MACROLIDES AND CLINDAMYCIN.ppt
- 1. ANTIBACTERIAL AGENTS The Macrolides & Clindamycin Charles Odongo Okot Gulu University, FOM
- 2. Chemistry and source • They are so called because of the many membered lactone ring to which are attached deoxy sugars • Erythromycin was discovered in metabolic products of Streptomyces erythreus • New synthetic derivatives: Clarithromycin, Azithromycin and Roxithromycin have advantages over erythromycin like less frequent dosing, less GI toxicity increased efficacy and higher tissue levels
- 3. Antibacterial spectrum • Active against gram positive aerobes and some gram negatives like Neiserria, Haemophilus, Bordetella, Campylobacter and Legionella species • Also active against Chlamydia, Rickettsia Mycoplasma and Ureaplasma • Clarithromycin is 2-4X more active than erythromycin against most staphylococcus & streptococcus strains as well as the above gram negatives
- 4. Resistance • This is uncommon but known to occur by 1. Alteration in the 50S ribosomal protein 2. Plasmid mediated methylation of adenine moiety in the 50S ribosomal RNA 3. Enzymatic inactivation 4. Decreased cell membrane permeability of drug Cross resistance among this group occurs
- 5. Pharmacokinetics • They are adequately absorbed in the GIT although food may delay this absorption • Gastric acid also destroys the activity of erythromycin (overcome by acid resistant capsules or the stearate derivative) • They are well distributed in tissues and up to 75% protein bound. Tend to concentrate in the liver and spleen • Does not appreciably enter the CSF even in inflammation
- 6. • It is metabolized in liver by demethylation and excreted in both the urine and bile • Erythromycin has a short half-life of about 1.5 hours, dosage is divided into 4 times • Recommended oral dose ranges between 20-50mg/kg/day Adverse effects • Gastrointestinal effects: these represent a major limitation to erythromycin • Incidences are lower in newer derivatives • Ototoxicity: more likely with I.V use
- 7. • Hepatotoxicity: seen as jaundice, pruritus, fever, hepatomegaly and eosinophilia. It is limited upon discontinuation of drug • Thrombophlebitis is common with I.V use Drug interactions • Has been shown to inhibit cytochrome P450 enzymes increasing theophyline and cyclosporine levels • The concomitant use of terfenidine and astemizole leads to elevated levels of their metabolites, this may lead to arrhythmias
- 8. Therapeutic applications • Useful as a penicillin substitute in treating staphylococcal, streptococcal and pneumococcal infections • Treatment of Mycoplasma and Chlamydia infections • Eradication of bordetella pertusis and diptheriae from the nasopharynx • Eradication of H. pylori and triple therapy • Treatment of gonorrhea and syphilis • Atypical mycobacteria Tx in AIDS patients
- 9. CLINDAMYCIN • A derivative of Lincomycin isolated from products of soil Streptomyces lincolnensis • Belongs to the group called lincosamides • Antibacterial spectrum are similar to that of Macrolides (gram positive organisms) • They are also active against anaerobic bacteria like Bacteroides
- 10. Pharmacokinetics • Well absorbed from the GIT producing a peak in 1-2 hours • Serum levels may reach 4-5 µg/ml • I.M and I.V preparations available and give peak concentrations of 14-15 µg/ml • It is widely distributed in the body, does not appear to concentrate in any particular organ, moderate CSF penetration (40%) • It is highly protein bound (90%)
- 11. • Metabolized in the liver to the dimethyl and sulfoxide derivatives. The former is more active than parent drug • Metabolites are lost via bile with only 28% reaching the kidney • Has a half-life of 2-4 hours • Administered as 10-25 mg/kg/day dosage in four equal doses
- 12. Adverse effects • Gastrointestinal effects as with Macrolides is the major limitation • Pseudomembranous colitis (due to growth of toxin producing Clostridium difficile Indications • Treatment of anaerobic infections in intra- abdominal or pelvic locations, aspiration pneumonias, periodontal infections and pleuropulmonary infections
- 13. • A useful alternative to penicillin in infection with staphylococcus and streptococcus or in prophylaxis for these organisms • Topically effective in acne vulgaris • Combination with primaquine in treatment of Pneumocystis carinii pneumonia • Combination with pyrimethamine in the treatment of toxoplasmosis • Combination with Quinine in treatment of chloroquine resistant malaria