Clinical Implications of Varying Degrees of Vancomycin Susceptibility in Methicillin-Resistant Staphylococcus aureus Bacteremia

Mitchell J. Schwaber, Sharon B. Wright, Yehuda Carmeli, Lata Venkataraman, Paola C. DeGirolami, Aneta Gramatikova, Trish M. Perl, George Sakoulas, Howard S. Gold


Emerging Infectious Diseases. 2003;9(6) 

In This Article

Abstract and Introduction

We conducted a retrospective study of the clinical aspects of bacteremia caused by methicillin-resistant Staphylococcus aureus (MRSA) with heterogeneously reduced susceptibility to vancomycin. Bloodstream MRSA isolates were screened for reduced susceptibility by using brain-heart infusion agar, including 4 mg/L vancomycin with and without 4% NaCl. Patients whose isolates exhibited growth (case-patients) were compared with those whose isolates did not (controls) for demographics, coexisting chronic conditions, hospital events, antibiotic exposures, and outcomes. Sixty-one (41%) of 149 isolates exhibited growth. Subclones from 46 (75%) of these had a higher MIC of vancomycin than did their parent isolates. No isolates met criteria for vancomycin heteroresistance. No differences in potential predictors or in outcomes were found between case-patients and controls. These data show that patients with vancomycin-susceptible MRSA bacteremia have similar baseline clinical features and outcomes whether or not their bacterial isolates exhibit growth on screening media containing vancomycin.

Staphylococcus aureus is an important cause of illness and death and accounts for about one-fifth of bacteremia cases in the United States.[1] In 1997, Hiramatsu et al. reported the first clinical strain of methicillin-resistant S. aureus (MRSA) that exhibited reduced susceptibility to vancomycin.[2] A report of other such isolates, classified as vancomycin-intermediate S. aureus (VISA), soon followed.[1] Infection with VISA has been associated with vancomycin treatment failures, but it is a rare phenomenon, with worldwide prevalence limited to isolated case reports and a single limited outbreak.[1,3] Rarer still in S. aureusis the phenomenon of vancomycin resistance (VRSA), with only two clinical VRSA isolates reported to date, both in 2002.[4,5] Far more common than VRSA and VISA, however, are MRSA isolates that exhibit "heteroresistance" to vancomycin (hetero-VISA), whereby subpopulations within the strain exhibit reduced susceptibility, although the overall MIC for the isolate is within the susceptible range (≤4 mg/L). A recent survey in Japan found this phenotype in up to 26% of clinical MRSA isolates collected in university hospitals.[6]

Clinical laboratories do not perform heteroresistance testing for a number of reasons: Such testing is cumbersome, no standardized testing methods exist, and, perhaps most important, the clinical significance of this phenotype is not known.[7] Although clinical MRSA isolates exhibiting hetero-VISA have now been reported from several countries,[7,8,9,10,11,12,13,14,15,16] no study has demonstrated that patients with infections caused by these strains fare differently than patients with comparable infections caused by MRSA strains that are homogeneously susceptible to vancomycin.

Throughout this article, we use the following terms to describe different phenotypic features of S. aureus isolates: Vancomycin-susceptible S. aureus (VSSA) refers to isolates that are susceptible to vancomycin, according to NCCLS criteria (MIC ≤4 mg/L).[1] VISA refers to isolates that have intermediate susceptibility to vancomycin per NCCLS criteria (MIC 8-16 mg/L).[17] Hetero-VISA refers to isolates for which the MIC of vancomycin for one or more subpopulations is >4 mg/L, whereas the overall MIC is ≤4 mg/L. VRSA refers to isolates with an MIC of vancomycin ≥32 mg/L.[17]

Many investigators who have looked at hetero-VISA (so named because the resistant subclones have intermediate susceptibility) have first screened for reduced susceptibility to vancomycin and then confirmed hetero-VISA status by demonstrating MICs above the susceptible range (i.e., >4 mg/L) among subclones of those isolates with positive screening results.[6,9,10,12,13,14,15,16] No study has examined isolates that meet screening criteria yet fail to qualify as hetero-VISA on confirmatory testing. Such isolates are composed of subpopulations that, although susceptible to vancomycin, demonstrate varying degrees of susceptibility. Thus they may be capable of a certain degree of growth on screening media containing vancomycin, despite an absence of subpopulations that demonstrate intermediate resistance to vancomycin by MIC criteria. If, as has been suggested, VISA arise from homogeneously vancomycin-susceptible S. aureus through a multistep process,[18] hetero-VISA and, ultimately, VISA may be selected from just such a population of isolates that display heterogeneously reduced susceptibility to vancomycin but do not meet criteria for hetero-VISA. We studied patients with MRSA bacteremia in our institutions to determine the prevalence, among the infecting strains, of hetero-VISA, and of nonhetero-VISA isolates that nevertheless exhibited varying degrees of susceptibility to vancomycin among subpopulations. Additional objectives were to identify factors predictive of bacteremia with such isolates and to determine whether bacteremia with such isolates affected patient outcomes.


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