu GA. Sepsis. Actualiti i controverse. Ed. Ager Press,
Bucureti, 2002;100-130.
9. Rubin HR, Hirsch HH, Marty FM, Fisher RA. Cyomegalovirus Infection and Disease in
the New Era of Immunosuppression Following Solid Organ Transplantation.
Transplant Infectious Disease. 2009; 11(3):195-200.
10. Streinu Cercel A. Boli infeciose. Note de curs pentru studeni i medici
practicieni. Ed.Sigma, 2004; 80-120.
11. Torok E, Moran ED, Cooke F. Oxford Handbook of Infectious Diseases and
Microbiology, Oxford Univ. Press, 2009; 64-147.
231
CHAPTER 8
INFECTION WITH THE HUMAN IMMUNODEFICIENCY VIRUS HIV
(HIV)
Carmen Chiriac
The acquired imunodeficiency syndrome (AIDS), consequence of the infection with HIV, has
been recognized in USA in 1981, when CDC reported 5 cases of pneumonia with Pneumocystis
jiroveci (carinii) diagnosed in homosexual patients (from Los Angeles) and 26 patients with
Kaposi sarcoma associated or not with pneumonia, in New York and Los Angeles. Subsequently,
similar cases have been reported in intravenous drug users, recipients of blood transfusions,
hemophiliacs.
Etiology
Human imunodeficiency virus (HIV) belongs to the Retroviridae family. Viruses belonging to
retroviruses, are defined by their way of replication: the reverse transcriptase enzyme
retranscribes the viral RNA into proviral DNA. According to the retroviruses pathogenesis we
may distinguish three subfamilies:
1. Oncoviruses: are the most widespread retroviruses, associated with tumors and
leukemias: HTLV1, HTLV2 (Human T-Cell Leukemia Virus)
2. Lentiviruses: are viruses which cause diseases with a lent evolution, pneumoniae,
neurological disorders and they are cythopathogenic in culture. HIV1 and HIV2
(Human Immunodeficiency Virus) belong to this subfamily. These two types of
viruses have been identified in 1983, respectively in 1986.
3. Spumaviruses: identified in numerous mammals but non-associated with a known
pathology, either in animals, or in human.
HIV Target Cells. Cells that have on their surface the CD4 receptor and one of the co-receptors
(CCR5, CXCR4).
-
T Lymphocytes helper CD4
Monocytes, macrophages
Follicular dendritic cells
Brain microglial cells
Langerhans cells
Genetic Variability of HIV

HIVs origin is 650 years old, the origin of HIV-1-2 jointly with SIV-1 (Cercopithecus monkey).
The genetic organization of HIV +, HIV+2 and SIV is similar.
Based on the genetic modifications between the isolated strains of HIV+1 from HIV1 patients,
they are classified in three distinct groups: M,N,O and P.
Group M (major) regroups 9 subtypes of HIV-1: A-D,F-H,J-K
Group O (outlier) identified in Cameroon, Gabon
232
Group N 5 cases in Cameroon

Group P
HIV2 is widespread mostly in West Africa, Angola, Mozambique, Portugal, France etc.
Geographical distribution of HIV subtypes
-
Africa: all HIV-1 subtypes are spread
Europe: predominates HIV-1B (in the Western and Southern Europe);
Eastern Europe: HIV 1 type G (Russia);
Romania: HIV 1 F
America: HIV 1 B less subtypes A, C
Asia: HIV 1 C, B, E
Epidemiology
1981 first AIDS case USA
1959 first serologic test which marks out antibody and HIV human serum in a patient
from Congo-Zair
1972 cases diagnosed with HIV infection in Uganda, Malawi
The first case of HIV infection reported in Europe was a Norwegian sailor infected
probably in 1966, deceased in 1976.
In Romania, the first AIDS case in adults has been diagnosed in 1985, in children in
1989.
Epidemiologic Process
1. Source of infection: persons infected with HIV
2. Modes of transmission of HIV infection
a). The sexual transmission of HIV is predominantly transmission rout worldwide.HIV is
transmitted by both heterosexual and homosexual contact. High viral concentrations are
found in blood and semen, in infected mononuclear cells or in free form. The virus
focuses in the semen due to certain genital infections, the number of leukocytes and
monocytes is high (sexually transmitted diseases). HIV has been demonstrated in vaginal
fluids also. There are a series of factors that favour the sexual transmission: lesions of
mucouses, of tegument. The risk of sexual transmission is significantly higher if the HIVseropositive partner is in an advanced stage of immunodeficiency.
b). Transmission by blood and blood products: HIV is transmitted by blood ,blood
products or transplanted tissue. Intravenous drug users, hemophiliacs, contaminated
blood recipients, medical staff, the tattoos and piercing consumers are exposed. Drug
users are exposed to HIV infection under the conditions in which drugs are administered
parenterally (intravenous, intramuscular,,muscling,, or subcutaneous,skin popping,,), the
risk grows proportionally with the injection duration, the number of partners with which
is made the exchange of accessories (syringes, needles, water in which drugs are
dissolved, filter).
The transmission of HIV via blood and blood products has been reduced on a global
scale.All blood donors are tested for HIV-1 via antibody tests, by ELISA technique,but
233
the risk is not completely eliminated.To identify donors who may be in the window of
seroconversion,PCR test is performed.
Persons so-called risk behavior:IV drug users,sexually active mans and women,persons
from hig-prevalence countries are excluded from blood donation.
c). Vertically transmission : HIV can be transmitted from the infected mother to her child,
intrauterine, during delivery, or by breastfeeding.The most important risk factor is viral
load of the mother during pregnancy, and at the time of delivery.The probability of
vertical transmission of HIV,in the absence of intervention, range from 15-25% in
developed country and 25-35% in developing countries.Since 1995,the mother to child
HIV transmission has been reduced to 1-2%,trough the prophylactic antiretroviral
therapy,elective caesarian section prior to the start of labor,avoinding the breastfeeding.
d).Occupationallyacquired HIV infection:the risk of HIV infection of health care
workers,laboratory personel, and others who work with HIV-containg materials-sharp
objects is small, estimated to be around 0,3.Exposures that is at risk to transmitted HIV
are : needlestick injury,cut with a sharp object,or contact of mucous membrane /nonintact
skin with blood or others potentially infectious body fluids.The use of antiretroviral drugs
as postexposure prophylaxis (PEP),decreases the risk of HIV infection.
Structural aspects of HIV
HIV-1 Genome is constituted of three regions named: gag, pol i env, which codify the internal
proteins of the virion, the enzymes necessary for viral replication and the surface proteins of the
virion. On each extremity of the viral DNA there is a sequence of variable length: Long Terminal
Repeat (LTR) that allows DNA integration under the form of provirus, into host cell genome and
contains promoter elements necessary to genes expression. Except the three classic genes, HIV
genome contains also two particular regions, located between pol and env genes, and
respectively in the extension of the env. gene. They contain six supplementary viral genes
named: tat, rev, vif, vpr, vpu-vpx and nef. Codified proteins by these supplementary genes are
involved in the regulation of viral proteins expression and implicitly in the viral replication.
HIV viral particles have a unique morphology: spherical with a 90-120 nm diameter
The envelope is constituted of a lipid bilayer crossed by two glycoproteins gp120, gp 41.
Nucleocapsid, dense, trapezoidal shape, contains: protein p24 (marker of viral replication), p17
Enzymatic equipment: reverse transcriptase, integrase, protease.
HIV Replication Cycle.
1. First step starts with binding and penetration inside host cell, gp120 binding to host
cell receptor-CD4 molecule, which is found predominantly on the surface of T helper
lymphocytes and macrophages. Fixation of gp20 is followed by the conformational
modification of gp120 that allows the recognition of V3a gp120 domain by other surface
molecules named co-receptors. The major co-receptors of HIV are CCR5 and CXCR4.
2. The second step is the reverse transcription: RNA genome is copied into proviral DNA
via reverse transcriptase
3. Integration of proviral DNA in the genome of the host cell due to the viral integrase
4. Transcription of proviral DNA in messenger RNA
5. Synthesis of viral proteins
6. Assembly and maturation of viral proteins via viral protease
234
HIV frequently modifies its genetic structure with the apparition of quasispecies:
Syncytia inducing strains (fast replication, high titer)
Non-syncytia inducing strains (reduced replication, low titers)
HIV fragile in outer environment
Sensitive at certain common disinfectants activity: chloramine, 70% ethyl

alcohol, oxygenated water, quaternary ammonium salts, glutaraldehyde
Pathogenesis and immunopathology

The main characteristic of HIV infection is profound immunodeficiency, consequence of
qualitative and quantitative deficit of T helper lymphocytes. This subset of lymphocytes is
defined by the presence on their surface of the CD4 molecule, which constitutes the major
receptor of HIV. The CD4 molecule is expressed also by cells of the monocytes-macrophages
series, dendritic cells, Langherhans cells, microglial cells. The perfect fusion with CD4 receptor
and penetration of HIV virus into the target cell needs also the presence of a co-receptor. HIV
uses two co-receptors: CCR5 and CXCR4, known as receptors for chemokines (chemokines are
low molecular weight polypeptides involved in inflammation and infection). CCRC5 is
expressed of TCD4 activated macrophages and lymphocytes. HIV-1 strains that use the
chemokine receptor CCR5 (R5) are capable of replication in monocytes and macrophages and
are called M- tropic and are non-syncytia inducing.
HIV-1 strains + CXCR4 tropic (X4) replicate of preference in T lymphocytes, they are much
more virulent and syncytia inducing.
CCR5 has a special importance as co-receptor for HIV-1, because R5 strains are responsible of
almost all cases of sexually transmitted HIV infection. It has been demonstrated that R5 viruses
are predominant in early stages of HIV infection. The variants that use CXCR4, tend to appear
later together with the accelerated depletion of CD4 + cells and fast progression of the infection
towards final stages.
HIV replicates actively constituting an early viral reservoir at the level of the lymphatic organslymphatic ganglia (in follicular dendritic cells from germinal centers is formed the primoinfection). A particular role in the early dissemination of the virus and subsequent determination
of the chronic infection has the immune system of the intestinal mucous, GALT (gut-associated
lymphoid tissue) that possesses most of T lymphocytes of the organism which also expresses the
CCR5 co-receptor.
Through the tropism for this co-receptor the virus may access an important population of target
cells generating massive viral replication that will give birth to a wide diversity of new viral
variants, capable to elude the natural primary immune response of the host.
At the same time, T memory cells continue to generate new cells that express on their surface
CCR5 co-receptors favoring this way the perpetuation of infection. Dendtritic cells have an
important role in initiating the HIV infection.
The human organisms immune response to HIV-1 aggression is reduced and seems to be too
little, too late. Although it is set off a combined response of cytotoxic T lymphocytes (CTL) and
of humoral immunity, leading to a decrease of the viremy, the infection persists for years and
marks the evolution towards the secondary stage, of chronic infection. In spite of a humoral and
cellular robust immune response the virus keeps replicates itself further establishing the chronic
persistent infection. In the following weeks: in the plasma are detected RNA-HIV and infectious
viral particles (antigen p 24). Virus sanctuaries are constituted: nervous system, genital organs,
235
lymphatic ganglia (elude the defense mechanisms of the host) and transform the HIV infection in
chronic infection.
Immune response of the host:
-
Humoral: neutralizing antibodies guided against all HIV proteins (detected by

ELISA and Western Blot) appear at approximately 6-12 weeks from HIV
infection, they modify fast their coat proteins getting rid of the action of the
humoral response
Cellular: mediated by CD4 T lymphocytes and CD8 T cytotoxics. Cells infected

with the virus but not the latently infected ones. The plasmatic viremy level
decreases to low values (set point after 2-4 months).
The marked turnover of CD4 T lymphocytes holds for years!
Balance/production CD4 cells depletion: - divers mechanisms:

- cytopathic effect, formation of syncitya
- immunologically mediated depletion
- programmed death of apoptosis cell
- superantigens intervention
- signal alteration
- abnormal secretion of cytokines (TH1/TH2 switching)
HIV Infection Diagnosis
Early diagnosis is very important: allows to patient the access to antiretroviral therapy, controls
HIV transmission. It is based on serological tests: immunoenzymatic method (ELISA), the fourth
generation tests identify simultaneously, anti HIV1,2 antibodies and p24 antigen. Negative test,
confirms the absence of infection, except the cases in which there is suspicion of exposure to
HIV in the last 6 weeks.
Positive test is confirmed by Western-Blot test (immunoblot): viral proteins are separated
according to their molecular weight, by electrophoresis and transferred to a membrane
subsequently used as a strip test. The strip test is incubated together with the patients serum or
plasma..
-
Western-Blot test is considered positive if there are guided antibodies against an

internal protein of the virus (anti-p24) and a guided antibody against a coat
protein (anti-gp41, anti-gp120). If WB test is negative or indeterminate, a viral
load is performed. If it is positive the infection is considered to be recent.
The detection period of post-infection antibodies: 2-12 weeks
In emergency situations fast tests are used - based on the

immuno+chromatographic method, the fourth generation, identify Antibody plus
Antigen p 24. The result is confirmed by classical tests.
Immunological window diagnosis antibodies production starts in 2 weeks
since exposure, antibodies may be detected after 4 weeks.
Newborn diagnosis
Maternal antibodies remain detectable until the age of 18 months.
Viral Quantification
236
plasmatic viral RNA (viral load) determined by genomic amplification (PCR)
the viral load is a predictive factor of the disease evolution and the fundamental
parameter in therapeutic monitoring and HIV infection diagnosis at infants born
by a HIV-seropositive mother.
Immunologic evaluation: number of T CD4 lymphocytes
Antigen p24 detection (useful in the immunological window period few weeks
up to 3-6 months after infection)
Viral culture
Resistance tests: viral replication in the presence of antiretroviral medication =

therapeutic failure = Antiviral resistance. HIV resistance: is realized by mutations
at the reverse transcriptase or protease level.
Genotypation tests
Phenotypation tests
Indications of HIV testing and counseling

-
Legislation enforces appropriate counseling of the person who is to be tested: pretesting, post- testing counseling
Observance of confidentiality
Testing is recommended for: persons who personally demand the test, the person
belonging to the groups of risk (tuberculosis, sexually transmitted diseases),
compulsory testing of pregnant women
Clinical aspects in adults
Natural history of HIV infection
1. Acute stage: lasts a few weeks. 50-60% of patients present unspecific clinical manifestations
that realize a pseudo-influenza syndrome: fever, dysphagia, cephalalgia, myalgias, asthenia. The
most frequent relevant clinical signs are diarrhea, oral or genital ulcerations, adenopathies,
neurological events (meningitides, encephalitides, facial paralysis, peripheral neuropathy,
myelopathies). The manifestations disappear spontaneously in a few weeks (2-6 weeks) from
infecting contact. Retroviral acute syndrome (similar to infectious mononucleosis). The
symptoms persist a few weeks, gradually the immune response to HIV is developing, the
plasmatic viremy decreases. Biological manifestations: leukopenia, thrombocytopenia,
mononucleosis-like syndrome, moderate growth of transaminases, high plasmatic viral load, anti
HIV antibodies positive p24 antigen. Clinical severity is proven at persons whom have
neurological signs present in acute stage, and it is given a prognosis of risk of accelerated
evolution and HIV disease progression.
2. Asymptomatic stage (clinical)
Patient infected with HIV do not present clinical symptomatology or present unspecific
symptoms: fatigue, depression, memory disorders, progressive loss of weight. Viral replication
continues.
3. Chronic stage
Generalized lymphadenopathy: symmetric adenopathies with cervical, axyllary, submaxillary,
237
occipital location. Cutaneous-mucouses manifestations: seborrheic dermatitis, chronic prurigo,

folliculitis, zoster herpes, verrucas, molluscum contagiosum, oral/genital candidosis, lingual
leucoplakia (EBV)
General manifestations:
-
Alteration of the general condition
Moderate persistent fever
Nocturnal abundant perspirations
Extended diarrhea > 1 month
Without identifiable causes
AIDS
Opportunistic infections
Tumors
Manifestations of SN
Profound depression of cellular immunity
High viremy
The CDC classifies HIV infection into 3 categories, as follows:
Category A: Asymptomatic HIV infection without a history of symptoms or AIDSdefining conditions
Category B: HIV infection with symptoms that are directly attributable to HIV infection
(or a defect in T-cellmediated immunity) or that are complicated by HIV infection
Category C: HIV infection with AIDS-defining opportunistic infections
These 3 categories are further subdivided on the basis of the CD4+ T-cell count, as follows:
> 500/L: Categories A1, B1, C1
200-400/L: Categories A2, B2, C2
< 200/L: Categories A3, B3, C3
Classification of HIV infection (CDC 1993)

Lymphocytes
number
CD4/mm3
Clinical categories
A asymptomatic, B symptomatic HIV
infection, C SIDA
1. 500
A1
B1
C1
2. 200 - 499
A2
B2
C2
3. < 200
A3
B3
C3
238
Late serious consequence of HIV infection is the AIDS stage. It is characterized by the
appearance of infectious and tumor opportunistic manifestations of vital risk, due to profound
depletion of immunity or as direct manifestations of the cytopathic effect of HIV.
Opportunistic infections indicating AIDS are in fact reactivations of prior chronic infections,
they may affect certain apparatuses and systems, or the entire body evolves chronically with
recrudescences and correlates itself with the degree of immunosuppression.
Currently there are two main circumstances associated to opportunistic infections.
Patients of whom HIV infection is unknown, is not treated, and at whom opportunistic infections
manifest themselves in an inaugural manner, late presenters patients.
A second category is represented by the HIV infected patients who find themselves in a
therapeutic failure, with a number of TCD4 cells <200/mm3.
INFECTIONS THAT INAUGURATE THE AIDS STAGE
Parasites
Agent
Localization
Pneumocystis jiroveci
Pneumonia
(carinii)
Toxoplasma gondii
Central nervous system,

systemic infection
Cryptosporidium
Digestive tube, billiary tract
retina,
lungs,
Isospora belli
Fungi
Bacteria
Mycrosporidium
Digestive tube, sinuses
Candida
Digestive tube, lungs, dissemination
Cryptococcus
Nervous system
Histoplasma
Systemic dissemination
Aspergillus
Lungs, systemic dissemination
Sarmonella non- typhi
Recurrent septicemias
Mycobacterii tuberculosis
M.Kansasii
complex
Viruses
Tumors
Lungs, ganglia, nervous system, systemic

M.Avium dissemination
Cytomegalovirus
Retina, digestive tube, central nervous

system, lungs
Herpes viruses
Teguments, mucouses, digestive

central nervous system, lungs
Papovavirus
Progressive multifocal leukoencephalopathy
tube,
Kaposi sarcoma, non-Hodgkin lymphomas,

invasive cervical cancer
239
The most important opportunistic manifestations, evocating the AIDS stage are the following:
Pneumonia with Pneumocystis jiroveci
Initially known as pneumonia with Pneumocystis carinii, name reserved to a species of
Pneumocystis that infects rodents, it constitutes the important opportunistic infection associated
with AIDS. Pneumocystis jiroveci fung ubiquitar (biologically close to protozoa) affects
organisms with cellular immunity deficiency either by reactivation of a latent infection, or by a
new exposure, realizing a hypoxemia inducing pneumonia.
Clinical manifestations install themselves progressively: non-productive cough, fever, dyspnea
of progressive intensity, thoracic pains. Sometimes the onset is abrupt-brutal with severe
tachypnea and cyanosis with the clinical picture of an acute respiratory insufficiency.
Diagnosis is realized via pulmonary radiography that reveals diffuse bilateral interstitial
infiltrates or infiltrative nodules, in severe forms are described cavities, bubbles, cysts. The
specific complication that may appear at a reduced number of patients is the pneumothorax.
The certainty diagnosis is realized by emphasizing the cystic forms of pneumocystis in the
bronchoalveolar lavage fluid or in the post induced expectoration sputum, by
immunofluorescence or specific Gomori staining.
As extrapulmonary manifestations are described: affection of lymphatic ganglia, spinal cord,
spleen, liver.
The election treatment consists in the administration of trimetoprim-sulfametoxazol, appropriate
doses, for 21 days. It is associated with corticosteroids, oxygen.
Pneumocystosis is associated with a smaller T CD4 number than 200 cells/mm.
For pneumocystosis prevention it is recommended to respect the prophylactic medication in
immunosuppressed patients.
Cryptococcosis
Cryptococcus is a fungus responsible of approximately 5 % of the disease associated to AIDS
stage. The most frequent manifestation is the meningitis or the subacute meningoencephalitis,
which start with fever, cephalalgia, consciousness disorders, convulsions, neurological signs of
infection focus.
The neurologic picture may be accompanied by systemic manifestations: pneumonia, cutaneous
lesions, ocular lesions.
Diagnosis is suggested by the clinical picture, confirmed by the detection of cryptococcal antigen
through the latex agglutination test in serum, cephalorachidian liquid, cultures on special media.
Treatment recommends Amphotericin B associated with Flucytosine followed by Fluconazol.
Prophylaxis with Fluconazol, is compulsory in patients who passed through the clinical disease
and have a smaller number of T CD4 than 50/mm.
Mycobacterium avium Complex infections
Infections caused by Mycobacterium avium Complex (MAC) are detected in patients without
antiretroviral therapy, deeply immunosuppressed, without appropriate prophylaxis.
The specific clinical manifestation is multiorganic dissemination. Typical symptoms include
fever, nocturnal perspirations, marked weight loss, asthenia, abdominal pain, diarrhea. It also
240
manifests within the immune reconstitution inflammatory syndrome (IRIS) characterized by fast
increase of T CD4 cells, after the initiation of antiretroviral therapy.
Other clinical manifestations of MAC dissemination, include pneumonia, pericarditis,
osteomyelitis, abscesses of teguments and subcutaneous tissue, genital ulcers, infections of the
central nervous system.
Diagnosis is confirmed by MAC isolation in cultures.
Bacteriemia is direct and final. Biopsy and cultures from suspected sites (lymphatic ganglia) may
also isolate mycobacteria.
Specific identification is realized by technical PCR.
Preferential treatment of MAC disseminated infection is Clarithromycin associated with
Etambutol and/or Rifabutin. As alternatives may be used parenterally fluorochinolone and
amikacina.
In parallel is initiated as soon as possible antiretroviral therapy.
Prophylaxis is initiated in patients with T CD4 values under 50/mm and consists in
administration of Azithromycin/ Clarithromycin or Rifabutin.
Cytomegalovirus Infection
Cytomegalovirus (CMV) is a frequent opportunist associated to infections in patients with AIDS.
The infection is realized through reactivation of latent focuses due to advanced
immunosuppression.
CMV Retinitis: is the most frequent clinical manifestation of the CMV infection. It evolves
unilateral or bilateral, peripheral or central. Peripheral lesions are characterized by scotomas or
visual field reduction, central retinal lesions are associated with diminishment of visual acuity.
CMV colitis evolves with fever, anorexia, loss of weight, abdominal pains, persistent diarrhea.
Potential complications are gastro-intestinal hemorrhage and perforation.
Esophagitis is manifested through odynophagia, retrosternal discomfort, fever.
Less frequent pneumonia may set off hypoxemia.
Neurologic disorders, with severe prognostic are frequent: encephaloventriculitis, dementia,
ascending poliradiculomyelopathy.
The certainty diagnosis consists in CMV detection by PCR technique.
The CMV antibodies titer is not very useful, a CMVIgG negative titer, does not exclude viremy.
Therapeutic options recommend valganciclovir, ganciclovir, cidofovir, foscarnet, antivirals that
are not lacking of side effects: neutropenia, trombocytopenia, nausea, diarrhea, renal
dysfunction.
Prophylaxis is recommended to patients with CMV retinitis and for those with T CD4 values <
100/mm3.
Cerebral toxoplasmosis
The most important opportunistic infection in HIV-infected patients remains cerebral
toxoplasmosis.Toxoplasma gondii is an intracellular parasite that infects birds,mammals and
humans.
241
Cerebral toxoplasmosis occurs at CD4T cell count bellow 100cell/ul.The major signs include
focal neurological deficits such as paresis,speech problems,sensory loss.A febrile status with
headaches,confusion are also frequent signs.CT or MRI scan of haead should be performed in
every case of focal neurological deficit.
Progressive multifocal leukoencephalopathy (PML)
PML is a progressive demyelinating condition of advanced HIV disease caused by the John
Cunningham virus (JCV) and presents with focal neurological signs, changes in personality and
ataxia. The diagnosis is by MRI. There is no specific treatment and the patient usually dies
within six months unless effective ART is used. Some patients develop PML during combined
ART in the setting of immune reconstitution. Steroids may be useful in such cases.
Kaposi Sarcoma
Description of Kaposi sarcoma in young people, American homosexuals, constituted one of the
clinical events that signed the act of birth of AIDS disease. In AIDS evolution, Kaposi sarcoma,
an angioproliferative tumor associated to the infection with human Herpes virus 8 (HHV-8) takes
an aggressive evolution, with dissemination at the cutaneous-mucouse level, but visceral also,
difficult to treat.
Clinically, is characterized by the aspect of nodular lesions with lavender like colour,
disseminated on the face, neck, upper third of the body, limbs. Lesions may evolve at the level of
the oral cavity, palatine arch. Visceral dissemination is more frequent at the level of the digestive
tube and evolves often asymptomatically.
The pulmonary localization evolves with dyspnea, non-productive cough, sometimes
hemoptysis, pleurodynia.
Histopathological diagnosis is the certainty diagnosis. It may be associated to PCR technique
which documents the infection with HHV-8.
The treatment associates administration of recombinant interferon alpha in antiretroviral therapy.
Neurologic diseases In HIV infected persons,the neurologic manifestations are developed
primary by HIV itself, secondary,to opportunistic infections,or neoplasm. HIV-associated
neurocognitive disorder
is
the term used to describe a spectrum of
neurologic
manifestations,that are be classfified in three categories ,in the order of descending severity.
1.HIV- associated asymptomatic neurocognitive impairment (ANI)-the impairment does not
interfere with everyday functioning;
2.HIV-associated mild neurocognitive disorder(MND)-at least mild interference in daily
functioning
3.HIV-associated dementia(HAD)-marked acquired impairment in cognitive functioning
Antiretroviral Treatment
Specific treatment of HIV infection has achieved remarkable progresses since 1996 the year in
which the concept of extreme active therapy has been introduced, HAART (Highly Active
Antiretroviral Therapy), which consists in the association of antiretrovirals capable to achieve
the following challenges: clinical, lifespan prolongation and improvement of life quality,
virological: reduction of HIV viremy up to the lowest values possible having as purpose
prevention of infection progress and limitation of the HIV development resistance to
antiretroviral drugs.
242
From an imunologic point of view, the antiretroviral therapy has as objective the restoration and
preservation of the immune system function, increasing the number of T CD4 lymphocytes to
values which inhibit the development of opportunistic infections. Efficient antiretroviral therapy,
has also an epidemiologic role, reduces the rate of transmission of the infection
Antiretroviral medication used currently contains substances that activate in different phases of
the viral replication cycle.
Nucleoside reverse transcriptase inhibitors have as mechanism of action inhibition of viral
reverse transcriptase, by replacing some of its nucleosides with others, inappropriate ones.
Through this mechanism the DNA synthesis fails.
Zidovudine (AZT, Retrovir) was the first synthesized medicine used in HIV treatment in 1987.
Subsequently have been also synthesized other substances with similar action.
Generic Name
FDA approval
Zidvudine ( AZT)
1987
Didanosine ( ddi)
1991
Zalcitabine ( ddC)
1992
Stavudine ( d4T)
1994
Lamivudine (3TC)
1996
Zidovudine /lamivudine/ abacavir
2000
Tenofovir DF ( TDF)
2001
Entricitabina ( FTC)
2003
Abacavir/lamivudine
2004
Emtricitabine/tenofovir
2004
a). Non-nucleoside reverse transcriptase inhibitors are active molecules which also activate on
the reverse transcriptase, by direct and non-competitive binding, followed by alteration of its
function.
Non-nucleoside reverse transcriptase inhibitors
Name
Year of approval
Nevirapine
1996
Delaviridine
1997
Efavirenz
1998
Etravirine
2008
Rilpivirine
II B under study
Protease inhibitors
243
1. HIV protease with a key role in the assembly of viral particles is a protein composed of
two identical symmetrical subunits of 99 amino acids, which delimitate in the central
position of the active site of the enzyme that cuts out the polyproteins produced at the end
of the viral replication cycle, in 9 subunits. The appearance of protease inhibitors
constitutes an incontestable event that has revolutionized the treatment of HIV infection.
Numerous clinical studies have proven the efficiency of the therapy with one or two
protease inhibitors in association with two reverse transcriptase inhibitors. Since 1996,
the protease inhibitors synthesis has developed very much.
Protease inhibitors
Name
Year of approval
Indinavir
1996
Ritonavir
1996
Saquinavir
1995
Nelfinavir
1997
Amprenavir
1999
Lopinavir/ritronavir
2000
Atazanavir
2003
Fosamprenavir
2003
Tipranair
2005
Darunaiviri
2. Fusion inhibitors, block the virus binding to the host cell through the competitive
inhibition mechanism activated at level gp41. The medicine used currently is enfuvirtide
(fuzeon) approved in 2003.
3. CCR5 co-receptors inhibitors, CCR5 antagonists have a potent antiviral activity both in
vitro and in vivo against a population of HIV-1 strains with tropism for CCR5 coreceptors, but not against the strains using CXCR4. The approved substance is called
Maraviroc and has demonstrated in several clinical trials, favorable results.
4. Integrase inhibitors
Raltegravir is the first integrase inhibitor approved to be used in the antiretroviral therapy of
experienced patients.
New class of antiretrovirals recently approved or under development for treatmentexperienced patients.
Class
Name
Antagonist CCR5
Maraviroc,
Anti CD4 antibodies
TNX- 355 ( stadiu II of study)

244
Integrase inhibitors
Raltegraviri, Elvitegraviri
Maturation inhibitors
Bevirimat (stage II of study)
A major obstacle in the therapys success is represented by the capacity of HIV virus to generate
genetic mutations. HIV resistance to antiretrovirals was reported for the first time in 1989 at
patients treated with zidovuzine. Therapy diversification, the HAART concept has generated
new mechanisms of resistance and implicitly the therapeutic failure.
On the other hand the pharmacokinetic profile of antiretroviral drugs intercrosses with the one
of other medications used in the patients management. Protease inhibitors are metabolized
through the inhibition of 3A4 enzyme of P-450 cytochrome. The inhibition of this enzyme has
important pharmacokinetic implications. The intervention which has revolutionized the use of
protease inhibitors was the administration of low doses of ritonavir that blocks the metabolism of
the other inhibitors favoring high concentrations of the latter for a longer period of time.
It is important that this aspect be known because the use of other medicines in HIV/AIDS
infected patients, including antifungals, antituberculous, oral contraceptives, anticonvulsivants,
methadone, hypolipemiant drugs (statins) interact with protease inhibitors in an unfavourable
manner.
Antiretroviral complex therapy has reduced morbidity and mortality by HIV infection, but
opened new chapters of pathology, as lipodystrophic syndrome, alteration of carbohydrate and
lipid metabolisms, mitochondrial toxicity, cardiovascular, osteoarticular disorder.
Prevention of HIV infection.
The most effective way to prevent transmission of HIV is education,counseling and behavior
modification.
When the HIV status of the partner is not know or the partner is HIV infected,use of condoms
can decrease the risk of HIV transmission.
To prevent transmission of HIV among IV drugs users,the most effective strategy is to stop the
use of injectabile drugs.
Transmission of HIV by blood and blood products has been decreased by screening of all blood
donors.
Prevention the transmission of HIV from mothers to child, consist in a lot of
methods:antriretroviral therapy for mother,and for child afters biths,caesarian section,the
avoidance of breastfeeding.
245

CURS ENGLEZA Boli Infectioase

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

CURS ENGLEZA Boli Infectioase

Uploaded by

Copyright:

Available Formats

INFECTIOUS DISEASES

salmonellae, tuberculosis and staphylococci, severe acute respiratory distress syndrome

Infection may be transmitted by sexual contact, including sypihilis, gonorrhoea,

Insect or animal bite

Infections transmitted by bites include malaria, leishmaniasis, trypanosomiasis, typhus, rabies,

direct detection with microscopy; microscopic examinations of body fluids, exudates,

Treatment of infectious diseases

a, the drugs mechanism of action

Cefaclor, Cefamandole, Cefminox, Cefonicid, Ceforanide, Cefotiam,

is Aztreonam, resistant to many beta-lactamases.

streptococcal pharyngitis and cellulitis

-strains of Proteus mirabilis,

- and prophylaxis for endocarditis

-Enterococcus faecalis ampicillin-resistant E Ampicillin is administered intravenously for

Ureidopenicillins(available even in combination with the beta-lactamase inhibitor tazobactam).

Severe infections with sensitive germs

Plurimicrobial infections: biliary, digestive,

250 mg, clavulanic acid

Table . Antimicrobial spectrum and therapeutical indications of penicillins combined with

infections with sensitive germs

-lack of penicillin-binding proteins,

indole-positive Proteus and

some are active against are superior to firstgram-negative anaerobes;

Enhanced activity versus

Modest activity against Febrile

are more stable

against Severe Infections:

In meningitis in older patients, third-generation cephalosporins should be combined with

be used in the treatment of meningitis.

like imipenem plus extendedspectrum

Prophylaxis of infection of most

Severe infections with susceptibile

Imipenem. Dosage adjustment is required in renal insufficiency.

Pneumonia with Legionella

Corynebacterium (including diphtheria),

Enteral infections (Yersinia, Campylobacter,

They are useful alternatives in the treatment Infections in stomatology

Methicillin- resistant Staphylococcus

Pharmacokinetics and Administration

H influenzae(azithromycin > clarithromycin > treatment of streptococcal pharyngitis,

bronchitis, acute sinusitis

Azithromycinis used as single-dose therapy (1

Macrolides are inactive on Fusobacterium necrophorum,the etiologic agent in Lemierre

They are strongly inhibitory for

Tetracyclines also have some

Cholerae, genital infections

-psittacosis, -Lyme disease

- amebiasis, (in combination

Pharmacokinetics and administration

-gram-positive bacteria: methicillin-resistant -complicated

-multidrug resistant aerobic gram-negative -intra-abdominal infections

A loading dose of 100 mg is administered intravenously with maintenance at 50 mg every 12

S. aureus, S. epidermidis, S. pneumoniae, Chloramphenicolis an alternative to more

Chlamydia, Mycoplasma, Rickettsies

-active tuberculosis when

Neomycin, often combined

closely related to neomycin and asymptomatic

The addition of gentamicinto cell -serious infections caused by

It is active against many severe

semisynthetic derivative Proteus,

less ototoxic and less nephrotoxic severe

Gram positive organisms (S.aureus, S.pneumoniae,

Gram negative organisms (E.coli, Klebsiella, Salmonella,

E coli, Klebsiella, Enterobacter, urinary tract infections, -acute prostatitis,