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

  1. Fred C. Tenover1 and
  2. Robert C. Moellering Jr.2
  1. 1Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia
  2. 2Beth Israel Deaconess Medical Center, Boston, Massachusetts
  1. Reprints or correspondence: Dr. Fred C. Tenover, Div. of Healthcare Quality Promotion, Centers for Disease Control and Prevention (G-08), 1600 Clifton Rd., Atlanta, GA 30333 (fnt1{at}cdc.gov).
 
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Abstract

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.

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 (8–16 µg/mL) or borderline-susceptible (4 µg/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 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” [1] (the vancomycin resistance breakpoint was also lowered because of the high likelihood of clinical failure at MICs of 16 µg/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.

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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 [7–9]. The original vancomycin-intermediate S. aureus strain (VISA) was designated Mu50. Subsequently, VISA strains were reported in the United States [10, 11] and around the world [12–14]. 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 4–6 µg 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., 8–16 µg/mL). These organisms were designated as vancomycin-heteroresistant S. aureus (hVISA) strains. The prototype hVISA strain was S. aureus Mu3, a clinical isolate recovered from a Japanese patient with staphylococcal pneumonia [15]. Hiramatsu et al. [15] reported that such heteroresistant strains, which could lead to vancomycin treatment failure, could be differentiated from Mu50-like strains of S. aureus (that were “homogeneously” resistant) by plating a large number of organisms on a BHI agar plate containing 4 µg/mL vancomycin and incubating the plate for 24 and 48 h. Heavy growth on the BHI agar screen plate after 24 h indicated a likely VISA strain, and growth that appeared only after 48 h was likely to represent an hVISA strain [15]. Population analysis curves using incremental dilutions (rather than doubling dilutions) of vancomycin were used to demonstrate the subpopulations of vancomycin-resistant cells [15]. This technique has been used by a number of investigators to study the incidence of hVISA among S. aureus isolates in hospitals [17–19]; however, no population-based studies of heteroresistance have been conducted in the United States.

In June 2002, the first naturally occurring vanA-containing S. aureus isolate was recovered from a patient in Michigan [20]. The vancomycin MIC for the vancomycin-resistant S. aureus (VRSA) isolate was 1024 µg/mL, which is 1000 times the normal vancomycin MIC for S. aureus (i.e., 1 µg/mL) [21–23]. Six additional VRSA isolates for which the vancomycin MICs ranged from 16 to 512 µg/mL [27] have been recovered from patients in Pennsylvania [24], New York [25], and Michigan [26].

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Vancomycin Heteroresistance: A Reassessment

The advent of the “real” (i.e., vanA-containing) VRSA strain overshadowed the discussion of the clinical significance of hVISA strains (i.e., Mu3-like strains that contained subpopulations of cells that were resistant to vancomycin) [15]. Many physicians and microbiologists were skeptical that this difficult-to-detect heteroresistant phenotype signaled MRSA infections that would be refractory to vancomycin therapy, particularly because such strains were susceptible to vancomycin by reference MIC methods [28]. Surveillance studies for hVISA strains rarely commented on clinical outcomes of patients infected with such isolates. British and Japanese literature, which used 8 µg/mL as the breakpoint for vancomycin resistance, preferred the term “hetero-VRSA” (hVRSA) [15, 29]. Data from multiple laboratories demonstrated that the “resistant” subpopulations (i.e., vancomycin MICs of 8–16 µg/mL) typically represented ⩽1 in 105 to 1 in 106 colony-forming units (CFUs) (figure 1), which is why the standard MIC tests—which use only 5 × 104 CFU/well (broth microdilution) or 1 × 104 CFU/spot (agar dilution)—failed to detect these subpopulations.

Figure 1
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Figure 1

Population analysis of a Staphylococcus aureus isolate. The horizontal line at 100,000 colony-forming units represents the limit of detection of the standard broth microdilution MIC reference method. The curve on the left side of the figure represents a vancomycin-susceptible organism. The curve on the right represents a vancomycin-intermediate S. aureus (VISA) strain. The middle curve is a vancomycin-heteroresistant S. aureus (hVISA) isolate that demonstrates the presence of a subpopulation of cells for which the vancomycin MICs are 3–8 µg/mL. This resistant subpopulation is unlikely to be detected by the broth microdilution reference method, because the number of colony-forming units demonstrating the elevated vancomycin MICs (i.e., 3–8 µg/mL) are present in <1 of every 100,000 colony-forming units. VSSA, vancomycin-susceptible S. aureus.

In a quest for better quantitation of hVRSA populations, Wootton et al. [17] used a spiral plating machine to generate population analysis profiles (PAP) of S. aureus isolates suspected of being hVRSA strains. They divided the PAP data by the area under the population curve (AUC) to produce PAP/AUC ratios. PAP/AUC values ⩽0.9 were designated as vancomycin-susceptible S. aureus (VSSA), those with ratios of 1.0–1.3 were defined as hVRSA, and those with ratios ⩾1.3 were designated as VRSA (MICs ⩾8 µg/mL and not those containing vanA). This PAP-AUC procedure became the “gold standard” for investigating the clinical relevance of hVRSA strains in several large surveillance studies. Using the PAP-AUC method, another study (A. Bolmström, unpublished data) demonstrated that, among a convenience sample of S. aureus isolates from around the world, heteroresistant strains could be detected, even among S. aureus isolates for which the broth microdilution MICs were 0.5 µg/mL (figure 2). Thus, there is a poor correlation between a vancomycin MIC result and the presence of heteroresistance. Additional studies from Turkey documented that the hVISA phenotype was not rare but was present in 46 (17.7%) of 256 MRSA isolates tested at Hacettepe University Hospital [30]. The vancomycin MICs of 45 of 46 isolates were 0.25–2 µg/mL, clearly in the susceptible range when tested by the CLSI broth microdilution method. A second study of vancomycin heteroresistant S. aureus isolates in France showed that 255 (11%) of 2300 isolates of S. aureus from Limoges Teaching Hospital were vancomycin heteroresistant, including 7 methicillin-susceptible S. aureus (MSSA) and 248 MRSA isolates [31]. Data on heteroresistance in the United States are lacking.

Figure 2
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Figure 2

Staphylococcus aureus isolates demonstrating heteroresistance to vancomycin therapy. The proportion of isolates demonstrating vancomycin heteroresistance in this selected set of S. aureus isolates (from studies performed at AB Biodisk Laboratories [Solna, Sweden]) is indicated in black, and the isolates in gray represent those isolates that did not show heteroresistance to vancomycin. Heteroresistance was determined by population analysis [17]. This demonstrates that heteroresistance can be detected in strains for which the vancomycin MICs are as low as 1 µg/mL.

Unfortunately, there is no technique that is suitable for routine use in a clinical microbiology laboratory that can detect hVISA strains with the same degree of sensitivity and specificity as the PAP-AUC method [17, 29]. The inability of both automated and standard reference susceptibility testing methods to detect the hVISA phenotype makes it difficult to identify those infections that may not respond to vancomycin therapy. Thus, confirming the presence of a heterogeneously resistant strain of S. aureus remains a difficult challenge for both microbiologists and physicians.

Recent genetic studies of hVISA and VISA isolates revealed mutations in either structural or regulatory genes associated with the accessory gene regulator (agr) pathway of some, but not all, hVISA isolates [32–34]. These mutations result in decreased production of several virulence factors and toxins, such as δ-lysin, but lead to increased production of biofilm matrix, thus rendering them “tolerant” to the killing action of vancomycin. These changes may be the precursor for further genetic alterations that ultimately result in increases in the cell wall thickness and elevated vancomycin MICs, both of which have become the hallmarks of VISA strains. Heteroresistance has been observed only in isolates of agr types 1 and 2 but from all 5 major clonal complexes [35]. Strains with decreased susceptibility to vancomycin may also show decreased susceptibility to daptomycin [36, 37].

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Clinical Relevance of Hvisa: The Beginnings of Outcomes Data

In 2003, Fridkin et al. [38] reported a study of 19 infections caused by S. aureus isolates that showed reduced susceptibility to vancomycin (SA-RSV; i.e., vancomycin MICs of 4 or 8 µg/mL) conducted by the Centers for Disease Control and Prevention (Atlanta, GA). The vancomycin MICs for 4 isolates were 8 µg/mL, and the MICs for the remaining isolates were 4 µg/mL. Forty-two control subjects (with MRSA infections for which the vancomycin MICs of the isolates were ⩽2 µg/mL) were also enrolled in the study. All SA-RSV cases (whether the vancomycin MICs for the isolates were 4 or 8 µg/mL) had similar outcomes. The attributable mortality rate of SA-RSV infection was 63%, compared with 12% for MRSA infection. The primary risk factors for being a case patient were exposure to vancomycin and having an MRSA infection during the previous 2–3 months. Predictors of inhospital death were bacteremia and SA-RSV infection. Thus, those patients with infections with S. aureus for which the vancomycin MICs were 4 µg/mL (susceptible, according to previous breakpoints) had similar outcomes to those with S. aureus infection for which the vancomycin MICs were 8 µg/mL (intermediate, according to previous breakpoints).

Several reports from Australia have focused on the clinical relevance of hVISA strains. Charles et al. [39] reviewed the clinical data for all 46 cases of MRSA bacteremia that occurred in their hospital during a single year. The MRSA isolates recovered from the bacteremic patients were tested blindly using the PAP-AUC method to identify hVISA and VISA isolates. No VISA isolates were identified, but 5 hVISA isolates were documented. The clinical data from chart reviews of the 5 patients infected with vancomycin-heteroresistant MRSA suggested that the patients had sustained fever and bacteremia, high-inoculum infections (i.e., greater bacterial loads), and inappropriately low vancomycin trough levels early in the course of their therapy (which may have selected for the emergence of strains with low-level resistance), compared with patients infected with non—vancomycin-heteroresistant MRSA. Although there were only 5 cases of hVISA, the study laid the groundwork for a second Australian study reported by Howden et al. [40]. This study reviewed the cases of 25 patients in which serious hVISA infections (8 cases of endocarditis, 9 cases of bacteremia with deep-seated infection, 6 cases of osteomyelitis/septic arthritis, and 2 cases of empyema) were confirmed by PAP-AUC analysis. The vancomycin MICs for the isolates ranged from 2 to 4 µg/mL. Of the 25 patients, 19 experienced vancomycin therapy failure (i.e., the patient was bacteremic for >7 days or had a positive sterile site culture result after 21 days of therapy with a glycopeptide). Strain typing studies demonstrated multiple PFGE patterns among the isolates, ruling out the spread of a single strain in the hospital. Four of the patients died. Of the 21 patients treated with agents other than vancomycin, 16 were cured (mostly with linezolid). Thirteen patients required surgical interventions. Aside from sustained bacteremia, there were no clinical features that differentiated cases of hVISA from other cases of MRSA.

A study conducted in the United States by Sakoulas et al. [41] among selected patients suggested that, when vancomycin MICs for MRSA isolates increase to ⩾2 µg/mL, the number of clinical failures for patients treated with vancomycin increases. These investigators reported that the isolates from patients that experienced failure of vancomycin therapy typically showed a decrease in a bactericidal killing assay of <4.1 logs (i.e., <99.99% kill rate) after 72 h, compared with a killing assay of >7.1 logs for isolates from patients who benefited from vancomycin therapy. Moise-Broder et al. [42] reported the results of a study of 63 evaluable patients with MRSA bacteremia of whom 45 experienced failure or were intolerant of vancomycin therapy. When the vancomycin MICs of the isolates increased from 0.5 to 2 µg/mL, the rate of therapeutic failure increased, even though all of the isolates would have been classified as vancomycin susceptible. It should be noted, however, that the cases in both the studies by Sakoulas et al. [41] and Moise-Broder et al. [42] were enriched for vancomycin therapy failures, and therefore, likely overestimate failure rates. Nonetheless, the relationship of MICs to vancomycin clinical failure is striking. A third study of 95 patients by Hidayat et al. [43] confirms that high vancomycin MICs, defined as 1.5–2.0 µg/mL (as measured by the Etest method), is an independent predictor of poor response to vancomycin therapy for MRSA infection, even when vancomycin trough levels >15 µg/mL are achieved. Limited studies using the rabbit endocarditis model also lend support to the importance of hVISA isolates as a cause of vancomycin treatment failure [44].

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Microbial Population Studies

Data from several surveillance studies demonstrate that the modal vancomycin MIC for S. aureus is typically 1 µg/mL [21–23] and that isolates for which the MICs are 4 µg/mL are rare. The Surveillance Network data from US laboratories confirm that vancomycin MICs of 4 µg/mL are rare (<1%) among over 240,000 S. aureus isolates (figure 3). Data from Europe that was made available via the European Union Committee on Antimicrobial Susceptibility Testing Web site [45] showed no S. aureus isolates for which the vancomycin MICs were 4 µg/mL among ∼85,000 organisms.

Figure 3
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Figure 3

The Surveillance Network data for 2005 showing the vancomycin MIC distribution for Staphylococcus aureus (top) and coagulase-negative staphylococci (bottom). These data demonstrate that S. aureus isolates for which the vancomycin MICs are ⩾4 µg/mL are rare in the United States.

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Data From Clinical Trials of Linezolid and Vancomycin

Two published studies compared the outcomes of patients with pneumonia who were treated with either linezolid or vancomycin [46, 47]. Both were retrospective subset analyses of previous trials in which vancomycin appeared to be less effective than linezolid for treatment of pneumonia due to MRSA infection (but not MSSA). These studies, although not without controversy, lend credence to the concept that at least some of the MRSA strains (all of which were “susceptible” to vancomycin by former CLSI criteria) respond less well to vancomycin than do MSSA strains. A similar observation was recently made in a clinical study of the effectiveness of linezolid and vancomycin for treatment of complicated skin and soft-tissue infections [48].

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Survey of the Emerging Infections Network

In February 2005, representatives of the Emerging Infections Network surveyed (via email and facsimile) 891 infectious diseases physicians regarding their experience with treating patients with persistent MRSA bacteremia [49]. Persistent MRSA bacteremia was defined as positive blood culture results for >7 days after initiation of vancomycin therapy. The survey also included questions about the treatment of 2 hypothetical cases of persistent MRSA bacteremia with strains for which the vancomycin MICs were either 2 or 4 µg/mL. A total of 453 physicians (51%) completed the survey. Among the respondents, 283 physicians (62%) estimated that they saw a total of 1147 patients with persistent MRSA bacteremia during 2004. Slightly greater than one-third of the respondents indicated that this was an increase in the number of cases over previous years.

When given the hypothetical case of a patient with persistent MRSA bacteremia with no apparent source, if the vancomycin MIC of the MRSA isolated from a positive blood culture was 2 µg/mL, 72% of the physicians would continue vancomycin therapy but would add another antimicrobial agent to the regimen, and 19% would switch to a different antimicrobial agent. Six percent would increase the dose of vancomycin. However, given the same clinical scenario, but with a MRSA isolate for which the vancomycin MIC was 4 µg/mL, 69% of physicians would switch therapy to an antimicrobial agent other than vancomycin, even though the MIC would still be considered to be in the susceptible range, and 29% would continue vancomycin therapy but add an additional antimicrobial agent. Only 2% would increase the vancomycin dose. These data suggest that the majority of infectious diseases clinicians responding to the Emerging Infections Network survey already considered a vancomycin MIC of 4 µg/mL to be “nonsusceptible.”

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Clinical Cases

Table 1 provides a list of 14 cases—the extent of those in the medical literature plus several personal communications—in which vancomycin therapy failure was documented in the therapy of infections due to staphylococci (mostly MRSA) for which the MIC of vancomycin was 4 µg/mL. In the majority of these cases, there was persistent bacteremia (for as long as 42 days), despite administration of therapeutic doses of vancomycin. The diseases represented include endocarditis, osteomyelitis, and bacteremia, including a case of bacteremia from an infected catheter (which was removed). Without proper denominator data, it is impossible to state with assurance the frequency with which therapeutic failures occurred among patients infected with strains of S. aureus for which vancomycin MICs are 4 µg/mL, nor can we determine how many patients infected with such strains may have responded to vancomycin therapy. It is highly likely, however, that such failures are widely underreported, because most clinical microbiology laboratories in the past would have considered these isolates “susceptible” to vancomycin therapy. Irrespective of the above considerations, the fact that therapeutic failures with prolonged bacteremia have already been documented among 14 patients would argue strongly for lowering the susceptibility breakpoints for vancomycin.

Table 1
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Table 1

Clinical failures of vancomycin therapy among patients infected with Staphylococcus aureus for which the MICs for vancomycin were 4 µg/mL.

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Summary

Surveillance data of >300,000 S. aureus isolates from the United States and Europe show that vancomycin MICs of 4 µg/mL are very unusual and represent <0.3% of all vancomycin MIC values for that species. Thus, lowering the vancomycin breakpoint by 1 doubling dilution would not significantly impact the distribution of “susceptible,” “intermediate,” and “resistant” results for S. aureus infection collected over the past decade but will likely improve the predictive value of a vancomycin-susceptible result. The resistance breakpoint was also lowered, reflecting the clinical judgment that a vancomycin MIC of 16 µg/mL was fully resistant. Data from PAP-AUC studies from England, Australia, and Sweden, and from additional studies using similar methods from Turkey and France, indicate that up to 17.7% of S. aureus isolates for which the vancomycin MICs are 0.5–4 µg/mL are heteroresistant (i.e., contain vancomycin-resistant subpopulations) and, thus, are more likely to result in clinical failure in patients treated with vancomycin. Currently, there is no practical, validated laboratory test that accurately and reproducibly detects heteroresistant S. aureus isolates and that could alert clinicians to patients at greater risk of experiencing vancomycin therapy failure. Lowering the intermediate breakpoint to 4 µg/mL flags those S. aureus isolates that are likely to be heteroresistant and cause vancomycin therapy failure, while retaining high specificity. Although pharmacokinetic data may suggest a susceptible breakpoint of ⩽1 µg/mL, such a breakpoint would encompass 16.2% of S. aureus isolates from the United States (figure 3). This breakpoint was considered but rejected by the CLSI AST Committee. Ultimately, the identification of heteroresistant VISA isolates for which the standard broth microdilution vancomycin MICs are ⩽2 µg/mL will require the development of more sophisticated tests.

On the basis of these data and the clinical experiences of the AST Subcommittee members who are infectious diseases clinicians, the AST Subcommittee lowered the susceptible breakpoint for vancomycin therapy for S. aureus isolates from ⩽4 µg/mL to ⩽2 µg/mL, redefined the intermediate category as 4–8 µg/mL, and lowered the resistance breakpoint to ⩾16 µg/mL. There was no change to the disk diffusion breakpoint for S. aureus isolates. There was also no change in the breakpoints for coagulase-negative staphylococci because of lack of clinical data supporting such as change.

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Acknowledgments

We are grateful to Dr. Daniel Sahm for sharing the Surveillance Network data and Dr. Anne Bolmström for sharing the vancomycin heteroresistance data.

Financial support. The Centers for Disease Control and Prevention.

Potential conflicts of interest. R.C.M. has served as a consultant to Pfizer Laboratories, Cubist Pharmaceticals, Astellas Pharmaceuticals, Targanta Pharmaceuticals, and Sanofi-Aventis. F.C.T.: no conflicts.

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Footnotes

  • The findings and conclusions in this article are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.

  • Received November 7, 2006.
  • Accepted January 1, 2007.
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References

  1. ↵
    CLSI. Performance standards for antimicrobial susceptibility testing. CLSI approved standard M100-S15. Wayne, PA: CLSI; 2005.
  2. ↵
    CLSI. CLSI approved standard M100-S16. Wayne, PA: CLSI; 2006. Performance standards for antimicrobial susceptibility testing.
  3. ↵
    1. Leclercq R,
    2. Derlot E,
    3. Duval J,
    4. et al
    . Plasmid-mediated resistance to vancomycin and teicoplanin in Enterococcus faecium. N Engl J Med 1988;319:157-61.
    MedlineWeb of Science
  4. ↵
    1. Uttley AH,
    2. Collins CH,
    3. Naidoo J,
    4. et al
    . Vancomycin-resistant enterococcus. Lancet 1988;1:57-8.
    CrossRefMedlineWeb of Science
  5. ↵
    Centers for Disease Control and Prevention. Interim guidelines for prevention and control of Staphylococcal infection associated with reduced susceptibility to vancomycin. MMWR Morb Mortal Weekly Rep 1997;46:626-35.
    Medline
  6. ↵
    1. Wenzel RP,
    2. Edmond MB
    . Vancomycin-resistant Staphylococcus aureus: infection control considerations. Clin Infect Dis 1998;27:245-51.
    FREE Full Text
  7. ↵
    1. Hiramatsu K,
    2. Hanaki H,
    3. Ino T,
    4. Yabuta K,
    5. Oguri T,
    6. Tenover FC
    . Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility. J Antimicrob Chemother 1997;40:135-6.
    FREE Full Text
    1. Cui L,
    2. Murakami H,
    3. Kuwahara-Arai K,
    4. Hanaki H,
    5. Hiramatsu K
    . Contribution of a thickened cell wall and its glutamine nonamidated component to the vancomycin resistance expressed by Staphylococcus aureus Mu50. Antimicrob Agents Chemother 2000;44:2276-85.
    Abstract/FREE Full Text
  9. ↵
    1. Hanaki H,
    2. Kuwahara-Arai K,
    3. Boyle-Vavra S,
    4. Daum RS,
    5. Labischinski H,
    6. Hiramatsu K
    . Activated cell-wall synthesis is associated with vancomycin resistance in methicillin-resistant Staphylococcus aureus clinical strains Mu3 and Mu50. J Antimicrob Chemother 1998;42:199-209.
    Abstract/FREE Full Text
  10. ↵
    1. Smith TI,
    2. Pearson ML,
    3. Wilcox KR,
    4. et al
    . Emergence of vancomycin resistance in Staphylococcus aureus. N Engl J Med 1999;340:493-501.
    CrossRefMedlineWeb of Science
  11. ↵
    1. Fridkin SK
    . Vancomycin-intermediate and -resistant Staphylococcus aureus: what the infectious disease specialist needs to know. Clin Infect Dis 2001;32:108-15.
    CrossRefMedlineWeb of Science
  12. ↵
    1. Oliveira GA,
    2. Dell'Aquila AM,
    3. Masiero RL,
    4. et al
    . Isolation in Brazil of nosocomial Staphylococcus aureus with reduced susceptibility to vancomycin. Infect Control Hosp Epidemiol 2001;22:443-8.
    CrossRefMedlineWeb of Science
    1. Ploy MC,
    2. Grelaud C,
    3. Martin C,
    4. de Lumley L,
    5. Denis F
    . First clinical isolate of vancomycin-intermediate Staphylococcus aureus in a French hospital. Lancet 1998;351:1212.
    MedlineWeb of Science
  14. ↵
    1. Kim MN,
    2. Pai CH,
    3. Woo JH,
    4. Ryu JS,
    5. Hiramatsu K
    . Vancomycin-intermediate Staphylococcus aureus in Korea. J Clin Microbiol 2000;38:3879-91.
    Abstract/FREE Full Text
  15. ↵
    1. Hiramatsu K,
    2. Aritaka N,
    3. Hanaki H,
    4. et al
    . Dissemination in Japanese hospitals of strains of Staphylococcus aureus heterogeneously resistant to vancomycin. Lancet 1997;350:1670-3.
    CrossRefMedlineWeb of Science
  16. ↵
    1. Tenover FC,
    2. Lancaster MV,
    3. Hill BC,
    4. et al
    . Characterization of staphylococci with reduced susceptibilities to vancomycin and other glycopeptides. J Clin Microbiol 1998;36:1020-7.
    Abstract/FREE Full Text
  17. ↵
    1. Wootton M,
    2. Howe RA,
    3. Hillman R,
    4. Walsh TR,
    5. Bennett PM,
    6. MacGowan AP
    . A modified population analysis profile (PAP) method to detect heteroresistance to vancomycin in Staphylococcus aureus in a UK hospital. J Antimicrob Chemother 2001;47:399-403.
    Abstract/FREE Full Text
    1. Ariza J,
    2. Pujol M,
    3. Cabo J,
    4. et al
    . Vancomycin in surgical infections due to meticillin-resistant Staphylococcus aureus with heterogeneous resistance to vancomycin. Lancet 1999;353:1587-8.
    CrossRefMedlineWeb of Science
  19. ↵
    1. Van Griethuysen A,
    2. Van t Veen A,
    3. Buiting A,
    4. Walsh T,
    5. Kluytmans J
    . High percentage of methicillin-resistant Staphylococcus aureus isolates with reduced susceptibility to glycopeptides in the Netherlands. J Clin Microbiol 2003;41:2487-91.
    Abstract/FREE Full Text
  20. ↵
    1. Chang S,
    2. Sievert DM,
    3. Hageman JC,
    4. et al
    . Infection with vancomycin-resistant Staphylococcus aureus containing the vanA resistance gene. New Engl J Med 2003;348:1342-7.
    CrossRefMedlineWeb of Science
  21. ↵
    1. Rybak M-J,
    2. Hershberger E,
    3. Moldovan T,
    4. Grucz RG
    . In vitro activities of daptomycin, vancomycin, linezolid, and quinupristin-dalfopristin against staphylococci and enterococci, including vancomycin-intermediate and -resistant strains. Antimicrob Agents Chemother 2000;44:1062-6.
    Abstract/FREE Full Text
    1. Streit JM,
    2. Jones RN,
    3. Sader HS
    . Daptomycin activity and spectrum: a worldwide sample of 6737 clinical Gram-positive organisms. J Antimicrob Chemother 2004;53:669-74.
    Abstract/FREE Full Text
  23. ↵
    1. Jones RN,
    2. Stilwell MG,
    3. Sader HS,
    4. Fritsche TR,
    5. Goldstein BP
    . Spectrum and potency of dalbavancin tested against 3322 gram-positive cocci isolated in the United States Surveillance Program (2004). Diagn Microbiol Infect Dis 2006;54:149-53.
    CrossRefMedlineWeb of Science
  24. ↵
    1. Tenover FC,
    2. Weigel LM,
    3. Appelbaum PC,
    4. et al
    . Vancomycin-resistant Staphylococcus aureus isolate from a patient in Pennsylvania. Antimicrob Agents Chemother 2004;48:275-80.
    Abstract/FREE Full Text
  25. ↵
    Centers for Disease Control and Prevention. Vancomycin-resistant Staphylococcus aureus: New York, 2004. MMWR Morb Mortal Wkly Rep 2004;53:322-3.
    Medline
  26. ↵
    1. Madhavan T,
    2. Sievert D,
    3. Rudrik J,
    4. Torresan J,
    5. Schulman D
    . Program and abstracts of the 43rd Annual Meeting of the Infectious Diseases Society of America. San Francisco, CA: Alexandria, VA: Infectious Diseases Society of America; 2005. Vancomycin-resistant Staphylococcus aureus infection of a gangrenous toe in a community hospital [abstract 1073].
  27. ↵
    1. Carey R,
    2. Patel JB,
    3. McAllister M,
    4. et al
    . Program and abstracts of the 44th International Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: Washington, DC: American Society for Microbiology; 2004. Failure of automated systems to detect vancomycin-resistant Staphylococcus aureus [abstract D-66].
  28. ↵
    1. Goldstein FW,
    2. Kitzis MD
    . Vancomycin-resistant Staphylococcus aureus: no apocalypse now. Clin Microbiol Infect 2003;9:761-5.
    CrossRefMedlineWeb of Science
  29. ↵
    1. Walsh TR,
    2. Bolmstrom A,
    3. Qwarnstrom A,
    4. et al
    . Evaluation of current methods for detection of staphylococci with reduced susceptibility to glycopeptides. J Clin Microbiol 2001;39:2439-44.
    Abstract/FREE Full Text
  30. ↵
    1. Sancak B,
    2. Ercis S,
    3. Menemenlioglu D,
    4. Colakoglu S,
    5. Hascelik G
    . Methicillin-resistant Staphylococcus aureus heterogeneously resistant to vancomycin in a Turkish university hospital. J Antimicrob Chemother 2005;56:519-23.
    Abstract/FREE Full Text
  31. ↵
    1. Garnier F,
    2. Chainier D,
    3. Walsh T,
    4. et al
    . A 1-year surveillance study of glycopeptide-intermediate Staphylococcus aureus strains in a French hospital. J Antimicrob Chemother 2006;57:146-9.
    Abstract/FREE Full Text
  32. ↵
    1. Sakoulas G,
    2. Eliopoulos GM,
    3. Moellering RC Jr,
    4. et al
    . Accessory gene regulator (agr) locus in geographically diverse Staphylococcus aureus isolates with reduced susceptibility to vancomycin. Antimicrob Agents Chemother 2002;46:1492-502.
    Abstract/FREE Full Text
    1. Sakoulas G,
    2. Eliopoulos GM,
    3. Moellering RC Jr,
    4. et al
    . Staphylococcus aureus accessory gene regulator (agr) group II: is there a relationship to the development of intermediate-level glycopeptide resistance? J Infect Dis 2003;187:929-38.
    Abstract/FREE Full Text
  34. ↵
    1. Sakoulas G,
    2. Eliopoulos GM,
    3. Fowler VG Jr,
    4. et al
    . Reduced susceptibility of Staphylococcus aureus to vancomycin and platelet microbicidal protein correlates with defective autolysis and loss of accessory gene regulator (agr) function. Antimicrob Agents Chemother 2005;49:2687-92.
    Abstract/FREE Full Text
  35. ↵
    1. Howe RA,
    2. Monk A,
    3. Wooton M,
    4. Walsh TR,
    5. Enright MC
    . Vancomycin susceptibility within methicillin-resistant Staphylococcus aureus lineages. Emerg Infect Dis 2004;10:855-7.
    MedlineWeb of Science
  36. ↵
    1. Cui L,
    2. Tominaga E,
    3. Neoh H,
    4. Hiramatsu K
    . Correlation between reduced daptomycin susceptibility and vancomycin resistance in vancomycin-intermediate Staphylococcus aureus. Antimicrob Agents Chemother 2006;50:1079-82.
    Abstract/FREE Full Text
  37. ↵
    1. Sakoulas G,
    2. Alder J,
    3. Thauvin-Eliopoulos C,
    4. Moellering RC Jr,
    5. Eliopoulos G
    . Induction of daptomycin heterogeneous susceptibility in Staphylococcus aureus by exposure to vancomycin. Antimicrob Agents Chemother 2006;50:1581-5.
    Abstract/FREE Full Text
  38. ↵
    1. Fridkin SK,
    2. Hageman J,
    3. McDougal LK,
    4. et al
    . Epidemiological and microbiological characterization of infections caused by Staphylococcus aureus with reduced susceptibility to vancomycin, United States, 1997–2001. Clin Infect Dis 2003;36:429-39.
    Abstract/FREE Full Text
  39. ↵
    1. Charles PG,
    2. Ward PB,
    3. Johnson PD,
    4. Howden BP,
    5. Grayson ML
    . Clinical features associated with bacteremia due to heterogeneous vancomycin-intermediate Staphylococcus aureus. Clin Infect Dis 2004;38:448-51.
    Abstract/FREE Full Text
  40. ↵
    1. Howden BP,
    2. Ward PB,
    3. Charles PG,
    4. et al
    . Treatment outcomes for serious infections caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility. Clin Infect Dis 2004;38:521-8.
    Abstract/FREE Full Text
  41. ↵
    1. Sakoulas G,
    2. Moise-Broder PA,
    3. Schentag J,
    4. Forrest A,
    5. Moellering RC Jr,
    6. Eliopoulos GM
    . Relationship of MIC bactericidal activity to efficacy of vancomycin treatment of methicillin-resistant Staphylococcus aureus bacteremia. J Clin Microbiol 2004;42:2398-402.
    Abstract/FREE Full Text
  42. ↵
    1. Moise-Broder PA,
    2. Sakoulas G,
    3. Eliopoulos GM,
    4. Schentag JJ,
    5. Forrest A,
    6. Moellering RC Jr
    . Accessory gene regulator group II polymorphism in methicillin-resistant Staphylococcus aureus is predictive of failure of vancomycin therapy. Clin Infect Dis 2004;38:1700-5.
    Abstract/FREE Full Text
  43. ↵
    1. Hidayat LK,
    2. Hsu DI,
    3. Quist R,
    4. Shriner KA,
    5. Wong-beringer A
    . High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections. Arch Intern Med 2006;166:2138-44.
    Abstract/FREE Full Text
  44. ↵
    1. Moore MR,
    2. Remington-Perdreau F,
    3. Chambers HF
    . Vancomycin treatment failure associated with heterogeneous vancomycin intermediate Staphylococcus aureus in a patient with endocarditis and in the rabbit model of endocarditis. Antimicrob Agents Chemother 2003;47:1262-6.
    Abstract/FREE Full Text
  45. ↵
    European Union Committee on Antimicrobial Susceptibility Testing. Vancomycin/Staphylococcus aureus: antimicrobial wild type distributions of microorganisms—reference database, EUCAST. Available at: http://217.70.33.99/Eucast2/SearchController/regShow.jsp?.Id=1214. Accessed 12 March 2007.
  46. ↵
    1. Wunderink RG,
    2. Rello J,
    3. Cammarata SK,
    4. Croos-Dabrera RV,
    5. Kollef MH
    . Analysis of two double-blind studies of patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia. Chest 2003;124:1789-97.
    Abstract/FREE Full Text
  47. ↵
    1. Rubenstein E,
    2. Cammarata SK,
    3. Oliphant TH,
    4. Wunderink RG
    ; Linezolid Nosocomial Pneumonia Study Group. Linezolid (PNU-100766) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double-blind, multicenter study. Clin Infect Dis 2001;32:402-12.
    Abstract/FREE Full Text
  48. ↵
    1. Weigelt J,
    2. Itani K,
    3. Stevens D,
    4. et al
    . Linezolid versus vancomycin in treatment of complicated skin and soft-tissue infections. Antimicrob Agents Chemother 2005;49:2260-6.
    Abstract/FREE Full Text
  49. ↵
    1. Hageman JC,
    2. Liedtke LA,
    3. Sunenshine RH,
    4. et al
    . Management of persistent bacteremia caused by methicillin-resistant Staphylococcus aureus: a survey of infectious diseases consultants. Clin Infect Dis 2006;43:e42-5.
    Abstract/FREE Full Text
    1. Kohner PC,
    2. Uhl JR,
    3. Cockerill FR III
    . Program and abstracts of the 102nd General Meeting of the American Society for Microbiology. Salt Lake City, UT: Washington, DC: American Society for Microbiology; 2002. Staphylococcus aureus cell wall thickness and the relationship to vancomycin resistance: what is VISA?. [abstract C-95].
    1. Huang V,
    2. Perri M,
    3. Vager D,
    4. Zervos M
    . Program and abstracts of the 16th European Congress of Clinical Microbiology and Infectious Diseases. Nice, France: Basel, Switzerland: European Society of Clinical Microbiology and Infectious Diseases; 2006. Phenotypic characterization of heterogeneous methicillin-susceptible Staphylococcus aureus correlates to patient outcome [abstract P1457].
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  1. Clin Infect Dis. (2007) 44 (9): 1208-1215. doi: 10.1086/513203
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