Lecture 6: Inhibitors of Protein Synthesis I

Macrolides drugs

Erythromycin – oral, IV

Clarithromycin - oral

Azithromycin – oral, IV

Macrolides

inhibition of protein synthesis

binds reversibly to 50 S

bacteriostatic

Oral absorption, biliary excretion, fecal elimination

Antibacterial Spectrum :

G+ most susceptible

Azithro- and clarithro- have broader spectrum coverage (more G-) compared to erythromycin

similar spectrum to penicillin G

Chlamydia pneumoniae DOC

Macrolides

Mycoplasma pneumoniae DOC

Macrolides or tetracycline

Legionella species DOC

Macrolides + rifampin or quinolone

Macrolide Resistance

efflux pumps (mrsA, mefA or mefE)

methylation of drug binding site on ribosome (ermABC)

macrolide hydrolysis

50S ribosomal mutation

Macrolides Adverse effects

Diarrhea

QT prolongation and CV events

Drug interactions- CYP3A4

IV erythro - ototoxicity

Hepatic changes

Macrolides GI

Dose-related effect on motilin receptors which stimulate the smooth muscle of the gastrointestinal tract – diarrhea

Erythro > Azithro > Clarithro

Macrolides QT interval prolongation & CV events

QT prolongation – Azithro > Clarithro > erythro

azithromycin and clarithromycin:

Risk of QT prolongation and potentially fatal torsades de pointes

Degree of risk higher in pt with CV disease and disease severity

Macrolides Drug Interactions

Erythro > Clarithro > Azithro

Clindamycin

50S ribosomal subunits

inhibits protein synthesis

active against aerobic G+ cocci and anaerobic G- and G+ organisms

oral, parenteral, and topical

either bacteriostatic or bactericidal

metabolized by the liver, minimally excreted by the kidneys

Osteomyelitis and Toxic Shock Syndrome

Clindamycin Toxicity

pseudomembranous colitis, overgrowth of Clostridium difficile

If symptoms of C. difficile infection arise, immediately stop clindamycin use and initiate vancomycin (oral) treatment

crosses placenta readily and is distributed into breast milk – avoid while nursing

Streptogramins

Dalfopristin and Quinupristin

Inhibit protein synthesis

50S subunit

combination is bactericidal

Aerobic G+

IV

Inhibition of the P450

hepatotoxicity, nausea/vomiting, pain, pruritus, and rash

Contraindications: breast-feeding, children, hepatic disease, pregnancy, streptogramin hypersensitivity

Linezolid

Oxazolidinones

Binds to 50S subunit → Inhibits protein synthesis

Aerobic G+ organisms

IV or oral (oral bioavailability is 100%)

Reversible, non-selective inhibitor of monoamine oxidase (MAO)

myelosuppression, peripheral/optic neuropathy, lactic acidosis

Contraindications: pheochromocytoma

Don’t use w/ SSRI’s → Serotonin syndrome

Pleuromutilin

Oxazolidinones

CABP

Binds to 50S subunit

Oral and IV

Adverse effects: QT, GI, potential for fetal harm → contraception required

Mupirocin

Inhibits protein synthesis

Binds to isoleucyl-tRNA synthetase

G+ and some G-

bacteriostatic at low/bactericidal at high concentrations

topical - skin or the nares (intranasal application for MRSA carriers)

treatment of impetigo caused by S. aureus and S. pyogenes