Page 822 - Basic _ Clinical Pharmacology ( PDFDrive )

808 SECTION VIII Chemotherapeutic Drugs

Peptidoglycan Amino acid peptide
G = N-acetylglucos-amine
(N-Ag)
G M G M G M G M
Bacterial cell wall M = N-acetylmuramic acid
(N-Am)
Periplasmic space M G M G M G M G

Cytoplasmic membrane
G M G M G M G M
Cytoplasm

Schematic of normal bacterial cell wall peptidoglycan
synthesis transpeptidation reaction.

G M + M G G M G M
Transpeptidase
Crosslinking

M G M G

Vancomycin binds the D-Alanine D-Alanine
terminus of the amino acid peptide, inhibiting V
crosslinkage. V A
A N
N
Vancomycin
G M + M G G M M G

V No crosslinking
A
N

FIGURE 43–8 Schematic of a bacterial cell wall and normal synthesis of cell wall peptidoglycan via transpeptidation; M, N-acetylmuramic
acid; Glc, glucose; NAcGlc or G, N-acetylglucosamine. Vancomycin binds the d-Alanine d-Alanine (d-Ala d-Ala) terminus of the amino acid
peptide, inhibiting cross-linkage of the cell wall.

strains (MIC ≥ 16 mcg/mL), which have acquired the enterococcal dividing; the rate is less than that of the penicillins both in vitro
resistance determinants. The underlying mechanism for reduced and in vivo. Vancomycin is synergistic in vitro with gentamicin
vancomycin susceptibility in vancomycin-intermediate strains and streptomycin against Enterococcus faecium and Enterococcus
(MIC = 4–8 mcg/mL) of S aureus is not fully known. However, faecalis strains that do not exhibit high levels of aminoglycoside
these strains have altered cell wall metabolism that results in a resistance. Vancomycin is active against many Gram-positive
thickened cell wall with increased numbers of d-Ala-d-Ala resi- anaerobes including C difficile.
dues, which serve as dead-end binding sites for vancomycin. Van-
comycin is sequestered within the cell wall by these false targets Pharmacokinetics
and may be unable to reach its site of action.
Vancomycin is poorly absorbed from the intestinal tract and is
Antibacterial Activity administered orally only for the treatment of colitis caused by
C difficile. Parenteral doses must be administered intravenously.
Vancomycin is bactericidal for Gram-positive bacteria in con- A 1-hour intravenous infusion of 1 g produces blood levels of
centrations of 0.5–10 mcg/mL. Most pathogenic staphylococci, 15–30 mcg/mL for 1–2 hours. The drug is widely distributed
including those producing β-lactamase and those resistant to naf- in the body including adipose tissue. Cerebrospinal fluid levels
cillin and methicillin, are killed by 2 mcg/mL or less. Vancomycin 7–30% of simultaneous serum concentrations are achieved if there
kills staphylococci relatively slowly and only if cells are actively is meningeal inflammation. Ninety percent of the drug is excreted