Lecture 5: Inhibitors of cell wall synthesis III

Vancomycin

Prevents transpeptidation – binds terminal D-ala-D-ala

Inhibits transglyosylation (lesser known mechanism)

Bactericidal

Resistance – mutation of terminal D-ala site

Parenteral (IV) administration: Effective only against G+

DOC against MRSA infections

Useful in treating G+ infections in penicillin-allergic patients

Given orally ONLY to treat infections caused by:

Clostridium difficile - DOC

Staphylococcus (GI superinfection)

Vancomycin Adverse effects

ototoxic

nephrotoxic

“red man” syndrome, flushing from histamine release from mast cells/basophils; more common following a rapid IV infusion

can cause thrombophlebitis on IV injection

Telavancin

derivative of vancomycin, bactericidal against G+ → MRSA

I.V.

Binds D-ala-D-ala to prevent transpeptidation

Increases cell membrane permeability

Use:

complicated skin and skin structure infections

last line agent for nosocomial infections caused by Staphylococcus aureus

Adverse Effects:

Metallic taste

Nephrotoxic, embryofetal toxic

not recommended for use during pregnancy and with preexisting renal insufficiency

Fosfomycin

inhibits cell wall synthesis

prevents NAG to NAM reduction

structurally unrelated to other drugs

active against both G+ and G-

Oral; excreted by kidney

used for uncomplicated lower UTIs in women

combination of fosfomycin and a β-lactam, aminoglycoside or fluoroquinolone is synergistic

Bacitracin

Interferes with final dephosphorylation step in phospholipid carrier cycle → Can’t transport NAG-NAM across the inner membrane

Parenteral (nephrotoxicity) and topical polypeptide antibiotic

active mainly against G+ bacteria

commonly used in combination with neomycin and polymyxins (G- coverage)

Bacitracin most commonly is used topically to prevent superficial skin and eye infections following minor injuries