Management of serious meticillin-resistant Staphylococcus aureus infections: what are the limits?

Abstract

Severe (life-threatening) meticillin-resistant Staphylococcus aureus (MRSA) infection continues to be treated with vancomycin despite accumulating evidence of poor outcome, increasing resistance and unachievable pharmacokinetic/pharmacodynamic (PK/PD) targets. The minimum inhibitory concentration (MIC) susceptibility breakpoint for vancomycin was recently reduced to 2 mg/L. Whilst the great majority of clinical isolates are thus still classified as susceptible, the available clinical evidence argues for a method-dependent breakpoint of 0.5 mg/L (broth dilution) or 1.0 mg/L (Etest), which would classify many strains as resistant, or at best intermediate. However, automated susceptibility testing systems are not currently capable of performing accurately at this low level, and such low breakpoints are unsatisfactory because the poor reproducibility of tests (plus or minus one doubling dilution) results in a critical non-reproducibility around the modal MIC of 1 mg/L described in most published data. Therefore, vancomycin should be used with caution in severe (life-threatening) staphylococcal disease and the MIC should always be reported by method. Daptomycin is generally preferred for bacteraemia/endocarditis and linezolid for pneumonia. Better outcome data for vancomycin, based on achievable PK/PD targets and using robust MIC tests, are urgently required.

High Prevalence of Isolates with Reduced Glycopeptide Susceptibility in Persistent or Recurrent Bloodstream Infections Due to Methicillin-Resistant Staphylococcus aureus

“…A number of clinical studies led to controversial opinions on the efficacy of glycopeptide therapy against severe MRSA infections (8,35), especially in bacteremic patients (7,13,18,24,27,40,49). Failure of glycopeptide therapy against invasive MRSA infections may result from suboptimal vancomycin dosing regimens, yielding inadequate tissue levels at the true sites of serious MRSA infection (8,35,40), and/or from its relatively slow bactericidal activity (3,34,36).…”

“…The emergence of intermediate glycopeptide resistance in some MRSA bacteremic isolates represents an additional concern regarding glycopeptide therapy (7,8,18,24,28,35,49). Most of the MRSA isolates that display low-level, endogenously acquired glycopeptide resistance are hard to detect by phenotypic assays.…”

“…Most of the MRSA isolates that display low-level, endogenously acquired glycopeptide resistance are hard to detect by phenotypic assays. Vancomycin-intermediate S. aureus (VISA) isolates are defined by vancomycin MIC breakpoints of Ն4 g/ml and Ͻ16 g/ml and the absence of any vancomycin or teicoplanin resistance determinants (vanA, vanB, or vanC) found in vancomycin-resistant Enterococcus faecalis or high-level vancomycin-resistant (vancomycin MIC, 16 g/ml) S. aureus (VRSA) isolates (7,18,22,24,49). Since VISA isolates are almost uniformly cross-resistant to teicoplanin (28,44), they are frequently designated glycopeptideintermediate S. aureus (GISA).…”

“…hGISA detection by using standard microbiological methods is problematic, and this has triggered the development of alternative assays (24,49), the most popular one being the modified population analysis profile (PAP)-area under the curve (AUC), which utilizes plots of the number of viable colonies against vancomycin concentrations (52,53). However, PAP-AUC is frequently viewed as labor-intensive and expensive, thus being inappropriate for GISA prevalence studies (18,24,33,49,50).…”

“…Indeed, several clinical studies reported higher rates of vancomycin treatment failures and increased median times to bacteremic clearance in patients infected with either hVISA or MRSA isolates for which vancomycin MICs (2 g/ml) were at the upper limit of susceptibility than in those infected with isolates with lower vancomycin MICs (Յ1 g/ml) (8,16,18,21,27,29,35,46,47). However, other recent reports challenged the predictive impact of hVISA detection by the PAP-AUC method in regard to the outcome of glycopeptide therapy in MRSA-infected patients (23,26,38,50).…”