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


We tested 173 MRSA bloodstream isolates from 154 patients. For the following reasons, we excluded 24 isolates from the analysis: 19 represented additional isolates from patients already included in the cohort, 4 came from outpatients, and 1 came from a patient whose hospital stay extended beyond the study period. Thus, we evaluated 149 isolates, each cultured from the blood of a unique inpatient, and will describe them here.

All isolates were susceptible to vancomycin (MIC50, 1 mg/L; MIC90, 1 mg/L; range 0.5-2 mg/L). Isolates from 61 patients (41% of the patient cohort) grew on screening media within 48 h. Subclones of 46 of these isolates (75%) exhibited a two- to fourfold increase in MIC compared with the parent strain. No subclones, however, exceeded the 4 mg/L NCCLS breakpoint for vancomycin susceptibility (the MIC of vancomycin for all but one subclone was ≤2 mg/L; for one subclone it was 4 mg/L).[1] We therefore did not characterize any of the isolates as hetero-VISA. We characterized isolates with positive results on our screening assay as having heterogeneously reduced susceptibility to vancomycin.

Pulsed-field gel electrophoresis of selected isolates, demonstrating predominant and secondary types.

a) Population analysis of parent isolates and reference strains.

The isolates comprised 11 different PFGE types. We assigned letters and numbers to PFGE types and subtypes, respectively. One hundred and three (69%) were variants of type A, which had 35 different subtypes. Twenty-two (15%) were variants of type B, which had seven different subtypes. The remaining 24 isolates (16%) consisted of nine different types. Type A was associated with the absence of heterogeneously reduced susceptibility (odds ratio [OR] 0.35; p=0.004), whereas type B was associated with its presence (OR 4.86; p=0.002). The results of strain typing and the relationship between type and screening results are summarized in Table 1 . Figure 1 shows the results of PFGE performed on several isolates.

We performed population analysis on eight isolates (four that exhibited growth on screening media and four with no growth) to determine the utility of population analysis in distinguishing between these two types of isolates. The results, represented graphically in Figure 2a, do not enable such a distinction to be made. A shift in the curve is apparent, however, for two isolates with positive screening results from the same patient cultured 14 months apart. For the earlier isolate, the MIC of vancomycin was 0.5 mg/L. For the later isolate, cultured after several interval admissions for MRSA bacteremia in which the patient received vancomycin, the MIC was 1.0 mg/L, and an upwardly shifted population curve (signifying a greater proportion of the population with higher MICs of vancomycin) was observed. A subsequent population analysis, run on selected parent-subclone pairs for isolates that grew on screening media, demonstrated an upward shift in the population curve for the subclone versus the parent when a corresponding increase in MIC existed. A representative population curve is shown in Figure 2b.

A comparison of patients with isolates with positive screening results (cases) to those with negative results (controls) demonstrated no significant differences in terms of age, sex distribution, coexisting chronic conditions, recent hospitalization, or hospital events before culture ( Table 2 ). Similarly, no differences were found between the groups with respect to administration of any antibiotic, administration of vancomycin specifically, or number of days of vancomycin exposure before culture ( Table 3 ). In the cohort analysis of the impact of the screening phenotype on patient outcomes, no differences were noted between cases and controls in the proportion who died during hospitalization (p=1.00; adjusted for severity of illness, p=0.98) or discharge disposition ( Table 4 ). Similarly, for patients who survived until discharge, the time to discharge did not differ between the two groups (hazard ratio 0.99; 95% confidence interval 0.67 to 1.47; p=0.97) after controlling for duration of stay prior to culture.

Given the absence of standardized criteria for determining the screening phenotype, we further analyzed the data using a number of more stringent definitions. If we considered growth on screening media within 48 h with an associated increase in MIC among the subclones as the criteria for a positive screening result (n=46), again no significant predictors of the phenotype and no differences in outcomes were found. Twenty patients (13%) had isolates that grew on screening media within 24 h. Using this characteristic as the screening criterion, we found that the only significant predictor of this phenotype was intensive care unit stay before culture (OR 2.95; 95% confidence interval 1.07 to 8.15; p=0.05); no differences in outcomes were found (data not shown).

Finally, since the criteria for isolate collection were not identical in the two study institutions, we performed a subgroup analysis using data from Beth Israel Deaconess Medical Center patients alone (n=120). This analysis did not change the results using the 48-h growth cutoff. Analysis of these data using the 24-h cutoff showed diabetes mellitus to be the only significant predictor of heterogeneously reduced susceptibility to vancomycin (OR 3.52; 95% confidence interval 1.04 to 11.96; p=0.05), with no differences in outcomes (data not shown).


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