PHL 424 Antimicrobials

5th Lecture

By

Abdelkader Ashour, Ph.D. Phone: 4677212 Email: aeashour@ksu.edu.sa

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

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 clindamycinClindamycin 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

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

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