OTHER CELL WALL SYNTHESIS INHIBITORS:

I. GLYCOPEPTIDES

VANCOMYCIN
Mechanism of Action:
- inhibits cell wall synthesis by interfering with the second stage of
peptidoglycan synthesis

Mode of Action:
Bactericidal

Pharmacokinetics:
1. poorly absorbed in GIT
2. given only intravenously since intramuscularly, it is very painful
3. 55% bound to plasma proteins
4. diffuses widely except in noninflamed meninges
5. excreted unchanged through the kidneys

Antimicrobial Spectrum:
1. virtually all gram-positive organisms
2. no significant activity against gram (-) bacteria

Mechanisms of Resistance:
1. permeability barrier provided by outer membrane of bacteria
2. altered target site in gram (+) bacteria
3. no cross-resistance with other antibiotics

Clinical Uses:
1. Alternative drug in:
a. Staphylococcal endocarditis
b. Methicillin-resistant infections
c. Enterococcal infections
d. Diphtheroidinfections
e. Clostridium difficile colitis

2. Synergistic effect with an Aminoglycoside in hard to treat infections.

Adverse Reactions:
1. "Red-neck" Syndrome - after rapid intravenous infusion
2. Ototoxicity - most important and irreversible
3. Nephrotoxicity - in impure preparations

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II. LIPOPEPTIDES

DAPTOMYCIN

 Cyclic lipopeptide fermentation product of Stretomyces roseosporus

 Spectrum: similar to Vancomycin
 More rapidly bactericidal in vitro
 Active against s. aureus and Vancomycin-resistant Enterococci

Mechanism of action;: Binds to cell-wall membrane via a calcium-dependent

insertion of its lipid tail = depolarization of cell membrane with effluc of K+ and
rapid cell death.
 Cleared renally
 May cause myopathy
 Monitor creatinine phosphokinase levels

III. FOSFOMYCIN TROMETAMOL

Mechanism of Action: Stable salt of Fosfomycin

Inhibits the cytoplasmic enzyme enolpyruvate transferase – covalently
binds to cysteine residue of the active site = blocks the addition of
phosphoenolpyruvate to UDP N-acetylglucosamine = blocks formation of N-
acetylmuramic acid (found only in bacterial cell walls)

1. Against both G (+) & G (-) organisms at concentrations ≤ 125 ug/ml

2. In vitro synergism with b-lactams, aminoglycosides, fluoroquinolones
3. Oral or parenteral
4. Oral bioavailability = 40 %
5. Half-life – 4 hours
6. Excretion – kidneys

IV. BACITRACIN

 Cyclic peptide mixture, active against G(+) bacteria

 500 units/g in ointment form (mixed with Polymyxin or Neomycin)
 Treatment of mixed bacterial flora infections in surface wounds, skin or
mucous membranes
 Solutions (100-200 units/ml) : in saline – for irrigation of joints , wounds or
pleural cavity

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Clinical use:
1. Uncomplicated lower urinary tract
2. infections in women
3. Single dose : 3 grams
4. Safe for pregnant women

V. CYCLOSERINE
1. Streptomyces orchidaceus
2. 0.25 g = 20-30 ug/ml (blood levels)
3. Widely distributed in tissues, Water-soluble, unstable in acid pH
4. Inhibits G(+) and G(-)
5. Excretion = kidneys

Mechanism of action: Structural analog of D-alanine

 Inhibits incorporation of D-alanine into peptidoglycan pentapeptide by
inhibiting alanine racemase, which converts L-alanine to D-alanine and
D-alanyl-D-alanine ligase

Adverse reactions:
 Dose-related CNS symptoms: headaches, acute psychosis, seizures
 Avoid effects: < 0.75 g/d