Other Protein Synthesis Inhibitor Course Coordinator Jamaluddin Shaikh, Ph.D. School of Pharmacy, University of Nizwa Lecture 6 February 16, 2013

Other Protein Synthesis Inhibitor Chloramphenicol Macrolids Erythromycin Clarithromycin Azithromycin Clindamycin 2

Chloramphenicol Active against a wide range of gram-positive and gram-negative organisms Because of its toxicity, its use is restricted However, it was previously used to life-threatening infections for which no alternatives exist

Chloramphenicol: Mechanism of Action Binds to the bacterial 50S ribosomal subunit and inhibits protein synthesis by preventing peptide elongation

Chloramphenicol: Antibacterial Spectrum Have a broad range of antibacterial activity Also effective against organisms other than bacteria, e.g., Rickettsia Rickettsia is a genus of non-motile, Gram-negative, non-sporeforming, highly pleomorphic bacteria that can present as cocci (0.1 μm in diameter), rods (1–4 μm long) or thread-like (10 μm long).

Chloramphenicol: Pharmacokinetics Well absorbed orally Can also be given by intramuscular and intravenous routes Widely distributed and CSF penetration is excelent Mainly undergoes hepatic glucuronidation Half-life is 6 hours. In neonates this is prolonged due to the immaturity of the glucuronidation enzymes

Cholramphenicol: Adverse Effects Hematologic Dose-related erythroid suppression is common, but in addition aplastic anemia occurs Gray baby syndrome The gray color is due to shock (hypotension and tissue hypoperfusion). Chloramphenicol accumulates in neonates (especially if premature) due to reduced glucuronidation in the immature liver Other effects Chloramphenicol can also cause sore mouth, diarrhea, encephalopathy and optic neuritis Erythroid: red-blood cell; Aplastic anemia: a condition where bone marrow does not produce sufficient new cells to replenish blood cells. Anemia refers to low red blood cell counts, but aplastic anemia patients have lower counts of all three blood cell types. Encephalopathy: disorder or disease of the brain. Optic neuritis: inflammation of the optic nerve

Chloramphenicol: Drug Interactions Inhibits metabolism of alcohol, warfarin, phenytoin and theophylline. This can cause clinically important toxicity if effects and/or plasma concentrations of these drugs are not monitored closely and their dose modified accordingly

Other Protein Synthesis Inhibitor Chloramphenicol Macrolids Erythromycin Clarithromycin Azithromycin Clindamycin 9

Erythromycin Uses include respiratory infections, whooping cough, Campylobacter enteritis, and non-specific urethritis A useful alternative to penicillin in penicillin-allergic patients Useful for skin infections such as low-grade cellulitis and infected acne, and is an acceptable drug for patients with an infective exacerbation of chronic bronchitis Urethritis is inflammation of the urethra; Cellulitis is a common skin infection caused by bacteria Campylobacter enteritis is an infection of the small intestine with Campylobacter jejuni bacteria 10

Erythromycin: Mechanism of Action Bind to a site on the bacterial 50S ribosomes, inhibiting the ribosomal translocation step of protein synthesis. 11

Erythromycin: Pharmacokinetics Well absorbed orally Food delays its absorption but may reduce GI side effects Distributed adequately to most sites except the brain and CSF 12

Erythromycin: Adverse Effects Erythromycin is a remarkably safe antibiotic, and may be used in pregnancy and children Nausea, vomiting, diarrhea and abdominal cramps are the most common adverse effects reported Cholestatic jaundice has been reported following prolonged use cholestasis is a condition where bile cannot flow from the liver to the duodenum 13

Erythromycin: Drug Interactions Erythromycin inhibits cytochrome P450 and causes accumulation of theophylline, warfarin and terfenadine. This can result in clinically important adverse effects 14

Comparison of Microlids Erythromycin Azithromycin Clarithromycin T1/2 1-1.5 h 40-60 h 5 h (approx.) Intravenous preparation available Yes No Gastrointestinal adverse effects Common Less common Tissue penetration Reasonable Extremely high High 15

Other Protein Synthesis Inhibitor Chloramphenicol Macrolids Erythromycin Clarithromycin Azithromycin Clindamycin 16

Clindamycin Same mechanism of action as macrolides Useful against anaerobes, such as Bacteroides fragilis Well absorbed by the oral route Distributes well into all body fluids except the CSF Undergoes extensive oxidative metabolism to inactive products Excreted into the bile or urine by glomerular filtration Side effects are skin rash and psudomembranous colitis 17