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MRSA With Reduced Susceptibility to Vancomycin
Abstract & Commentary
Synopsis: Receipt of vancomycin antedated isolation of MRSA with reduced susceptibility to vancomycin in 25 patients.
Source: 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.
Howden and colleagues examined the case histories of 25 patients with infections due to MRSA with reduced susceptibility to vancomycin (SA-RVS). The isolates all had broth microdilution MICs of 2-4 mg/mL and, thus, would be reported as susceptible by NCCLS standards. Reduced susceptibility was confirmed by population analysis profile testing. The latter method involves enumeration of colonial growth on agar containing increasing concentrations of vancomycin with plotting of vancomycin concentration against the viable count and derivation of an area under the curve (AUC). A ratio of the AUC of the test isolate to the corresponding AUC of Mu 3, a known vancomycin heteroresistant isolate, greater than 0.9 was evidence of reduced susceptibility.1
Nine patients had bacteremia without endocarditis and 8 had endocarditis, while 6 had osteomyelitis or septic arthritis and 2 had empyema. All patients had received vancomycin before isolation of SA-RVS, and 16 (64%) had had a trough serum vancomycin concentration < 10 mg/mL. All but 2 patients had MRSA detected prior to detection of SA-RVS, with a median interval between the 2 events of 22 days (range, 3 days-31 months).
Of the 21 patients who received treatment for their SA-RVS infection, linezolid was given, alone or in combination, to 18, with good responses in most.
Comment by 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.
All the isolates in this study would fit into the category of vancomycin-heteroresistant Staphylococcus aureus (hVISA) (see Table 1), although there is no standardized definition of this category. Heteroresistance is the consequence of the presence of clones with reduced susceptibility relative to the larger population of bacterial cells. A compilation of 14 published surveys suggests that 2.2% of MRSA demonstrate heteroresistance to vancomycin.2
The involvement of heteroresistant strains in serious infections is evidence that they retain significant virulence. The therapeutic implications of heteroresistance, however, remain poorly defined. In this study, all infections with SA-RVS were detected in patients who had received or were receiving vancomycin. Eradication of most of the infections occurred with the use of an antibiotic other than vancomycin, most frequently linezolid. Howden et al indicate that approximately two-thirds of the patients had had trough vancomycin concentrations < 10 mg/mL. This concentration (or one close to it) has, however, been somehow chosen by many as the upper limit of trough concentration allowable to avoid toxicity —a proposition for which there are no confirmatory data.
There appears to be an increasingly common general recognition that vancomycin is a "weak stick" against S aureus. A recent analysis of compiled data from 2 clinical trials indicates that linezolid, as an example, is superior to vancomycin in the treatment of nosocomial pneumonia due to MRSA.3 While it is possible that this is the result of the higher lung tissue concentrations achieved with the oxazolidinone antibiotic, it is likely that the relatively poor intrinsic activity of vancomycin played a role.
It is suggested that higher doses of vancomycin than are routinely used would prove more effective. Vancomycin, however, exhibits concentration-independent pharmacodynamics.4 The efficacy of such antibiotics depends primarily upon the proportion of time during the dosing interval that the concentration of the drug remains above the MIC of the infecting organism. For at least some concentration-independent antibiotic-bacteria pairs, it is necessary to remain above the MIC of the pathogen for 40-60% of the dosing interval. Elevating peak concentration to levels greater than 4 or 5 multiples of the MIC has no added effect on bacterial killing. Increasing the dose may, however, overcome some of the problems with tissue penetration.
Fortunately, there are several alternatives to vancomycin for many of these isolates. These include dalfopristin-quinupristin, linezolid, and daptomycin. There are, in addition, a large number of antibiotics in the pipeline with activity against Gram-positive organisms (see Table 2).
Wootton M, et al. J Antimicrob Chemother. 2001;47: 399-403.
2. Liu C, Chambers HF. Antimicrob Agents Chemother. 2003;47:3040-3045.
3. Wunderink RG, et al. Chest. 2003;124:1789-1797.
4. Craig WA. Infect Dis Clin N Am. 2003;17:479-501.