Quinolones

Drugs: norfloxacin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin Mechanism of action:

Inhibit bacterial DNA synthesis by inhibiting DNA gyrase and topoisomerase IV rapid cell death Post antibiotic effect: lasts 1 to 2 hours, increases with increasing concentration

Mechanism of resistance:
Chromosomal:
Alter target enzymes: DNA gyrase and topoisomerase IV Decreased drug penetration: Pseudomonas, E. coli

Plasmid: seen in some K. pneumoniae and E. coli Mutations in both target enzymes are needed to produce significant resistance

Quinolones
Parent drug: nalidixic acid

Classification
Quinolones (1st generation)
Highly protein bound Mostly used in UTIs

Fluoroquinolones (2nd, 3rd and 4th generation) Modified 1st generation quinolones
Not highly protein bound Wide distribution to urine and other tissues; limited CSF penetration.

Generation
1st

Drug Names
nalidixic acid cinoxacin norfloxacin ciprofloxacin enoxacin ofloxacin levofloxacin sparfloxacin moxifloxacin gemifloxacin *trovafloxacin

Spectrum
Gram- but not Pseudomonas species Gram- (including Pseudomonas species), some Gram+ (S. aureus) and some atypicals Same as 2nd generation with extended Gram+ and atypical coverage

2nd

3rd

4th

Same as 3rd generation with broad anaerobic coverage

*withdrawn from the market in 1999

Mechanism of Action
Dual MOA:
1. Inhibition of bacterial DNA Gyrase (Topoisomerase II)
1. 2. Formation of quinolone-DNA-Gyrase complex Induced cleavage of DNA Mechanism poorly understood

2.

Inhibition of bacterial Topoisomerase IV

1.

Mechanism of DNA Gyrase

Mechanism of Action

Quinolones
[Conc] > serum:
Prostate tissue Stool Bile Lung Neutrophils Macrophages Kidneys

[Conc] < serum:

Prostatic tissue fluid Bone CSF

Quinolones
Drug interactions:
absorption: Al3+, Mg2+, and Ca2+ antacids CYP450 inhibition potential drug interactions for ciprofloxacin (Ex) can increase warfarin exposure (real changes in INR are rare, but monitor)

Adverse effects:
GI: Nausea, vomiting CNS: HA, dizziness, confusion, insomnia, delerium, hallucinations, seizure (rare) Cardiovascular: Torsades de pointes (rare) Musculoskeletal: Rupture of tendon (rare) Neurologic: Polyneuropathy (rare)

Quinolones PK/PD

Bactericidal antibiotics Show both time-dependent and a combination of timedependent and concentration dependent killing Time-Dependent vs. Concentration-Dependent Killing

Ciprofloxacin
Administration [Usual Dosage]: IV, PO [500 750 mg q 8-12h] Spectrum: Gram- aerobic rods, and Legionella pneumophila, and other atypicals. Poor activity against Strep. pneumoniae. Indications:
-- Nosocomial pneumonia -- Intra-abdominal infections Uncomplicated/complicated UTI Anthrax exposure and prophylaxis

Unique Qualities:
Binds divalent cations (i.e. Ca & Mg) which decreases absorption -- Increased effects of warfarin

ADRs
QTC prolongation, torsades de pointes, arrhythmias Nausea, GI upset Interstitial nephritis

Levofloxacin

Brand Name: Levaquin, Quixin Administration [Usual Dosage]: IV, PO and ophthalmic [500-750 mg q24h] Spectrum: Gram-, Gram+ (S. aureus including MRSA & S. pneumoniae) and Legionella pneumophila, atypical resp. pathogens, Mycobacterium tuberculosis Indications:
- Chronic bronchitis and CAP Nosocomial pneumonia SSTIs Intra-abdominal infections

Unique Qualities:
Binds divalent cations (i.e. Ca & Mg) which decreases absorption ADRs Blood glucose disturbances in DM patients QTC prolongation, torsades de pointes, arrhythmias Nausea, GI upset Interstitial nephritis

Moxifloxacin
Brand Name: Avelox, Vigamox Administration [Usual Dosage]: IV, PO and ophthalmic [400mg q24h] Spectrum: Gram-, Gram+ (S. aureus including MRSA & S. pneumoniae) & atypicals (L. pneumophila, C pneumonia & M. pneumoniae), Mycobacterium tuberculosis, gram-negative anaerobes Indications:
Chronic bronchitis CAP Bacterial conjuctivitis Sinusitis

Unique Qualities:
Binds divalent cations (i.e. Ca & Mg) which decreases absorption Safety and efficacy not established in patients <18 y.o.

ADRs
Blood glucose disturbances in DM patients QTC prolongation, torsades de pointes, arrhythmias Nausea, GI upset Interstitial nephritis

Resistance Mechanisms
Mutations that enhance antibiotic efflux capability Bacterial chromosomal mutations for genes that encode for bacterial DNA gyrase and Topo IV Mutations in outer membrane porins (Gram-)

Metronidazole
Mechanism of action:
Enters bacteria via cell diffusion Activated via single reduction step by bacteria forms radicals reacts with nucleic acid cell death

Spectrum of activity:
Anaerobic bacteria Microaerophilic bacteria Protozoa

Resistance:
Rare Mechanism: decreased activation ( redox reaction) of drug

Metronidazole
Indications*:
Anaerobe infections C. difficile H. pylori Bacterial vaginosis Trichomonas vaginitis Amebiasis Giardiasis

Drug interactions:
EtOH Antacids CyA/tacrolimus Lithium Phenytoin Rifampin Warfarin

* Dose can vary by indication

Metronidazole
Distribution into tissue:
Therapeutic levels:
PMNs Unobstructed biliary tract Pancreas CSF Empyema fluid Peritoneal fluid Hepatic abscess Pelvic tissues Vaginal/seminal fluid

Adverse Effects:
GI: N, V, epigastric distress Metallic taste Darkening of urine Peripheral neuropathy Pancreatitis Hepatitis Fever Reversible neutropenia

Tetracyclines
Broad-spectrum activity
Includes aerobic G+ and G-, atypicals [Rickettsia spp, treponema spp, chlamydia spp, and others] Little to no effect on fungi or viruses

Tetracycline Doxycycline* Minocycline Tigecycline

www.3dchem.com

Mechanism of Action
Passive diffusion

www.solvo.com

Mechanism of Action
Once inside the cell
Bind 30S ribosomal subunit Blocks binding of aminoacyl-tRNA to acceptor site on mRNA-ribosome complex Protein synthesis is inhibited = bacteriostatic effect

http://genomebiology.com/content/figures/gb-2003-4-12-237-1.jpg

Tetracycline
Dosing:
Adult: 250 - 500 mg PO q6h Peds: 25 - 50 mg/kg/d q6h

Food and milk decrease absorption about 50% Administer at least 1-2 hours prior to or 4 hours after antacid or vitamins due to chelation [Al3+, Mg2+, Ca2+, Fe2+]

www.wikipedia.org

www.3dchem.co m

Tetracycline
Dosage forms:
Capsule: 250, 500 mg Tablet: 250, 500 mg Suspension: 125 mg/5 mL

Adverse Effects:
Photosensitivity Discoloration of teeth N/V/D Candidal superinfection Hepatotoxicity

Tetracycline - Special Populations

Pregnancy
Category D Enters breast milk

Renal insufficiency
CrCl: 50-80 mL/min: every 8-12 hours CrCl: 10-50 mL/min: every 12-24 hours CrCl: <10 mL/min: every 24 hours

Hepatic insufficiency
Avoid use If necessary, maximum 1g/day

Doxycycline
Dosing:
Adults: 100-200 mg/day in 1-2 divided doses PO or IV Peds: > 45 kg use adult dosing
< 45 kg: 2-5 mg/kg/day in 1-2 divided doses. [Max. 200 mg/day]

Give with meals to decrease GI upset Take with water and sit up for 30 minutes to avoid esophageal irritation

http://www2d.biglobe.ne.jp/~chem_env/chem8/doxycycline.gif

http://sitemaker.umich.edu/mc9/files/doxycycline.jpg

Doxycycline
Dosage forms:
Capsules
Hyclate, monohydrate: 50, 100 mg Coated pellets: 75,100 mg Variable release: 40mg - 30 immediate and 10 delayed

Adverse Effects
Discoloration of teeth Diarrhea Rash Photosensitivity Urticaria

Injection: 100 mg Suspension: 25mg/5mL Tablet:

Hyclate: 100 mg Monohydrate: 50,75,100 mg Delayed-release coated pellets: 75,100 mg

Doxycycline - Special Populations

Pregnancy
Category D, but use in pregnancy and Use in children single 5-7 day course for RMSF is safe

Renal Insufficiency
No adjustment necessary

Tigecycline
Dosing:
Adults: initial dose of 100 mg. Maintenance dose: 50 mg q12h x 514 days.

FDA indications: complicated SSTIs and intraabdominal infections

http://www.wyeth.de/images/packshot_tygacil_thumb.jpg http://www.rxlist.com/cgi/images/tygacil1.gif

Tigecycline
Dosage forms:
Injection: 50 mg

Adverse Effects:
N/V/D Hypertension Edema Hypotension Headache Rash Pruritus Local irritation

Administration
Infuse over 30-60 mins through dedicated line or via Y-site. Stable in D5W or NS

Tigecycline - Special Populations

Pregnancy
Category D Not recommended - crosses placenta

Renal Insufficiency
No dosage adjustment required

Hepatic Impairment
Severe: initial dose 100 mg followed by 25 mg q12h

Tigecycline
Aerobic and facultative gram negative organisms:
Citrobacter freundii Enterobacter cloacae Escherichia coli Klebsiella species

Anaerobic organisms:
Bacteroides species (including fragilis) Clostridium perfringens Peptostreptococcus micros

Tigecycline
Distribution: [Gall bladder], [Colon], [Lung] > [Serum] [Bone], [Synovial fluid] < [Serum] Elimination: Mostly feces/biliary excretion (59%) Some excretion in urine (33%) Adverse Effects (incidence): Nausea (29.5%) Vomiting (19.7%) Diarrhea (12.7%) Local reaction (9.0%)

TMP/SMX
Good activity against Gr (+) and Gr (-) organisms: MRSA, very active against PCP. Covers Stenotrophomonas maltophila, Nocardia, and enteric gram-negative rods. Exceptions: Pseudomonas aeruginosa, Group A strep, enterococcus, Gr (-) anaerobes. MOA: Sulfamethoxazole interferes with bacterial folic acid synthesis and growth via inhibition of dihydrofolic acid formation from paraaminobenzoic acid; trimethoprim blocks the production of tetrahydrofolic acid by inhibiting the enzyme dihydrofolate reductase. Use with caution in pts with severe G6PD deficiency Toxicity: GI upset, rash can progress to SJS and TEN, thrombocytopenia, leucopenia, hepatitis; hyperkalemia SMX:TMP is a 5:1 ratio, in oral and IV dosage forms. 10-20 mg/kg (of TMP) daily, in 2 to 4 divided doses (q 6 h) for PCP, Nocardia, Stenotrophomonas, GNR; DS 2 BID for MRSA.

Colistin (polymyxin E)
MOA: binds to lipopolysaccharide on outer cell wall of GNR; permeability change in cell envelope; leakage of cell content. Formulation, IV: colistimethate hydrolyzed to colistin. PK/PD: negligible oral absorption, predominant renal elimination; concentration-dependent activity.

Colistin
Spectrum: aerobic gram-negative rods, including Acinetobacter, Ps. aeruginosa, Stenotrophomonas. NOT active against: Burkholdaria, Proteus, Serratia, Brucella, gram-negative anaerobes, gram-positive cocci Adverse effects: ATN; Neurotoxicity dizziness, weakness, vertigo, visual changes, confusion, ataxia.

Colistin
Dosing regimens (poorly defined):
2.5 to 5 mg/kg/day in 2-4 doses For SCr 1.3 1.5: 160 mg q 12h SCr 1.6 2.5: 160 mg q 24 h SCr > 2.6: 160 mg q 36 h Hemodialysis: Load with 160 mg, then 80 mg after each dialysis.