P1: PSB Printer: Yet To Come
9780521704632c22 CUFX213A/Peck 9780521618168 December 29, 2007 14:51
Section IVOther important drugsGlycopeptides
Glycopeptides are naturally occurring agents that are therapeutically important
because of their gram-positive activity. They are active against most gram-positive
bacteria including Staph. aureus (especially methicillin resistant), coagulase-
negative staphylococci and gram-positive anaerobes such as Clostridia. They have
very limited gram-negative action because the drugs are too large to penetrate the
outer lipid layer of the bacteria. They are not used as first-line agents due to potential
toxicity but are used for prophylaxis in patients at high risk of endocarditis who are
allergic to penicillin.Vancomycinandteicoplaninare the only agents in this group
available in the United Kingdom. They have very similar spectrum and differ mainly
in pharmacokinetic and side-effect profiles.Mechanism of action
These agents are bactericidal antimicrobials that work by inhibiting glycopeptide
synthetase and thus preventing peptidoglycan formation in the bacterial cell wall.Vancomycin
Vancomycin is a complex glycopeptide containing vancosamine and several amino
acid moieties. Initial preparations were associated with a high incidence of nephro-
toxicity and ototoxicity but the incidence of this has declined as the commer-
cial preparations became more refined. Increased use of vancomycin has led to
isolated cases of vancomycin-resistantStaph. aureusin the United Kingdom and
vancomycin-resistant enterococcus has caused extensive outbreaks in other coun-
tries.Kinetics
Vancomycin is not absorbed from healthy intestine but is used orally for antibi-
otic associated pseudomembranous colitis due toClostridium difficile(C. difficile).
Following intravenous administration there is marked individual variability in drug
kinetics with an elimination half-life between 3 and 13 hours. Plasma protein-binding
is quoted between 10% and 80% (the variation is probably due to methodological dif-
ferences). It is well distributed to serous fluids but CSF penetration is very poor even
in the presence of meningitis. Bone penetration is similarly poor with undetectable
bone concentrations in 50% of patients treated for osteomyelitis. Ninety percent is
eliminated in the urine as unchanged drug.
Intravenous administration should be monitored with blood assays to ensure ade-
quate clearance bearing in mind that peak levels are governed predominantly by dose
and trough levels by dose and interval. Maintaining trough levels between 10 and 15
mg.lā^1 will ensure therapeutic efficacy whilst minimizing the chance of renal toxic-
ity. If appropriate doses are administered within therapeutic trough levels, then peak
levels will not exceed safe limits in adults and these levels are therefore not routinely
measured.