The Rationale for Revising the Clinical and Laboratory Standards Institute Vancomycin Minimal Inhibitory Concentration Interpretive Criteria for Staphylococcus aureus

Clinical Infectious Diseases, May 2007

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 >20 years ago. The disk diffusion breakpoints were modified in 1998 when it was recognized that vancomycin-intermediate S. aureus strains were not detected by this method. In 2006, the vancomycin MIC breakpoints for S. aureus were lowered (from ⩽4 µg/mL to ⩽2 µg/mL for “susceptible,” from 8–16 µg/mL to 4–8 µg/mL for “intermediate,” and from ⩾32 µg/mL to ⩾16 µg/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 ⩾4µg/mL.

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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. - 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)


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Fred C. Tenover, Robert C. Moellering Jr.. The Rationale for Revising the Clinical and Laboratory Standards Institute Vancomycin Minimal Inhibitory Concentration Interpretive Criteria for Staphylococcus aureus, Clinical Infectious Diseases, 2007, pp. 1208-1215, 44/9, DOI: 10.1086/513203