Vancomycin heteroresistance and methicillin-resistant Staphylococcus aureus.

Heteroresistance refers to the presence, within a larger population of fully antimicrobial-susceptible microorganisms, of subpopulations with lesser susceptibility. This phenomenon has been described in a wide range of microorganisms, but much recent attention has been directed toward its expression in Staphylococcus aureus. Although it has long been known that resistance to methicillin is characteristically heterogeneously expressed by this organism [1], the current focus revolves around its heteroresistance to vancomycin. Heteroresistant subpopulations of vancomycin-susceptible S. aureus (hVISA) were first described in 1997 [2], shortly after the initial description of vancomycin intermediately susceptible strains (VISA) [3]. hVISA have minimum inhibitory concentrations (MICs) in the intermediately susceptible range and likely represent a step on the path to the development of a fully VISA population. hVISA have been identified among clinical isolates of MRSA at widely varying frequencies, but some recent US reports have been more consistent. During 2003–2007, the proportion of MRSA found to harbor hVISA by the macro Etest in 3 Detroit-area hospitals was 8.3%; this represented an increase from 2.2% in 1986 –1993 and occurred without a contemporaneous increase in VISA isolations [4]. This prevalence in the most recent period is similar to that found in a prospective trial of treatment of S. aureus bacteremia and endocarditis (mostly in the United States), in which 7 (8%) of 89 MRSA isolates, were vancomycin heteroresistant [5]. Vancomycin heteroresistance is present in both hospital and community strains of S. aureus; in the Detroit experience, 56.9% of hVISA belonged to SCCmec type II and 39.4% to SCCmec type IV [4]. The proportion of methicillin-resistant S. aureus (MRSA) isolates demonstrating heteroresistance increases with increasing vancomycin MICs, but heteroresistance is observed in strains with MICs as low as 1.0 g/mL [6]. The phenomenon is inducible and may be either stable or unstable [7]. hVISA are not detected by standard susceptibility testing methods because they are ordinarily present at frequencies of only 10 5 to 10 6 [6]. The gold standard for the identification of hVISA is population analysis, but this is a laborintensive process not suitable for the clinical microbiology laboratory. An alternative method, the macro Etest, has recently been reported to have, relative to population analysis, sensitivities of 80% and 94% and specificities of 87% and 96% for detection of hVISA/VISA when examined at 24 h and 48 h, respectively [8]. The macro Etest, however, requires use of a nonstandard medium and inoculum. A newer method, the Etest GRD strip with incorporation of a nutrient that enhances growth of hVISA/VISA, uses a standard inoculum and medium and has sensitivities of 74% and 94% and specificities of 100% and 95% when read at 24 h and 48 h, respectively [8]. hVISA and VISA generally have a characteristic phenotype, with a thickened cell wall and increased D-ala-D-ala moieties, together with abnormal muropeptide residues and diminished cross-linking of peptidoglycan in association with reduced autolytic activity and slow growth in vitro [9, 10]. The excess dipeptides are believed to “trap” vancomycin, and this, together with the thickened cell wall, may act as a barrier to the diffusion of this large (molecular weight, 1485.7) glycopeptide molecule [11, 12]. It has been speculated that the thickened cell wall may also act as a barrier to daptomycin (molecular weight, 1620.7), thus accounting for vancomycin induction of daptomycin heteroresistance and a reported parallel increase in MIC for this lipopeptide in some Received 10 November 2008; accepted 10 November 2008; electronically published 21 January 2009. Potential conflicts of interest: S.D. is on advisory boards and/or speaking bureaus of Merck, Pfizer, Cubist, Johnson & Johnson, Targanta, Astellas, and Theravance. Financial support: none reported. Reprints or correspondence: Dr. Stan Deresinski, 2900 Whipple Ave., Ste. 115, Redwood City, CA 94062 ([email protected]; [email protected]). The Journal of Infectious Diseases 2009; 199:605–9 © 2009 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2009/19905-0001$15.00 DOI: 10.1086/596630 E D I T O R I A L C O M M E N T A R Y