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Chloramphenicol & Tetracyclines
This document discusses two broad spectrum antibiotics - chloramphenicol and tetracyclines. It provides details on their mechanisms of action, resistance mechanisms, pharmacokinetics, therapeutic uses, and adverse effects. Chloramphenicol and tetracyclines are bacteriostatic and inhibit bacterial protein synthesis. Their widespread use led to many resistant bacterial strains. Recent interest in their clinical use has increased due to fewer resistant bacteria. The document reviews specifics on the properties and use of each antibiotic.
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Chloramphenicol & Tetracyclines
- 1. Broad spectrum antibiotics: Chloramphenicol & Tetracyclines Dr.Sahil Kumar Department of Pharmacology Maulana Azad Medical College
- 2. Introduction Chloramphenicol andTetracyclines are bacteriostatic antimicrobials. Their widespread use (or misuse) many resistant strains of bacteria minimized clinical usefulness. Paradoxically, recent surge in interest in clinical use (due to almost complete lack of use loss of resistant bacteria from env.)
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- 4. CHLORAMPHENICOL (CHLOROMYCETIN) Isolated 1947; streptomycesvenezuelae Synthesized 1949 ; 1st completely synthetic a/m. Bacteriostatic, broad spectrum aerobic and anerobic gram (+)ve and gram(-)ve . Rickettsiae ; not against chlamydiae May be cidal for H. influenzae, N. meningitides & bacteroides.
- 5. Mechanism of Action Reversiblebinding to 50s inhibits peptidyl transferase (This MOA is similar to macrolides.)
- 6. Ribosomal protection– decreased affinity to ribosomal binding site. Drug less permeable to mutants. Plasmid encoded enzyme acetyltransferase –inactivates the drug Resistance Mechanisms
- 7. Pharmacokinetics Rapid andcomplete oral absorption. Can be given orally/ i.v. Widely distributed in body compartments including CSF. Glucuronyl conjugation in liver inactivation.
- 8. Pharmacokinetics Major excretion byurine (bile and feces also) Dose decreased in new born ; premature infants.
- 9. Therapeutic uses Bacterial meningitis:alternate to beta lactams , Penicillin resistant pneumoccoci or meningocicci Topical ear/ eye preps: conjunctivitis, otitis externa, endophthalmitis. Serious rickettsial infs :Typhus, Rocky mountain spotted fever. Children <8yrs where Tetracyclines are contraindicated. Earlier used to treat typhoid fever.
- 10. Adverse reactions Gastrointestinal disturbances:Nausea, Vomiting, Diarrhoea, Oral/Vaginal candidiasis Bone marrow disturbances: idiosyncratic, dose related ands reversible .Decrease in RBC production ,aplastic anemia. New born infants Toxicity: Def glucuronide conjugation dose >5omg/kg/d gray baby syndrome – vomiting ,hypothermia ,gray colour,collapse. Superinfection
- 11. Drug Interactions Chloramphenicol inhibitsmicrosomal enzymes that metabolize drugs. Chloramphenicol (static) antagonizes bactericidal drugs: Penicillins, Aminoglycosides.
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- 13. Have a nucleusof four (tetra) cyclic rings. Obtained from soil actinomycetes. Spectrum : aerobes, anaerobes, gram +ve, gram -ve, Chlamydia, Rickettsiae, Mycoplasma, Protozoa (plasmodium). Permeation into gram –ve cells : less understood, energy requiring. TETRACYCLINES
- 14. Mechanism of action Inhibitsbacterial protein synthesis. Binds to 30s bacterial ribosome, prevents access of amino acyl t RNA to acceptor site on mRNA –ribosome complex. Prevents addition of amino-acids to growing peptide. High conc impairs protein synthesis in mammalian cells.
- 15. Resistance Mechanisms 1.Decrease inintracellular concentration 2.Development of ribosomal protection proteins 3.Enzymatic inactivation Efflux pump encoded on plasmid Transmitted by transduction /conjugation Plasmids also encode resistance for – Aminoglycosides,sulfonamides,chloramphenicol Cross resistance with other tetracyclines ++
- 16. Short acting:(6-8hrs) Tetracycline, Chlortetracycline, Oxytetracycline Intermediate acting:(12 hrs) Demeclocycline, Methacycline Long acting (16-18 hrs) Minocycline, Doxycycline Glycylcycline: Tigecycline
- 17. Pharmacokinetics Orally remains ingut lumen, modifies flora Absorbed in upper small intestine Impaired by food (except doxy and mino) Ca, Fe, Mg, Al in dairy products and antacids. Distributed in body tissues and fluids, except CSF
- 18. Pharmacokinetics Cross placenta, excretedin milk, chelate with Ca and affect bone and teeth Carbamazepine, phenytoin, barbiturates are enzyme inducers hepatic enzymes are induced, half life reduced. Enterohepatic circulation 10-50% excreted in urine 10-40% excreted in feaces Doxycycline – non renal excretion
- 20. Therapeutic uses Rickettsial infections Mycopasmainfections – pneumonia Chlamydial infections – Lymphogranuloma Venereum - Doxy 100mg bd × 21 d Atypical Pneumonia, bronchitis 10-14 d Trachoma - Doxy 100mg bd × 14 d or Tetra 250mg qid × 14 d (Azithromycin single dose preferred) Non specific urethritis - Doxy 100 mg BD x 7d (Azithromycin single dose preferred)
- 21. Sexually transmitted diseases Uncomplicatedgonoccocal infections C. trachomatis - Doxy 100mg bd ×7 d . Pelvic inflamm diseases : C trachomatis Doxy 100 mg iv 12hrly × 48 hrs Followed by oral therapy –14d Non pregnant ; penicillin allergic patients Prim /sec/ latent syphilis (2nd line agents) Doxycycline 100mg bd ×2 wks ,not to be used in neurosyphillis.
- 22. Brucellosis Tularemia Plague Cholera – Doxy300mg single dose Acne (propionibacteria) -Tetra : 250 mg bd doxycycline 100mg od Minocycline last resort (fears of hepatitis / pneumonitis/ pigmentation) +cost factor
- 23. Adverse effects Gastrointestinal :epigastric burning, distress, nausea, vomiting, abd discomfort (with meals) avoid with dairy products, diarrhoea Pseudomemb. enterocolitis : Cl difficile : life threatening Photo toxicity : Demeclo, Doxy : lesser extent, severe with others, nail pigmentation
- 24. Hepatotoxicity : jaundice,more in pregnancy, oxytetra and tetra – least among group Renal toxicity : aggravate uremia in pts with renal disease. Fanconi syndrome – nausea, vomiting, proteinuria, polydipsia, acidosis, glycosuria, gross aminoaciduria due to outdated preps
- 25. Teeth : browndiscoloration –permanent Diabetes Insipidus – by antagonism of ADH action. Increased Intracranial pressure Vestibular Toxicity Hypersensitivity Reactions
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- 27. Glycylcycline: Tigecycline First memberof new class of synthetic tetracycline analogues. Introduced in 2005. Derivative of Minocycline. Active against bacteria resistant to classical tetracyclines. Apart from usual tetracycline spectrum, also active against MRSA, VRSA, VRE.
- 28. Lack of crossresistance b/w Tetracyclines and Tigecycline because efflux pumps are unable to pump it out. Ribosomal protection is also less effective against Tigecycline.
- 29. Only given byslow i.v. infusion. Approved only for serious pneumonia, complicated skin infections, complicated intra-abdominal infections. A/E – Nausea, vomiting, epigastric distress, diarrhea, skin reactions, photosensitivity, superinfections, pancreatitis. Contraindicated in children, pregnancy.
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