The Rationale for Revising the Clinical and Laboratory Standards Institute Vancomycin Minimal Inhibitory Concentration Interpretive Criteria for Staphylococcus aureus
0
Beth Israel Deaconess Medical Center
,
Boston, Massachusetts
1
Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention
,
Atlanta
,
Georgia
The Clinical and Laboratory Standards Institute (formerly, the NCCLS) established the susceptibility and resistance breakpoints for minimal inhibitory concentration (MIC) and disk diffusion testing of vancomycin against isolates of Staphylococcus aureus 120 years ago. The disk diffusion breakpoints were modified in 1998 when it was recognized that vancomycinintermediate S. aureus strains were not detected by this method. In 2006, the vancomycin MIC breakpoints for S. aureus were lowered (from 4 mg/mL to 2 mg/mL for susceptible, from 8-16 mg/mL to 4-8 mg/mL for intermediate, and from 32 mg/mL to 16 mg/mL for resistant) to increase detection of heterogeneously resistant isolates of S. aureus. This decision reflected a growing amount of microbiological and clinical data indicating that isolates of S. aureus are less likely to respond to vancomycin therapy when the vancomycin MICs are 4mg/mL.
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In January 2004, the Antimicrobial
Susceptibility Testing (AST) Subcommittee of
the Clinical and Laboratory Standards
Institute (CLSI; formerly, the NCCLS) began
consideration of a proposal to modify the
MIC interpretive criteria (i.e.,
breakpoints) for testing of vancomycin against
isolates of Staphylococcus aureus. Data in
the literature regarding the failure of
vancomycin therapy to cure S. aureus
infection when the vancomycin MICs of the
organisms were in the intermediate (816
mg/mL) or borderline-susceptible (4 mg/
mL) range suggested that the susceptibility
breakpoint used for MIC testing needed
to be reconsidered. The AST
Subcommittee reviewed the following: (1) in vitro
susceptibility testing data from the United
States and Europe, (2) clinical data on the
efficacy of vancomycin therapy for
treating S. aureus infection, (3) results of an
Emerging Infections Network survey on
treatment of persistent
methicillin-resistant S. aureus (MRSA) bacteremia, (4)
clinical trial data regarding vancomycin
versus linezolid for treatment of
pneumonia, and (5) data on vancomycin
heteroresistance in S. aureus isolates. Several
infectious diseases clinicians, serving as
members and advisors of the AST
Subcommittee, also presented their published
and unpublished clinical experiences using
vancomycin therapy to treat borderline
vancomycin-susceptible MRSA infection.
After considering the data presented at 4
meetings over a 2-year period, the AST
Subcommittee lowered the vancomycin
breakpoints from 4 mg/mL to 2 mg/
mL for susceptible, from 816 mg/mL to
48 mg/mL for intermediate, and from
32 mg/mL to 16 mg/mL for resistant
[1] (the vancomycin resistance breakpoint
was also lowered because of the high
likelihood of clinical failure at MICs of 16 mg/
mL). The new CLSI vancomycin
breakpoints for S. aureus were published in
January 2006 [2]. The data considered by
the AST Subcommittee and additional
supporting information will be presented
herein.
HISTORICAL PERSPECTIVE
Concern for the decreasing effectiveness
of vancomycin for treating S. aureus
infection did not begin with a report of
resistance in staphylococci, but rather with
2 reports from France and England of
vancomycin resistance in enterococci [3, 4].
The mechanism of vancomycin resistance
in the French enterococcal isolate was
encoded by a 5-gene operon that included
the novel vanA ligase gene. It was assumed
by many that the vanA-containing operon
would eventually be transferred from
enterococci to S. aureus, resulting in the loss
of vancomycin for treating staphylococcal
infections, particularly those caused by
MRSA isolates [5, 6]. It was a surprise
when the first reported case of
vancomycin resistance in a clinical isolate of
S. aureus was not because of acquisition
of vanA by a strain of MRSA, but rather
was the result of an unusually thickened
staphylococcal cell wall containing
numerous small dipeptides capable of
binding vancomycin, as well as several other
metabolic and structural changes in the
organism [79]. The original
vancomycinintermediate S. aureus strain (VISA) was
designated Mu50. Subsequently, VISA
strains were reported in the United States
[10, 11] and around the world [1214].
None of the isolates contained the vanA
gene. The isolates were classified as
vancomycin-nonsusceptible by the broth
microdilution method and by inoculating
brain heart infusion (BHI) agar screening
plates containing 46 mg of vancomycin
per mL [15]. However, reduced
susceptibility to vancomycin was not detected by
disk diffusion [16].
Use of BHI screening agar identified
groups of isolates that were susceptible to
vancomycin by standard broth
microdilution techniques but contained
subpopulations of cells for which the vancomycin
MICs were in the intermediate range (i.e.,
816 mg/mL). These organisms were
designated as vancomycin-heteroresistant S.
aureus (hVISA) strains. The prototype
hVISA strain was S. aureus Mu3 (...truncated)