Transcript PHL 424 5th S

PHL 424
Antimicrobials
5th Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
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
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
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