The Role of Vancomycin in the Treatment Paradigm
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Veterans Affairs Medical Center
, 500 W. Fort St., Boise,
Idaho 83702
(dlsteven @mindspring.com). Clinical Infectious Diseases 2006
;
42:S51-7 2005 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2006/4201S1-0008$15.00
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Dennis L. Stevens Infectious Disease Section, Veterans Affairs Medical Center
, Boise,
Idaho
Vancomycin was introduced in the United States in 1956 as a possible treatment for infections due to penicillinresistant Staphylococcus aureus, but it was not used widely because of toxicity and the nearly simultaneous development of semisynthetic antibiotics and cephalosporins. Thus, its main indication was the treatment of serious gram-positive infections in penicillin-allergic patients. For susceptible strains of S. aureus, vancomycin was more rapidly bactericidal than penicillin, nafcillin, or cefazolin, and, in a rabbit model of S. aureus endocarditis, sterilization of vegetations was more rapid with vancomycin. In clinical practice, however, nafcillin remained the treatment of choice for staphylococcal bacteremia, largely because it had failure rates of only 4%. With the appearance of methicillin-resistant S. aureus and coagulase-negative staphylococci, vancomycin became the drug of choice for these infections. Recently, the efficacy of vancomycin has been questioned because of vancomycin's increasing minimum inhibitory concentrations among staphylococci, poor tissue penetration, and apparently slower bacterial killing than previously was recognized.
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FAILURE OF VANCOMYCIN FOR THE
TREATMENT OF STAPHYLOCOCCAL
BACTEREMIA AND ENDOCARDITIS
For susceptible strains of Staphylococcus aureus,
vancomycin was more rapidly bactericidal than were
penicillin, nafcillin, or cefazolin [1], and, in a rabbit model
of S. aureus endocarditis, sterilization of vegetations was
more rapid with vancomycin [1]. In clinical practice,
however, nafcillin remained the treatment of choice for
staphylococcal bacteremia, largely because it had failure
rates of only 4% [2]. In 1977, Esposito and Gleckman
[3] reported cure rates of 63% but partial responses or
treatment failures in 37% of patients treated with
vancomycin for staphylococcal endocarditis. In 1981,
Geraci and Wilson [4] reported a 42% failure rate in
patients treated with vancomycin for endocarditis due to
methicillin-susceptible S. aureus (MSSA). Similarly, in
1990, Small and Chambers [5] reported failure rates of
38% among patients treated with vancomycin for
MSSA endocarditis, compared with failure rates of only
1.4% for patients receiving nafcillin. Finally, in the
treatment of endocarditis caused by MSSA, Gentry et
al. [6] demonstrated complete responses in 74% of
patients treated with nafcillin, compared with 50% of
patients receiving vancomycin. The duration of
bacteremia was 2 days in the nafcillin group and 5 days in the
vancomycin group.
Among patients with MSSA bacteremia, the failure
rate was also higher in patients receiving vancomycin
(20%) than in patients receiving nafcillin (4%) [7].
Bacteremia persisted for 13 days in 20% of patients and for
17 days in 12% of patients receiving vancomycin [7]. In
patients treated with vancomycin for methicillin-resistant
S. aureus (MRSA) endocarditis, the duration of
bacteremia was even more prolonged (mean, 7 days) [5].
IN VITRO SUSCEPTIBILITY, MINIMUM
BACTERICIDAL ACTIVITY, AND
BACTERIAL KILLING
Although susceptibility does not guarantee success,
resistance certainly predicts failure, and several factors
contribute to the failure of vancomycin in treating
staphylococcal bacteremia and endocarditis. First, as
described above, in patients with endocarditis due to
MSSA infection, the rate of bacterial clearance is slower
for vancomycin than for nafcillin. Recently, slower
bacterial killing has also been demonstrated in vitro. For
example, the rate of in vitro bacterial killing of MSSA
isolates was comparatively lower for vancomycin than for
nafcillin (figure 1) [5], a finding that differs from those of studies
performed with strains obtained during the 1960s and 1970s
[1]. Second, most strains remain susceptible to vancomycin;
however, minimum bactericidal concentrations (MBCs) have
been increasing over the course of several decades. The MBC
and its relationship to the MIC determine whether an agent is
bactericidal or bacteriostatic, and an antibiotic with an MBC:
MIC ratio of 1 against a specific pathogen is defined as
bactericidal for that agent. Generally, agents that are bacteriostatic
have MBC:MIC ratios of 48. For antibiotics that are generally
considered to be bactericidal against such pathogens as
staphylococcus (e.g., b-lactams), an MBC:MIC ratio of 132 is
defined as denoting tolerance. Remarkably, MBC:MIC ratios of
416 have been reported for vancomycin [8, 9]. The emergence
of glycopeptide-intermediate S. aureus (GISA),
vancomycinintermediate S. aureus (VISA), and heterogenous GISA and
VISA isolates among patients with serious infections has
become problematic, as (...truncated)