Vancomycin and MRSA: How Susceptible is "Susceptible"?

Abstract & Commentary

Synopsis: A laboratory report indicating susceptibility of MRSA to vancomycin does not guarantee successful therapy with this antibiotic since a significant risk for failure may be present despite MICs within the range considered susceptible.

Source: Sakoulas G, et al. Relationship of MIC and Bactericidal Activity to Efficacy of Vancomycin for Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia. J Clin Microbiol. 2004;42:2398-2402.

Sakoulas and colleagues examined the potential relationship between the outcome of treatment of MRSA bacteremia with vancomycin and the relative degree of in vitro inhibition and killing of the individual patient’s isolates by this antibiotic. Thirty "susceptible" bloodstream MRSA isolates from 30 patients, 23 of whom had failed therapy with vancomycin, were analyzed to determine their susceptibility or resistance to killing by vancomycin. Bactericidal activity was quantitated after 72 hours of incubation of an original inoculum of 107 to 108 CFU/mL in the presence of vancomycin at a concentration of 16 mg/mL.

In-vitro killing ranged widely from 0.17 log10 to 8.16 log10 CFU/mL at 72 hours. There was no significant correlation of bactericidal activity with the MICs of the organisms—all of which were < 2 mg/mL. Bactericidal activity and MIC did each, however, significantly correlate with outcome. The treatment success rate was 0% in those with < 4.71 log10 killing, 23% in those with 4.71 log10—6.26 log10 killing, and 50% in those with a 72 hour kill of > 6.27 log10 CFU/mL. The treatment success rate was 55.6% in those infected with an isolate with a vancomycin MIC < 0.5 mg/mL and only 9.5% in those with an MIC of 1 to 2 mg/mL (P = 0.01). Finally, multivariate analysis demonstrated a statistically significant relationship (P = 0.01) between the increased therapeutic efficacy of vancomycin and both lower vancomycin MIC and increased killing in vitro.

Comment by Stan Deresinski, MD, FACP

We recently discussed on these pages an analysis of 25 MRSA-infected patients who had microbiologic failure after vancomycin therapy, despite the fact that their bacterial isolates were considered vancomycin susceptible, with MICs of 2 to 4 mg/mL.1,2 These isolates were demonstrated by population analysis to have heteroreistance to vancomycin—ie the presence of clonal populations with elevated MICs within the larger, more susceptible population.

The current study did not look for heteroresistance, which likely was present in at least some of the cases examined. The major aim here was to examine the relationships between vancomycin MIC, the bactericidal activity of vancomycin against MRSA, and the therapeutic success or failure after treatment with this agent. This investigative group had previously found a relationship between vancomycin MIC and failure of vancomycin therapy in 87 patients by univariate analysis, but MIC did not prove to be an independent predictor in multivariate analysis.3 The current study found that the efficacy of vancomycin therapy is reduced for MRSA isolates with vancomycin MICs of 1 to 2 mg/mL, values within the range considered to demonstrate susceptibility to this glycopeptide antibiotic since the upper limit is < 4 mg/mL. Furthermore, the extent of in vitro killing of an initial large inoculum by vancomycin at 72 hours also correlated with therapeutic outcome.

The small sample and other aspects of this investigation make it necessary that further larger studies are required to draw firm conclusions. Nonetheless, these results add to the current concern regarding the relative efficacy of vancomycin in the treatment of serious MRSA infections. While it is possible that increasing doses beyond those currently recommended could overcome some of these problems, I believe we are fortunate in having a variety of alternative antistaphylococcal agents available, with more on the horizon.4

References

1. Howden BP,et al. Treatment Outcomes for Serious Infections Caused By Methicillin-Resistant Staphylococcus aureus With Reduced Vancomycin Susceptibility. Clin Infect Dis. 2004;38:521-528.

2. Deresinski S. IDA MRSA With Reduced Susceptibility to Vancomycin. Infectious Disease Alert. 2004.

3. Moise-Broder, et al. Accessory Gene Regulator (AGR) Group II Polymorphism In Methicillin-Resistant Staphylococcus aureus Predicting Failure of Vancomycin Therapy. Clin Infect Dis. 2004;38:1700-1705

4. Deresinski S. IDA MRSA With Reduced Susceptibility to Vancomycin. Infectious Disease Alert. 2004.

Stan Deresinski, MD, FACP, Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, and Editor of Infectious Disease Alert.