Clinical Therapeutics

Systematic Review and Meta-Analysis of the Significance of Heterogeneous Vancomycin-Intermediate Staphylococcus aureus Isolates

Sebastiaan J. van Hal, David L. Paterson
DOI: 10.1128/AAC.01133-10

ABSTRACT

The prevalence of heteroresistant vancomycin-intermediate Staphylococcus aureus (hVISA) is 1.3% in published studies. Clinical associations include high-inoculum infections and glycopeptide failure, with hVISA infections associated with a 2.37-times-greater failure rate (95% confidence interval [CI], 1.53 to 3.67) compared to vancomycin-sensitive Staphylococcus aureus (VSSA) infections. Despite this, 30-day mortality rates were similar to those for VSSA infections (odds ratio [OR], 1.18; 95% CI, 0.81 to 1.74). The optimal therapy for hVISA requires further study.

In the presence of selection pressure, vancomycin-susceptible Staphylococcus aureus (VSSA) isolates are able to transform their cell wall and become less susceptible to vancomycin (51). These vancomycin-intermediate S. aureus (VISA) isolates are defined by a vancomycin broth microdilution MIC of 4 to 8 μg/ml (57) and may progress through a precursor phenotype known as heteroresistant vancomycin-intermediate Staphylococcus aureus (hVISA) (11). Although the precise definition is disputed, heteroresistance refers to the presence of a resistant subpopulation (typically at a frequency of ≤10−5 to 10−6 CFU) in a fully susceptible isolate (a broth microdilution MIC of ≤2 μg/ml).

Detection.

hVISA detection is problematic, as commercial susceptibility platforms use inocula lower than the required threshold. As a consequence, multiple screening and detection methods using higher inocula and growth promotion of resistant subpopulations have been developed. Controversy remains, as some of these methods may select for resistant subpopulations in vitro rather than detect the in vivo presence of heteroresistance (60). The most accurate and reproducible method is the modified population analysis profile (PAP)-area under the curve (AUC), which utilizes the plot of the number of viable colonies against vancomycin concentration. An AUC ratio of the test strain to the reference strain (Mu3) of ≥0.9 confirms an hVISA isolate. However, PAP-AUC use is limited as it is expensive and labor- and time-intensive.

Epidemiology.

Following the first documented VISA (Mu50) and hVISA (Mu3) strains from Japan (22, 23), both phenotypes have been reported worldwide. The precise burden of hVISA is difficult to determine given the range of testing methodologies, definitions, and changes in vancomycin susceptibility breakpoints in 2006. This may explain the marked variation in hVISA prevalences detected across institutions, geographical regions, and patient populations, with surveillance studies generally confirming lower hVISA rates than those for selected clinical isolates. Nevertheless, the overall hVISA prevalence remains low at approximately 1.3% of all methicillin-resistant S. aureus (MRSA) isolates tested (Table 1) (1-6, 8, 9, 12-16, 18-20, 22, 24, 29-39, 41-47, 49, 50, 52, 55, 56, 58, 61).

View this table:
TABLE 1.

Prevalence of hVISA based on method of screening/detection, origin of study, and isolate selection

Clinical significance of hVISA.

All English-language studies containing the term S. aureus and any of the terms reduced susceptibility, intermediate susceptibility, and heteroresistance or heteroresistant to vancomycin or glycopeptides were identified through Medline (2006 to 2010) and reviewed. All articles with clinical details are summarized in Table 2 (2, 4, 5, 8, 16, 24, 28, 31, 33, 37, 38, 41). Considerable heterogeneity exists between studies due to the differing patient populations studied, testing methodologies used, and MRSA isolates selected (i.e., initial blood culture compared to final isolate). Despite this, high-inoculum infections (such as infective endocarditis, osteomyelitis, deep abscesses, and prosthetic device infections) (8, 16, 37) and vancomycin treatment failure (defined as persistent infection or bacteremia duration and/or ongoing signs of infection) (2, 4, 8, 16, 42) were common associations with hVISA infection. After the available data were pooled, the odds of glycopeptide failure were 2.37 times greater for hVISA than for VSSA infections (odds ratio [OR], 2.37; 95% confidence interval [CI], 1.53 to 3.67) (Fig. 1). Since high-inoculum infections are independently associated with bacteremic persistence (therapeutic failure) (10, 17, 31) and de novo hVISA infections do not always result in treatment failure, hVISA may reflect the consequence rather than the cause of treatment failure.

FIG. 1.
FIG. 1.

Forest plot (using Mantel-Haenszel analysis) of events denoting vancomycin (VAN) treatment failure (with all definitions regarded the same) in hVISA- compared to VSSA-infected patients. Squares indicate point estimates, and the size of the square indicates the weight of each study. *, data obtained by personal communication.

View this table:
TABLE 2.

Published studies containing clinical details of hVISA-infected patients

Intuitively, persistent bacteremia should result in greater morbidity. However, compared to VSSA infections, hVISA persistence does not lead to more metastatic complications (41). Other parameters of morbidity have not been extensively examined. A significant increase in the mean hospital stay in patients with hVISA infection has been documented in one study (16). Similarly, infection-related complications are generally not reported (secondary to the heterogeneity of the principal diagnosis) except for one study where hVISA infective endocarditis patients were more likely to develop congestive cardiac failure (4).

Significance of MIC in hVISA.

The proportion of hVISA detected is directly related to increases in vancomycin MIC with the majority (>80%) of hVISA isolates demonstrating an Etest MIC of ≥2 μg/ml (41). Although a detailed discussion of the clinical significance of higher MICs is beyond the scope of this review, several studies have documented greater mortality associated with higher-MIC-susceptible MRSA isolates (generally between 1.5 and 2 μg/ml) (21, 53). Only one study has examined both variables (vancomycin MIC and heteroresistance phenotype) in the same isolates, with neither variable predictive of overall mortality on multivariate analysis (41). Thus, the relative contribution of heteroresistance to MIC-related outcomes remains unclear and requires further study.

Mortality and hVISA.

Since hVISA is associated with parameters known to influence mortality (i.e., high-inoculum infections, persistent bacteremia, and high vancomycin MICs), one would expect an increased mortality compared to that of VSSA infections (Table 2). However, no study to date has had the power to detect such a difference. After all available data from comparative studies were pooled, hVISA was associated with a 30-day mortality rate similar to that of VSSA infections (OR, 1.18; 95% CI, 0.81 to 1.74) (Fig. 2). These findings can in part be explained by the reduced virulence and decreased host immune responses demonstrated in animal infection models and laboratory studies with hVISA infections (27, 40). A clinical study indirectly supports this link, with hVISA significantly more likely to be associated with colonization rather than infection (24).

FIG. 2.
FIG. 2.

Forest plot (using Mantel-Haenszel analysis) of 30-day mortality in hVISA- compared to VSSA-infected patients with “events” denoting deaths in each group. Squares indicate point estimates, and the size of the square indicates the weight of each study.

Conclusion and therapeutic implications.

The role of vancomycin in the treatment of hVISA remains unclear, as heteroresistance may emerge during glycopeptide therapy, especially in infections associated with poor antibiotic penetration (infective endocarditis and osteomyelitis) (8). Despite these deficiencies, no new antibiotic has been documented to be superior to vancomycin (17). Alternative agents have been used successfully in numerous case reports (25). However, potential concerns remain when prescribing these agents. These include toxicity with prolonged linezolid use (7), possible cross-resistance with lipoglycopeptides (54), and the clinical relevance of emerging low-level daptomycin nonsusceptibility during treatment of hVISA infections (48). An important adjunct to antimicrobial therapy and a key component of success is surgical debridement for high-inoculum hVISA infections (26). Irrespective of treatment choice, MRSA bacteremia mortality remains high (59). Therefore, further research should be aimed at developing new agents and defining the optimal pharmacodynamic parameters of current antibiotics, including vancomycin, in targeting specific clinical contexts.

FOOTNOTES

    • Received 16 August 2010.
    • Returned for modification 21 October 2010.
    • Accepted 2 November 2010.
    • Accepted manuscript posted online 15 November 2010.

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