1. PHL 424 Antimicrobials 5 th Lecture By Abdelkader Ashour, Ph.D. Phone: 4677212Email: aeashour@ksu.edu.sa

2. Inhibitors of bacterial protein synthesis, Clindamycin  Clindamycin is a chlorine-substituted derivative of lincomycin, an antibiotic produced by Streptomyces lincolnensis  Lincomycin, although structurally distinct, resembles erythromycin in activity, but it is toxic and no longer used  MOA:  Clindamycin, like erythromycin, inhibits protein synthesis by interfering with the aminoacyl translocation reaction. It may also interfere at other steps, such as transpeptidation (see MOA of macrolides)  The binding site for clindamycin on the 50S subunit of the bacterial ribosome is identical with that for erythromycin  Although clindamycin, erythromycin and chloramphenicol are not structurally related, they act at sites in close proximity, and binding by one of these antibiotics to the ribosome may inhibit the interaction of the others  There are no clinical indications for the concurrent use of these antibiotics

3. Inhibitors of bacterial protein synthesis, Clindamycin, contd.  Antimicrobial actions:  Clindamycin generally is similar to erythromycin in its in vitro activity against susceptible strains of gram -positive cocci (pneumococci and streptococci) Some strains of streptococci that are macrolide-resistant remain susceptible to clindamycin Clindamycin is more active than erythromycin or clarithromycin against anaerobic bacteria  Methicillin-susceptible strains of S. aureus usually are susceptible to clindamycin, but MRSA are resistant  Essentially all aerobic G-ve bacilli are resistant  Resistance mechanisms: 1.Mutation of the ribosomal receptor site 2.Modification of the receptor (bacterial ribosomal RNA) by a constitutively expressed methylase 3.Enzymatic inactivation of clindamycin 4.G-ve aerobic species are intrinsically resistant because of poor permeability of the outer membrane 5.The presence of an efflux pump  Resistance to clindamycin generally confers cross-resistance to macrolides

4. Inhibitors of bacterial protein synthesis, Clindamycin, contd.  Pharmacokinetics  Clindamycin is nearly completely absorbed following oral administration. The presence of food in the stomach does not reduce absorption significantly  It penetrates well into most tissues, with brain and CSF (even when the meninges are inflamed!) being important exceptions. It penetrates well into abscesses and is actively taken up and concentrated by phagocytic cells  The drug is about 90% protein-bound. It is metabolized by the liver, and both active drug and active metabolites are excreted in bile  Therapeutic Uses:  Clindamycin is indicated in the treatment of serious infections due to susceptible strains of streptococci, pneumococci and staphylococci The high incidence of diarrhea and the occurrence of pseudomembranous colitis limit its use to infections in which it is clearly superior to other agents  It is effective topically (or orally) for acne vulgaris and bacterial vaginosis  It is particularly valuable for the treatment of infections with anaerobes  It has replaced penicillin as the drug of choice for treatment of lung abscess and anaerobic lung and pleural space infections

5. Inhibitors of bacterial protein synthesis, Clindamycin, contd.  Side effects:  Pseudomembranous colitis (the most serious adverse effect ), abdominal pain, esophagitis, nausea, vomiting and diarrhea Antibiotic-associated colitis that has followed administration of clindamycin and other drugs is caused by overgrowth of toxigenic C difficile which elaborates necrotizing toxins This potentially fatal complication must be recognized promptly and treated with metronidazole (the preferred therapy; vancomycin should be reserved for a condition that does not respond to metronidazole)  Skin rashes occur in approximately 10% of patients treated with clindamycin  Impaired liver function (with or without jaundice) and neutropenia sometimes occur  It can inhibit neuromuscular transmission and may potentiate the effect of a neuromuscular blocking agent administered concurrently