ANTIBIOTICS

The first investigators to recognize the clinical potential of micro-

organisms as therapeutic agents were Pasteur and Joubert, who recorded

their observations way back in 1877.

The modern era of the chemotherapy of infection started with the

clinical use of Prontosil, a sulfonamide dye by Domagk in 1935. Sir

Alexander Fleming’s serendipity of penicillin in 1929 at St. Mary’s

Hospital in London is considered as one of the most noted discoveries of

that century. Chain and Florey then purified it (penicillin) and clinical use

in 1941 started the Golden age of antimicrobial therapy. In the 1940’s

Waksman and his colleagues discovered streptomycin from a group of soil-

microbes. All three groups of scientists – Domagk; Fleming-Chain-Florey;

Waksman received Nobel prize for their discoveries.

Definition

Antibiotics are chemical substances produced by various species of

micro-organisms that suppress the growth of or kill other microorganisms

at very low concentrations. However now-a days synthetic antibacterial

agents that are not products of microbes are also termed as antibiotics.

1
Classification

There are several methods used to classify and group antimicrobial

agents, and all are hampered by exceptions and overlaps. Historically, the

most common classification has been based on chemical structure and

proposed mechanism of action:

1 Agents that inhibit synthesis of or activate enzymes that disrupt

bacterial cell walls to cause loss of viability and often cell lysis.
E.g.: Penicillins, cephalosporins etc.

2 Agents that act directly on the cell membrane of the microorganism,

affecting permeability and leading to leakage of intracellular
compounds.
E.g.: Detergents, antifungal agents like: Nystatin, Amphotericin-B etc.

3 Agents that affect the function of bacterial ribosomes to cause a

reversible inhibition of protein synthesis; i.e. bacteriostatic drugs
E.g.: Chloramphenicol, erythromycin tetracyclines etc.

4 Agents that bind to the 30 S ribosomal subunit and alter protein

synthesis leading to cell death
E.g.: aminoglycosides.

5 Agents that affect nucleic acid metabolism

E.g.: Rifamycins, metronidazole.

2
 6 The antimetabolites, i.e. agents that block specific metabolic steps
that are essential to microorganisms.
E.g. trimethoprim, sulfonamides.

7 Nucleic acid analogs – agents that bind to viral enzymes that are
essential for DNA synthesis thus halting viral replication.
E.g. : Zidovudine – Acyclone.

II. Types of organisms against which primarily active

1. Antibacterial : Penicillins, etc.

2. Antifungal : Ketoconazole etc.

3. Antiviral : Acylovir etc.

4. Antiprotozoal : Metranidazole etc.

5. Antihelmintic : Mebendazole etc.

III. Based on spectrum of activitiy

1. Narrow spectrum – Penicillin, Streptomycin.

2. Broad spectrum – Ampicillin, Tetracyclines.

General considerations

Indication for prescribing antibiotics : It is most important that an

antibiotic be used to treat an infection.

1) If it seems likely that withholding the

antibiotic will result in failure to effectively manage severe or

potentially life threatening infection.

3
 2) When the patient is

immunocompromised or is at increased risk because of a systemic

condition.

Use of antibiotics should be based on clinical evaluation and the

judgment that antimicrobial therapy will have a beneficial / therapeutic

effect. Therapy should help contain and limit further extension of the

infection, shorten duration and discomfort or reduce risks of systemic

involvement or complications.

Antibiotics should definitely be considered for patients with oro-

facial infections when one or more of the following related signs,

symptoms or conditions are present.

1) Fever and or chills, current or in the last 24 hours.

2) Malaise, fatigue, weakness, dizziness, rapid respirations, or other

debilitation.

3) Trismus.

4) Cellulites, infection extending acutely (e.g. within 24 hours) into

adjacent spaces or tissues without clearcut localization.

5) Local systemic infection with H/O rheumatic fever, endocardins,

heart prosthesis, or other predisposing factors.

6) Immuno-compromised status (e.g. AIDS, Cancer, etc.).

4
 7) Allograph (cardiac, renal, bone marrow, liver and or osseous

implants).

8) Diabetes mellitus or other contributory systemic disease.

Situations in which antibiotic therapy is not necessary

1) Uncomplicated edema induced by trauma/chemicals.

2) Pain related to pulpitis or trauma.

3) Well localized minor abscess that is likely to respond well to

drainage and treatment of the local source of the infection, such as a

periapical abscess.

4) Uncomplicated dry socket.

5) Simple, well defined pericoronitis.

6) Bacteria limited to root canal.

7) Chronic uncomplicated draining sinus tract associated with a non-

vital tooth.

CHOICE OF ANTIBIOTIC AGENT

When an antibiotic is indicated the goal is to choose a drug that is

selectively active against the most likely infecting agents and that has the

least potential to cause allergic or toxic reactions in the specific patient

under treatment.

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The choice depends on :
a. The patient
b. The infecting organism
c. The drug

A) Patient factors

1) Age may affect kinetics of many antibiotics. E.g. i) Tetracyclines

are contraindicated below the age of 6 years (- discolour and

weaken the teeth) ii) Sulfonamides cause kernicterus in neonates

because their blood-brain barrier is more permeable.

2) Renal and hepatic function: Cautions use and modification of the

dose becomes necessary when the organ of its disposal is defective.

I) Drugs to be avoided in renal failure  related to dentistry

1. Tetracyclines (except doxycycline)

Dose reduction needed

1. Aminoglycosides.
2. Metronidazole.
3. Cephalosporins.

II) In liver disease : Avoid  Tetracyclines

Dose reduction  Metronidazole

3) Local factors :
1. Presence of pus and secretions.
2. Presence of necrotic material haematomas, foreign body.
3. Low pH at site of infection.

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 4) Drug allergy : H/O previous exposure to be taken.
5) Impaired host defence.
6) Pregnancy.
7) Genetic factors: Chloramphenicol, sulfonamides are likely to
produce haemolysis in G6PD deficient patient.

B) Organism related considerations

1) Clinical diagnosis itself directs choice of the antibiotic.

2) Choice to be based on basis of bacteriological examination – by

culture and sensitivity testing.

C) Drug factors
1) Spectrum of activity : Narrow/broad.

2) Type of activity: Bactericidal / bacteriostatic.

3) Sensitivity of the organism.

4) Toxicity.

5) Pharmacokinetics: for optimum action the antibiotic has to be

present at the site of infection in sufficient concentration for an
adequate length of time.

6) Route of administration: for less severe infections oral antibiotic is

preferred but for serious infections a parenteral antibiotic may be
chosen.

7) Evidence of clinical efficacy.

8) Cost.

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COMBINED USE OF ANTIBIOTICS

This is done only with specific purpose such as to achieve:

i) Synergistic action of the drugs.

ii) To reduce severity / incidence of adverse effects.

iii) To prevent emergence of resistance.

iv) To broaden the spectrum of antimicrobial action.

a) Treatment of mixed infection.

b) Initial treatment of severe infections.

Disadvantages of combinations
i) Increased chances of superinfections.

ii) Emergence of resistance may be promoted.

iii) Increased chances of adverse effects.

iv) Increased cost of therapy.

Problems that arise with the use of antibiotics:

1) Toxicity: a) Local irritancy – at the site of administration.

b) Systemic toxicity – dose related and predictable

E.g. Tetracyclines  Liver and kidney damage
 Antianabolic effect.

Aminoglycosides  8th cranial nerve damage.

 Kidney toxicity.

Chloramphenicol  Bone marrow depression.

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 2) Hypersensitivity reactions: Unpredictable and unrelated to dose –

rashes to anaphylactic shock.

3) Drug resistance :

1. Natural: E.g. gram-negative bacilli  unaffected by

penicillins.

2. Acquired.

It is the development of resistance by an organism (which was

sensitive before) due to the use of an antibiotic over a period of time.

This acquired resistance is by:

I] Mutation : It is a stable and heritable genetic change that occurs

spontaneously and randomly among micro-organisms. Any sensitive

population of a microbe contains few mutant cells which require higher

concentration of the antibiotic for inhibition. These are selectively

preserved and get a chance to proliferate when the sensitive cells are

eliminated by the antibiotic. Thus, in time it would appear that a sensitive

strain has been replaced by a resistant one. It may be a Single step

Multi step

II] Gene transfer : from one organism to another can occur by:
i) Conjugation : Transfer through sexual contact i.e. bridge
formation, sex pilus.

ii) Transduction : through a bacteriophage (virus).

iii) Transformation : through DNA.

9
 Mechanism of increased bacterial resistance to antibiotics:

i) Alteration of permeability of the bacterial cell for the drug.

ii) Changes in the target sites for the drug in the bacterial cell.

iii) Bypassing metabolic reactions blocked by the drug.

iv) Drug inactivation.

III] Cross resistance : Acquisition of resistance to one antibiotic

conferring resistance to another antibiotic, to which the organism has not

been exposed, is called cross resistance. This is more commonly seen

between chemically or mechanically related drugs.

Prevention of drug resistance

 No indiscriminate and inadequate or unduly prolonged use of

antibiotics should be made.

 Proper rapidly acting and selective antibiotics whenever

possible.

 Combination antibiotics should be used in cases of prolonged

therapy.

 Infection by organisms notorious for developing resistance

must be treated intensively.

4) Superinfection : Appearance of a new infection as a result of

antimicrobial therapy.

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 Use of most antibiotics causes some alteration in the normal

microbial flora of the body. The normal flora contributes to host defense by

elaborating substances called bacteriocins which inhibit pathogenic

organisms. Further, ordinarily the pathogen has to compete with the normal

flora for nutrients etc to establish itself. Lack of competition may allow

even a normally non-pathogenic component of the flora, which is not

inhibited by the drug to predominate and invade. More complete the

suppression of body flora, greater are the chances of developing

superinfection. Thus, it is commonly associated with the use of broad /

extended spectrum antibiotics such as tetracyclines, chloramphenicol,

ampicillin, newer cephalosporins.

Superinfections are more common when host defense is compromised, as

in
- Corticosteroid therapy.

- Leukemias and other malignancies.

- AIDS

- Agranulocytosis.

- Diabetes, disseminated lupus erythematosus.

To minimize superinfections

a) Use specific antibiotics whenever possible.

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 b) Do not use antimicrobials to treat self limiting or viral

infections.

c) Do not necessarily prolong antimicrobial therapy.

5) Masking of an Infection : A short course of an antibiotic may be

sufficient to treat one infection but only briefly suppress another one

contacted concurrently. The other infection will be masked initially,

only to manifest later in a severe form.

Antibiotics in Periodontal Therapy

Rationale:

Periodontal diseases are due to bacterial infections. To control these

infections, it is essential to control the organisms that cause them. Systemic

periodontal antimicrobial therapy is based on the theory that specific

microorganisms cause destructive periodontal disease and that the

antimicrobial agents in the periodontal pocket can exceed concentrations

necessary to kill the pathogens.

The goal of antimicrobial therapy is simple in principle yet often

difficult to achieve 14 – to eradicate periodontal pathogens in the oral

cavity.

Concept of Antibiotic Therapy : In treating infections, it is essential to

understand the environment in which the pathogen is located, so as to

select a route to get the antimicrobial agent to that environment in a high

12
enough concentration for a long period of time to affect the organism

adversely. Unfortunately, periodontal pathogens reside in more than a

single location, 3 principle environments communicate with the

periodontium through which antibacterial agents can be administered.

1. Supragingival environment – topical administration.

2. Subgingival environment – local administration.

3. Systemic environment – Systemic administration.

Compared to mechanical debridement and topical application of

antiseptics, systemic antibiotic therapy has certain advantages.

1) Via serum, systemic antibiotics reach

microorganisms at the base of the deep periodontal pockets, furcation

areas and may also affect organisms residing within the gingival

epithelial and connective tissue. The possibility of eradicating

periodontal pathogens from the entire may reduce the risk for

subgingival recolonization of pathogens for future disease activity.

Selection and Requirements of an Antibiotic

Two critical factors should be considered in selection of a systemic

antibiotic
1) Gingival fluid concentration (C GCF)
2) Minimum inhibitory concentration (MIC90).

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 CGCF provides information on the peak levels achieved by systemic

delivery in the periodontal pocket.

MIC90 is an in vitro determination of the concentration that will

inhibit growth of 90% of the bacterial strains of a species tested.

Antimicrobial activity can be defined as a relationship between CGCF

and MIC90.

100 x CGCF = Antimicrobial activity expressed as % for each

MIC90 antibiotic and each organism

By this data transformation, antibiotics that can achieve 90%

inhibition of growth of an organism appear on the 100% line and those that

do not fall between 0-100%. The most effective antibiotics for treatment of

a particular periodontal pathogen are those that equal or exceed the 100%

value.

An ideal antibiotic for use in the prevention and treatment of

periodontal diseases should (Gibson 1982)

1) Act specifically on periodontal pathogens.

2) Travel readily to the infection site and concentrate in therapeutic

levels in the crevicular fluid and gingival tissues for a long

enough period.

3) Should not be in general use for treatment of other diseases.

4) Be substantive.

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 5) Not be allergic or toxic.

6) Have a positive benefit to risk ratio.

7) Not be expensive.

Currently, there is no ideal antibiotic for treatment of periodontal

diseases.

Prophylactic use of Antibiotics :

Why antibiotic prophylaxis in periodontics ?

There are two major reasons for utilizing prophylactic antibiotics.

First, to reduce the risk of metastatic infection where bacteria are

transported through the blood stream to other parts of body, resulting in

infection. This indication applies to conditions such as subacute bacterial

endocarditis, rheumatic heart disease and prosthetic heart valves (Leport et

al, 1995). The second reason for employing prophylactic antibiotics is if

there is an increased infection risk due to impaired host resistance (e.g.,

diabetic patients, patients treated with cancer chemotherapy or

immunosuppressive drugs), and situations where foreign bodies are

introduced into the body, such as insertion of implants or bone grafting

procedures (Hall et al 1994).

All dental procedures which induce bleeding will usually be

followed by a transient bacteria, which rarely persists for more than 15

mm. In the healthy individual this event does not necessitate any

15
therapeutic interaction, but serious systemic infections may develop in

certain patient populations as a result of the haematogenic spread of oral

bacteria.

Concluding Remarks:

Patients with diseases of cardiovascular system who are at risk of

developing endocarditis, antibiotic prophylaxis is mandatory in conjunction

with dental procedures inducing bleeding. Patients with impaired immune

response, asplenic patients, diabetic and patients with joint prosthesis; in

these cases, the initiation of antibiotic prophylaxis is based on an individual

assessment of the patients underlying disease and current microbiological

status, for which reason the patients physician should be consulted before

making a decision about antibiotic prophylaxis.

Individual Drugs

I] Agents that act by reversible inhibition of protein synthesis:

Classification of tetracyclines

Group I Group II Group III

Chlorotetracycline Demeclocycline Doxycycline
Oxytetracycline Methacycline Minocycline
Tetracycline Lymecycline

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 1. Tetracyclines

Description:

The tetracyclines comprise a group of broad spectrum antimicrobial

agents, produced naturally from certain species of streptomyces or derived

semisynthetically. Introduced in late 1940’s.

Structure:

Structural formula of ploycyclic napthacenecarboxamide from

which all tetracyclines are derived.

Agents used in the management of periodontal disease include:

tetracycline hydrochloride, doxycycline and minocycline which are all

semisynthetic tetracyclines.

Tetracycline Hcl derived from chlortetracycline.

Doxycycline derived from oxytetracycline.

Pharmacological properties:

Absorption:

Both doxycycline and minocycline exhibit greater oral absorption

(93% and 100%) are more extensively protein bound and have more

prolonged half lives than tetracycline Hcl. (Barzccheife, 1977).

As a consequence, systemic dose regimens for doxycycline is

100mg/day after an initial loading dose of 200 mg and for minocycline 100

17
mg x 2 / day, while for tetracycline hydrochloride- 250mg x 4/day. Such

dosage schedules for doxycycline and minocycline offer distinct

advantages when prolonged course of treatment is indicated and more

patient compliance is required.

The tetracycline Hcl is a chelating agent and chelates Ca2-, MG2+

and Al3+ in the G.I. tract (Ericsson et al, 1982). These ions are present in

various food substances. Since this chelate is absorped, tetracycline Hcl

should be taken either ½ an hour before or after food. Food does not

interfere with the absorption of doxycycline or minocycline.

Both doxycycline and minocycline are more lipid soluble than

tetracycline and thus have better ability to pass through the lipid bilayer of

the bacterial cell wall- (antibacterial action).

Properties (Scymour et al 1995)

Property Tetracycline Hcl Doxycycline Minocycline
Systemic 250mg x 4 day Loading dose of 100mg x 2 day
dosage 200mg followed
By 100mg/day
Oral absorption Irregular E.g. 93% 100%
incomplete
Protein binding 36-50% 82-93% 76%
Peak Serum concern 2mgµ 31-35mgµ 2-3mgµ
GCF concern 4-8mgµ 6-10mgµ 4.8-6mgµ
Plasma half life 8.5hrs 18-22hrs 12-16 hrs
Lipid solubility + ++ +++

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Pharmacokinetics

All tetracyclines are removed from the circulation by the liver and

excreted into the G.L. tract via the biliary system. There is some

reabsorption of the drug which prolong their duration of action.

Doxycycline is partly-excreted in the faces while the other tetracyclines are

excreted by glomerular filtration via the kidneys (caution in renal

insufficiency) with the exception of minocycline, the tetracycline are

excreted unchanged.

Antibacterial actions:

Spectrum

Tetracycline are primarily bacteriostatic and are effective against

rapidly multiplying bacteria. They are against all gm+ve bacteria and many

gm-ve species.

Mechanism of Action

1) Tetracyclines exert their antibacterial activity by inhibiting

microbial protein synthesis (Chopra and Howe 1978). This requires

access to the inside of the bacterial cell. Doxycycline and

minocycline are more lipid soluble and thus pass through the lipid

bilayer of the bacterial cell wall. Once through this layer, an energy

dependent mechanism pumps the drugs through the inner

cytoplasmic membrane. Within the cell, tetracycline bind

19
 specifically to the 30s ribosomes. This binding appears to prevent

access of aminoacyl RNA to the acceptor site of mRNA-ribosome

which in turn prevents the addition of aminoacids to the growing

peptide chain (Hogenouer and Turnowsky, 1972).

2) Tetracycline may cause alterations in the bacterial cytoplasmic

membrane and thus facilitating the leakage of nucleotides and other

compounds from the cell (Pato 1977). This action would explain the

rapid inhibition of DNA replication when cells are exposed to

concentration in excess of that needed for protein inhibition.

Antibiotic resistance

Most of the subgingival microorganisms are susceptible to

tetracycline at an MIC_1-2 mg/ml (Rams and Solts 1990).

Resistance occurs due to acquisition of genetic information carried

by extrachromosomal DNA molecules called plasmids. R plasmid

tetracycline resistance is often the result of a new active transport system

that pumps the drug out of the cell and prevent it from accumulating

intracellularly and inhibiting growth (Genco, 1981). A tetracycline

resistance gene isolated from the ECO RI Hind III fragment of plasmid

PAT 101 has been shown to confer resistance to approx. 12% of total

bacterial counts taken from periodontally diseased sites (Lacroix, 1993). Of

concern to the periodontist is the tetracycline resistance (MIC_16mg/ml)

exhibited by E-corrodens, P-oralis, selenomonas campylobacter veilonella

20
and some bacteroides which are greater than levels attainable in the GCF

by systemic dosing.

Other properties of tetracyclines

1. Their ability to concentrate in GCF after systemic dosing.

Concentrates in GCF at higher concentrations than in plasma

approx. 7 time.

2. Substantivity : These drugs exhibited substantivity to dentine while

maintaining antimicrobial activity within the pocket. (Bjouratan

1983). The mechanism of tetracycline sequestration is uncertain but

may be related to the binding of the drug to and its subsequent

release from the root surface or to chelation with Ca++ ions in

crevicular fluid. Substantivity is directly proportional to the

concentration of tetracycline.

Local higher concentration of tetracycline enhances their

bacteriostatic actions and inhibits development of resistant strains. By

incorporating drugs in to controlled release device, crevicular fluid

concentrations of tetracycline in excess of 1300 mg/ml with minimal side

effects can be attained.

3. Anticollagenase activity

Interstitial collagenases are proteinase enzymes which degrade

connective tissues. These enzymes are derived from a variety of sources

21
including fibroblasts, epithelial cells, macrophages (mature

metalloproteinase 1, M MP-1) and neutrophils (MMP-8). Collagenases

derived from neutrophils (MMP-8) are more susceptible to a tetracycline

inhibition whereas those derived from human fibroblasts or GCF

collagenase harvested from deep pockets appear more resistant to the drugs

(Ingman, 1993). Anticollagenase activity does not appear to be related to

the drugs antibacterial properties but to the source of the enzyme and the

tetracycline used. This selective action on collagenase inhibition can be

utilized to determine the cellular source of interstitial collagenase.

Doxycycline is the most potent tetracycline for collagenase

inhibition (Burns et al, 1989) because it binds to Zn++ more strongly. Low

doxycycline (LDD)-20mg bid inhibits collagenase and possibly other

collagenase enzymes produced by the host tissue resulting in a reduced rate

of collagen breakdown (Golub et al, 1985). In conjunction with NSAIDS it

increases bone formation and express more potent anticollagenase activity

as NSAID increase the absorption of LDD through the tissues (Greenwald

et al, 1992).

In LJP patients, a significant source of collagenase is the fibroblast

(MMP-1), while in adult periodontitis and diabetes mellitus the source is

the neutrophil (MMP-8). This suggests that different dose/drug regimens

are required for various forms of periodontal disease.

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Mechanism of action

1. It has been suggested that anticollagenolytic activity of tetracyclines

relates to the drugs ability to bind with Ca++ and Zn++ ions Ca++ ions

and Zn++ ions are required by the enzyme to maintain its proper

configuration and hydrolytic activity Zn++ ions are located at the

active site of the enzyme while Ca++ are an exogenous co-factor.

2. A further mechanism may be associated with the ability of

tetracyclines to scavenge oxygen radicals (E.g. hyroxyl or

hypochlorous acids) produced by PMNs (Gabler and Creamer,

1991). These oxygen radicals activate latent collagenase. This

inhibitory effect of tetracyclines may also prevent a wider spectrum

of tissue destruction. Also these drugs may have general

antiproteolytic properties. (Gelatinase, Type IV collagenase,

macrophage, elastase).

Tetracyclines and bone resorption:

The antiproteolytic properties of tetracycline, together with their

specific anticollagenase activity has resulted in the application of these

drugs to inhibit bone resorption. Tetracyclines inhibit bone resorption

induced by parathyroid hormone, prostaglandins and bacterial endotoxin

(Golub et al, 1974).

23
 Tetracyclines including chemically modified tetracyclines CMTs

inhibit bone resorption in vitro at concentrations 5-10mg/ml within the in

vivo therapeutic range. This inhibition is reversible; removal of tetracycline

after 48 hours, resulted in resumption of bone resorption.

Mechanism of action:

1. Reduction in ruffled border of osteoclasts function, so decreased

function.

2. Also affect osteoclasts adhesion properties (Rifkin et al, 1993).

3. tetracyclines might inhibit bone degradation by decreased secretion

of collagenolytic cathepsins.

Mechanism of action

1. Osteoclast mediated bone resorption is facilitated by collagenases

secreted by osteoblasts. Tetracyclines (Golub et al especially the

CMT’s inhibit osteoblast collagenase in vivo 1991).

2. These drugs may also have a modifying effect on osteoclasts (Rifkin

et al 1992). This action may be mediated by an altered regulation of

cytoplasmic calcium.

24
5] Antiinflammatory action

Potential anti-inflammatory properties include:

1. The ability of tetracyclines to suppress PMN activity, in particular

the savenging action on reactive oxygen metabolites (Gabler and

Creamer 1991).

2. Alternatively, these drugs may block synthesis arachidane

(especially PGE2) by inhibiting phospholipase A2 activity (Vadas et

al 1991). Therefore treatment effective for ballous pemphigoid,

Rosaca, α 1 antitrypsin deficiency pahhiculitis etc.

6] Tetracycline and fibroblast attachment:

Fundamental to periodontal regeneration is the ability of periodontal

ligament fibroblasts to attach to the root surface. In vitro studies have

shown that pretreatment of dentine with tetracyclines enhances fibroblast

attachment and colonization (Terranova 1986).

These findings suggest that tetracyclines both condition the root

surface and influence the attachment properties of fibroblasts.

These drugs also enhance fibronectin binding.

Mechanism of action:

It is uncertain whether the action of tetracyclines on dentine are due to a:

1. Chemical modification of the properties of dentinal surfaces; or

25
 2. To the release of matrix components from the dentine (i.e. Type I

collagen, proteoglycans, osteonectin and growth factors).

Clinical efficiency of tetracyclines in periodontal therapy:

1. Chronic adult periodontitis little / no advantage over a conventional

therapy.

2. Refractory periodontal disease:1g/day for 14-2 blays + conventional

(Rams 1985) therapy.

3. Juvenile periodontitis 1g/day for 14 days and surgical / non-surgical

treatment (Lindhe 1982).

4. Prepubertal periodontitis after 8 years of age after sensitivity testing

(when crowns of permanent teeth have calcified (Mandell, 1996).

5. Desquamative gingivitis: doxycycline used for treatment of oral

lichen planus or pemphigoid, 11/14 patients showed improvement

(Roenbud et al, 1996).

Other uses:

Tetracyclines can be used in various cutaneous diseases:

1. Root conditioning: disappointing results (Seymour and Heasman).

2. As adjuncts to bone grafting – tetracycline combined with

betatricalcium phosphate, hydroxyapatite, freeze dried and freed

26
 fried bone allografts have been tried and given encouraging results

(Marby et al).

3. Tetracyclines may be benefit to new attachment procedures like

GTR combined with eptfe membrane) [Markman et al, 1995].

4. Recently Golub et al (1992) developed a series of chemically

modified analogous of tetracyclines (CMT’s) which retain their anti-

matrix metalloproteinases (MMP) activity, but which are no longer

antimicrobials- may be useful in various connective tissue disorders.

5. Tetracycline + Antifungal agents – diabetes and debilitated patients,

bullous pemphigoid.

Side effects:

1. Gastrointestinal disturbances diarrhoea, nausea and vomiting,

colitis, oesophageal ulceration.

2. Overgrowth of resistant organism : stomatitis, vaginitis.

3. Photosensitivity.

4. Skin rashes.

5. Hyper sensitivity reaction.

6. Verstibular disturbance (minocycline only).

7. Increase in intracranial pressure.

27
Contraindications Possible sequela

1. Pregnancy Staining of deciduous teeth,

depression of bone growth
(reversible)

2. Breast feeding Staining of deciduous teeth, git

disturbances in children

3. Children < 8 years Staining of developing teeth

4. Renal impairment Axotaemia and aggrevate uraemia

(use doxycycline)

5. Hepatic disease Fatty changes

6. Systemic lupus Exacerbation of lesions

Erythomatosis

Drug interactions Possible sequelae

1. Penicillin and other Antagonism of bactericidal action

bactericidal antibiotics (Bactericidal act during cell
division which is impaired by
bacteriostatic drugs).

2. Antacids and Iron Impaired absorption of

preparations tetracyclines.

3. Insulin Oxytetracycline enhances the

hypoglycemic action of insulin

4. Contraceptive pill Pill failure

5. Warfarin sodium Enhanced anticoagulent effect

28
II] Erythromycin

Description

Produced by streptococcus erytheus in 1952. They are classified as

macrolide antibiotics. One of the safer antibiotics in use and often a

satisfactory alternative to penicillin particularly in patients allergic to

penicillin.

Mechanism of action:

Binds to 305 ribosomes, thereby inhibiting protein synthesis.

Absorption:

Destroyed by gastric acid. So administered in Lenteric water tablet,

(Erythromycin).

Excretion

Via urine and bile.

Clinical use

It does not concentrate in GCF and is not effective against most

putative periodontal pathogens. Therefore, it is not recommended as an

adjunct to periodontal therapy.

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III] Clindamycin

Description

A chemical derivative of lincomycin produced by streptomyces

lincolnesis.

Mechanism of action

Same as erythromycin

Specturm

It is active against most anaerobic bacteria.

Absorption

Almost total, after oral administration.

Excretion

Metabolized in liver and excreted in bile.

Adverse effects

Most frequently – diarrhoea (10-20%), Cramping. Most important G.I.

complication – pseudomembraneous colitis.

Clinical use:

Clindamycin has shown efficacy in periodontitis refractory to

tetracycline therapy (Tyler et al, 1998). This agent should considered only

30
with medical consultation in penicillin allergic patients when serious

anaerobic infection is present or for the medically compromise patient.

IV] Spiramycin

Description

It is a macrolide antibiotic and is retained in the active state for

prolonged periods in bone, saliva and salivary glands.

Spectrum

It is active against gram +ve organisms including S.mutans and

A.viscous.

Clinical use:

It is used as an adjunct to periodontal therapy in Canada and

Europe. It has shown encouraging results in gingival index, plaque index,

pocket depth and GCF flow (Keyes and Coworkers). In addition it is safe.

Nontoxic drug with few and infrequent side effects and is not in general

use for medical problems.

31
V] Kanamycin

Description:

Chemically similar to streptomycin and neomycin. It has been

studied by Loesche as a topically applied preparation of 5% antibiotic in

orabase in selected mentally handicapped patients and has been found to

improve gingival health. Due to its toxicity and marginal results achieved

with kanamycin it would appear to limit. Its use in all but a small number

of individuals who are not able to maintain oral hygiene with routine

procedures. (Gibson, 1982).

II Inhibition of Cell Wall Synthesis

1. Penicillin

Description

Penicillins are natural and semisynthetic derivatives of both cultures

of penicillin mould with different properties of antibacterial action and

similar properties for allergicity. They have potent antibacterial action on

susceptible species, low toxicity and allergic cross-reactivity with each

other.

Structure

Penicillins are all β -lactams and they have the β -lactamic chain

incorporated in the β -lactam ring.

32
Mechanism of action

They are bactericidal antibiotics; they act on the development of the

bacterial cell wall. The β -lactamic area of penicillins is structurally

similar to the part of the muramic acid pentapeptide which is fundamental

component of the bacterial cell wall. Thus, these antibiotics interfere with

bacterial cell wall synthesis and development, leading to cell lysis.

Penicillin other than amoxycillin and amoxycillin clavulanate

potassium (augmentin) have not been evaluated and their use in periodontal

therapy does not appear to be justified.

Side effects : They may induce allergic reaction (10% of patients allergic

and bacterial resistance.

Amoxicillin

1. It is a semisynthetic penicillin with an extended antimicrobial

spectrum that includes gram+ve and gram-ve bacteria.

2. It demonstrates excellent absorption after oral administration.

3. susceptible to penicillinase (a β -lactamase enzyme) produced by

certain bacteria that opens the lactamic ring and there by renders

penicillin ineffective.

4. Penetrates well into GCF but rapidly hydrolysed if significant levels

of β -lactamases are present.

33
 5. Clinical use- Broad spectrum penicillin for use against a variety of

bacteria that do not produce β -lactamdse (E.coli, Neisseria,

proteus). It may be useful in the management of patients with

refractory or juvenile periodontitis (Carranza, 1996).

Dosage : 500mg.tid.

Penicillinase resistant penicillin

Cloxacillin dicloxacillin and methicillin : They are resistant to

penicillinase (β -lactamase). Indicated for infections known by culture

identifications to be caused by penicillinase secreting staphylococcus

cloxacillin and dicloxacillin are gastric acid stable-well absorbed orally.

Amoxicillin-clavulanate potassium (Augmentin)

Inhibitors of β -lactamase : These agents such as clavulanic acid are

β -lactams lacking antibacterial action. When associated with amoxicillin,

they protect the drug against lactamase hydrolysis and increase the

spectrum of activity of amoxicillin including all bacteria capable of

synthesizing β -lactamase. Augmenting penetrates well in GCF.

Bueus and co-workers reported that augmentin arrested alveolar

bone loss in periodontitis patients that were refractory to treatment with

other antibiotics including tetracycline, metronidazole and clindamycin.

34
III Inhibition of DNA synthesis

Quinolones

Ciprofloxacin is a quinalone active against gram-ve rods, including

all facultative and some anaerobic putative periodontal pathogens. Because

it exerts minimal effect on streptococcus species which are associated with

periodontal health, ciproflaxacin therapy may help in the establishment of

microflora associated with periodontal health. At present, it is the only

antibiotic in periodontal therapy to which all strains of

A.actinomycetumcomitans are susceptible. It has also been used in

combination with metronidazole (Carranza, 1996).

Metronidazole

Description

Metronidazole is a nitro midazole compound developed in France in

1950s to treat protozoan infections.

Structure:

Absorption

It is well absorbed orally, concurrent food ingestion does not inhibit

bioavailability; however absorption may be slowed.

35
Pharmacokinetics

Prior to drug degradation, metronidazole enters tissues,

cerebrospinal fluid, saliva and can be detected in GCF. Increased systemic

dosages of metronidazole (i.e. 500µg tid) would consistently provide a

therapeutic level within pockets to inhibit a larger number of periodontal

pathogens. The drug is primarily metabolized in liver and its metabolites

are excreted in urine and feces.

Spectrum

It is bactericidal at low concentrations for most anaerobes such as

bacteroides (P.gingivalis, P.intermedia), fusabacteria and treponemes

(Concentrations of 0.25 to 5-4 mg/ml required).

Bacteria often inaffected by metronidazole include aerobic

microaerophillic and facultative organisms. Facultative organisms

(A.actinomycetumcomitans), capnocytophaga and Eikinella corrodens)

may be protected. However, metabolites of metronidazole may increase

activity in vivo against these organisms. F.nucleatum inactivates

metronidazole by metabolization which results in protection to other

pathogens (Lacroix, 1981). It also suppresses spirochetes.

Mechanism of action

After drug ingestion, metronidazole enters mammalian cells as well

as aerobic and anaerobic bacteria by diffusion. When the nitro group of this

36
component is reduced by nitroreductase (a ferrodoxin like electron

transport protein), a concentration gradient is developed and more drug

enters the cells. Reduction precipitates release of toxic products (nitro,

nitroso-free radicals and hydroxylamine derivatives). It is believed that

these immediates interfere with DNA synthesis causing disruption of

involved organisms. The reduction process occurs at low oxidation

potentials associated with anaerobic conditions and therefore the drug is

relatively specific for anaerobes.

Resistance

Few organisms appear to be resistant after long term utilization (i.e.

some strains of T.vaginalis and B.fragilis). two mechanisms were proposed

to account to rare instances of acquired resistance.

1. Lowered ability to reduce metronidazole.

2. Decreased drug absorption.

Clinical use

1. As monotherapy – metronidazole is inferior and at best only

equivalent to root planning in the treatment of periodontitis.

2. Metronidazole has been used successfully for treating acute

necrotizing ulcerative gingivitis (Shin, 1962).

3. Administered systematically (750-1000mg/day for 14 days), this

drug reduces the growth of anaerobic flora including spirochetes

37
 and decreases clinical and histopathological signs of periodontitis

(Lindhe et al, 1983).

4. Loesche and coworkers found that 250mg tid for 7 days was of

benefit to patients with diagnosed anaerobic periodontal infection.

5. Combined with conventional therapy, it reduced the need for

surgery when compared with root planning alone. (Loesche, 1992).

6. Combined with augmentin, metronidazole may be of value in

management of patients with refractory or juvenile periodontitis

(Soder and coworkers).

Dosage

The most commonly prescribed drug regimen is 200-250 mg tid for

7 days. As a general rule, antibiotics are usually employed for 48 hours

after eliminating signs of infection. Most periodontal infections can

probably be tested with 14 days or less antibiotic therapy.

Adverse effects

Safe antibiotic: In general, short term utilization of metronidazole is well

tolerated and result in few side effects which resolve upon cessation of

drug intake.

1. GIT discomfort, diarrhoea, nausea, loss of apatite, metallic taste,

uticaria, discoloured urine-Gastric discomfort can be minimized if

medication is taken with meals.

38
 2. Minor and rare C.N.S. effects include vertigo, headaches, and with

high doses, peripheral neuropathy.

3. Blood dyscracias rare.

4. Metronidazole poses little thread of inducing acute toxicity,

mutagenesis and cancer when the drug is used according to

proposed dosing regimens for current therapeutic indications

(Greenstein, 1993).

5. Teratogenecity – Studies involving pregnant women receiving

metronidazole during pregnancy did not report an incidence of teeth

tetratogenecity (Robbie et al, 1993).

Currently, the centers for disease control suggest that metronidazole

should be used during pregnancy only when clearly indicated and avoided

during the first trimester.

Drug interactions Sequelae

1. Alcohol Antabuse effect. Response α to

the amount of alcohol ingested
and results in severe cramps,
nausea and vomiting. To avoid
these effects, patients need to
refrain from using alcholic
products during therapy and 1 day
afterward.

2. Anticoagulants Inhibition of metabolism-

39
 prolonged prothrombin times.

3. Lithium Elevated serum lihium levels.

4. Phenytoin/phenobarbitol Reduced plasma levels of

metronidazole

When metronidazole is administered, patients caries status also

needs to be monitored because this drug is not a good antiplaque agent. It

was found that S.mutans increased after metronidazole therapy and so

caries prone individuals receiving this drug may need supplemental

fluoride therapy (Loesche et al, 1991).

Combination and serial antimicrobial therapy

Rationale:

Since the subgingival microbiota in destructive periodontal disease

consists of various putative pathogens that may differ in antimicrobial

susceptibility, the use of a combination of two or more antibiotics may

represent a valuable approach in periodontal chemotherapy.

Combination antibiotic therapy may help:

1. To broaden the antimicrobial range of the therapeutic regimen

beyond that attained by any single antibiotic.

2. To prevent or forestall the emergence of bacterial resistance by

using agent with overlapping antimicrobial spectra.

40
 3. To lower the dose of individual antibiotics by exploiting possible

synergy between two drugs against targeted organisms.

Disadvantages

1. Increased adverse reactions.

2. Antagonistic drug interactions with improperly selected drugs – A

bactericidal antibiotic should not be used simultaneously with a

bacteriostatic agent because the bactericidal agent exerts activity

during cell division that is impaired by the bacteriostatic drug. E.g. :

of serial antimicrobial therapy.

3. Metronidazole plus amoxicillin, augmenting or ciprofloxacin have

been used successfully in the treatment of advanced periodontitis,

especially with A.actinomycetumcomitans associated infections.

4. Metronidazole + Ciprofloxacin useful for mixed periodontal

infections. Since this combination does not affect most gm+ve

facultative bacteria, it may facilitate recolonization of pocket by

facultative streptococci of low periodontopathic potential and E.g.

of serial antani crabial therapy.

Systemic doxycycline administered initially and then followed

either by augmenting or metronidazole. Sequential use of drugs overcomes

the potential risk of antagonism between bacteriostatic and bactericidal

antibiotics.

41
Guidelines for use of antibiotics (Genco, 1981)

1. For most adults with marginal gingivitis or periodontitis, and no

underlying contributory systemic disease, antibiotics like

tetracycline offer little or no advantage over conventional therapy.

2. For adults with refractory periodontal disease which does not

respond to conventional therapy, a course of systemic antibiotics

may help reduce periodontopathic flora and lead to healing of the

periodontal lesion. Preliminary data indicate that for an adult of

average weight 250mg of tetracycline taken every 6 hours for 14

days is adequate for patients who have antibiotic resistant flora.

Careful anaerobic and aerobic culture of the subgingival flora from

several periodontal lesions, and determination of antibiotic

susceptibility of predominant cultivable organism should be done,

and use of an antibiotic on the basis of these studies.

3. In patients with localized juvenile periodontitis, systemic

administration of antibiotics such as tetracycline appears as a useful

adjunct to non-surgical conventional therapy. Ideally, antibiotic

susceptibility testing should be done prior to selection of the

antibiotic.

4. In patients with systemic disease such as diabetes mellitus, Down’s

syndrome, neutrophil dyscrasias, endocrine disorders or nutritional

deficiencies which influence the severity of periodontal disease, or

42
 in patients taking medication which adversely affect the

periodontium, adjunctive antibiotic therapy should be considered.

For e.g. topical kanamycin applied to teeth and gingiva help reduce

supragingival plaque levels for long periods in institutionalized,

mentally retarded children.

There is a rationale for cultural studies of the periodontal microflora

in systemically compromised patients and administering the appropriate

antibiotic as an adjunct to conventional therapy.

5. When antibiotics are used, the patient should be appropriately

informed of potential side effects and should be evaluated closely

for the occurrence of these adverse reactions.

6. Periodontal patients who are taking antibiotics should be monitored

regularly for clinical changes in the periodontal soft tissues and

alveolar bone and for alteration in the subgingival flora.

Selection of antibiotic regimen

When to use which antibiotic regimen systemic antimicrobial agents

tested and found useful for the treatment of various forms of periodontal

disease : (Proceedings of IInd European Workshop on Periodontics, 1997).

1. Tetracyclines may be indicated for monoinfections of periodontal

A.actinomycetemcomitans (Kornman et al 1997). But they may not

provide sufficient suppression of subgingival pathogens in mixed

43
 infections and thus fail to arrest destructive disease activity (Lindhe,

1982).

2. Metronidazole plus amoxicillin provides a relatively predictable

eradication of periodontal A.actinomycetemcomitans and

P.gingivalis in early onset forms of periodontitis and in refractory

adult periodontitis (Kornman et al, 1984), Ciprofloxacin may

substitute for amoxicillin in case of allergy to β -lactam drugs

(Pavicic et al, 1992).

3. Metronidazole arrest disease progression in refractory periodontitis

patients with P.gingivalis and /or P.intermedia without other

potential pathogens (Loesche et al 1992).

4. Clindamycin has demonstrated efficacy in refractory periodontitis. It

may be considered in periodontal infections with high levels of

peptostreptococcus, β -haemolytic streptococcus and various oral

gm-ve anaerobic rods. (Walker and Gordon, 1990) caution : side

effect: pseudomemranous colitis-superinfection with clostridium d.

5. Amoxicillin plus clavulanicacid may comprise an alternative to

clindamycin in the treatment of periodontitis (Magnusson et al,

1997). It may also increased the gain of clinical attachment obtained

by GTR procedures by killing periodontal pathogens (Nowzari

1995, Nowzari and Slots 1994).

44
 6. Ciprofloxacin may be combined with metronidazole or a β -lactam

drug for treatment of mixed anaerobic infections (Slots and Van

Winkelhoff, 1993). It is effective against enteric rods, pseudomonas,

staphycocci, A.actinomycetemcomitans and other periodontal

organisms (Slots, 1993).

LOCAL DRUG DELIVERY

Why? – When systemic agents are taken orally they are introduced

in pulses that produce peak concentration that differs in time and level for

each body compartment. After the drug reaches a peak blood level there

will be a decrease in concentration, the kinetics of which depend on the

drug metabolism and redistribution within the individual. The systemic

agent is then readministered in pulses with large fluctuations in

concentration. In order to achieve a prolonged effect with systemic agents,

one must either take frequent doses or have an agent that remain active and

is slowly removed from the body. The latter situation is risky as in may

result in toxicity in some individuals.

In addition, high total doses must be used to achieve therapeutic

levels at local sites. Perhaps the greatest concern is that wide use of oral

antibiotics appears to have created resistance to multiple antibacterial

agents in some bacterial strains and resistance factors may be transferred

among intestinal bacterial, thereby increasing the number of resistant

bacterial strains.

45
 Such multiple resistance could limit the usefulness of several

important antibacterial agents and provides one of the principle advantages

of local delivery of antibacterial agents.

Target area in the oral cavity for management of periodontitis is the

subgingival area.

Delivery systems

1) Oral rinses: The primary advantage is that high concentration of the

agent can be delivered to the local site and oral rinses are easy to

use.
Disadvantage : - Requires patient compliance.
- Drug pulses and concentration fluctuations may
limit efficacy.
- Limited to supragingival use.

2) Oral irrigation:

Advantages
1. Easy to use.

2. High concentration of the agent can be delivered to the local

site.

3. Recent advancement has made it possible to safely irrigate

the subgingival area.

Disadvantages: - Requires patient compliance.

- Requires greater patient dexterity.
- Produces fluctuations in drug concentration.

46
 3) Controlled release devices: It refers to delivering active chemicals to

a specified target at a rate and duration designed to accomplish the

intended effect.

Advantages:
1. Reproducible and prolonged constant rate of delivery.
2. Less frequent administration.
3. Greater patient compliance.
4. Reduced side effects as compared to systemic administration.

Disadvantages: Must be professionally applied.

The most widely studied controlled-release device in periodontics

has been tetracycline fibers. Although hollow fibers were initially used, the

current fiber is a monolithic design in which tetracycline permeates an

ethylene / vinyl acetate polymer. The fiber is inserted in the periodontal

pocket and the moisture in the area dissolves the drug from the fiber

surface as well as its interior as the polymer begins to dissolve.

Tetracycline is initially released at a high rate, followed by relatively

steady-state delivery for atleast 10 days.

Goodson J.M. (1987) conducted a study in periodontal pocket which

just 12.7mg of tetracycline fiber when placed in delivered between 643 to

1,590µg/mL over a 10 day period as compared with a total oral dose of 10

g required to maintain therapeutic levels of 4 to 8µg/mL 14 gingival fluid

for 10 days.

47
 CONTENTS

HISTORY

DEFINITION

CLASSIFICATION

GENERAL CONSIDERATION
b) Indications
c) Contraindications
d) Choice of an antibiotic agent
(i) Patient Factors
1. Age
2. Renal and hepatic function
3. Local factors
4. Drug allergy
5. Impaired host defense
6. Pregnancy
7. Genetic factors

(ii) Organism Related Considerations

1. Clinical diagnosis
2. Culture and sensitivity tests

(iii) Drug Factors

1. Spectrum of activity
2. Type of activity
3. Sensitivity of the Organism
4. Toxicity
5. Pharmacokinetics
6. Route of administration

48
 7. Evidence of clinical efficacy
8. Cost

e) Combined use of antibiotics

- Advantages
- Disadvantages

f) Problems that arise with use of antibiotics

i) Toxicity Local
Systemic
ii) Hypersensitivity reactions
iii) Drug resistance Natural
Acquired
Acquired Mutation Conjugation
Genetransfer Transduction
Transformation

49