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. 2010 Nov 15;55(1):405–410. doi: 10.1128/AAC.01133-10

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

Sebastiaan J van Hal 1,*, David L Paterson 2
PMCID: PMC3019654  PMID: 21078939

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).

TABLE 1.

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

Screening testa Confirmationa Country or region (reference[s]) Isolate source No. of MRSA isolates No. (%) of hVISA isolates detected
No screening test Macromethod Etest Israel (37, 38) Blood 487 43 (8.8)
Singapore (16) Blood 56 3 (5.4)
USA (41) Blood 489 71 (14.5)
PAP-AUC Australia (8, 24) Blood/any 170 64 (37.6)
World (4) Blood 65 19 (29.2)
Japan (42) Blood 20 2 (10)
Simplified PAP USA (14, 45, 56) Blood 738 3 (0.4)
Europe (50) Any 302 0 (0)
Germany (20) Any 85 7 (8.2)
Simplified PAP PAP Asia (52) Any 1,357 58 (4.3)
Spain (2) Device related 19 14 (73.7)
Japan (22, 29) Any 7,774 35 (0.5)
Korea (32, 33) Any 4,045 24 (0.6)
Germany (6) Any 367 2 (0.5)
Variation of simplified PAP PAP Greece (30) Any 72 1 (1.4)
Italy (39) Any 179 2 (1.1)
Thailand (36, 58) Any 1,049 15 (1.4)
France (44) Any 171 2 (1.2)
Mexico (12) Any 152 1 (0.7)
Belgium (13) Any 2,145 4 (0.2)
Macromethod Etest PAP USA (35) Any 982 2 (0.2)
PAP-AUC USA (46, 47) Blood/any 3,299 140 (4.2)
Ireland (15) Any 3,189 73 (2.3)
UK (34) Blood/nasal 2,550 86 (3.4)
Canada (1) Any 475 25 (5.3)
Screening agar PAP Turkey (49) Any 256 46 (18)
Belgium (43) Nasal/skin 455 3 (0.7)
Korea (9) Any 37,856 18 (<0.1)
PAP-AUC France (19) Any 2,300 255 (11.1)
China (55) Any 200 26 (13)
USA (31) Blood 22 3 (13.6)
Simplified PAP France (5) Any 48 13 (27.1)
MIC based UK (3) Any 11,242 0 (0)
Hong Kong (61) Blood 52 3 (5.8)
MIC based PAP USA (18) Blood 30 0 (0)
Total 82,698 1,063 (1.3)
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a

Screening and/or confirmation testing included the following tests. For a more detailed discussion on the performance of each test, see reference 25. Simplified population analysis profile (PAP): growth of (1 to 30) colonies on brain heart infusion agar supplemented with 4 mg/liter vancomycin at 48 h is considered positive for hVISA. Variations of simplified PAP include using different inoculum sizes (>10 μl), inoculum concentrations (>0.5 McFarland standard), media (Mueller-Hinton agar), antibiotics (teicoplanin), and/or vancomycin concentrations (3 or 6 mg/liter). PAP: hVISA is present when the graph of isolated colonies on brain heart infusion agar or Mueller-Hinton agar plotted against increasing vancomycin concentration at 48 h is similar to that for the reference (Mu3) strain. Analysis can be standardized using the area under the curve (PAP-AUC) with hVISA being confirmed when the ratio of the test strain to the control strain (Mu3) is between 0.9 and 1.3. Macromethod (2 McFarland standard) Etest on brain heart infusion agar is defined as positive for hVISA if the vancomycin and teicoplanin MICs are ≥8 μg/ml or the teicoplanin MIC is ≥12 μg/ml for the isolate. Screening agars: ≥1 colony isolated after 24 to 48 h on either brain heart infusion agar or Mueller-Hinton agar supplemented with vancomycin or teicoplanin is considered positive for hVISA. MIC-based testing includes standard Etest or vancomycin broth microdilution of resistant subpopulations.

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.

TABLE 2.

Published studies containing clinical details of hVISA-infected patients

Study (reference no.) Publication description No. (%) of hVISA isolates detecteda No. (%) of therapeutic failures, hVISA: VSSA Therapeutic failure definition used in study No. (%) of infections with 30-day mortality, hVISA: VSSA Other clinical finding(s)
Ariza et al., 1999 (2) MRSA orthopedic device infections (n = 19); retrospective 14 (74) 12 (86): 1 (20) (P not stated) Persistence or reappearance of infection after 6 weeks of therapy No data All patients cured following device removal
Kim et al., 2002 (33) Consecutive S. aureus isolates from any site (n = 3,363); retrospective 24 (0.7) 0: 0 Not stated 3 (14): 0 15 colonized patients, 7 infected patients
Bert et al., 2003 (5) Consecutive MRSA isolates from any site (n = 48); retrospective 13 (27) 1 (10): 0 Persistent bacteremia of >5 days 1 (7): 6 (17) (P = NSb) 3 colonized, 10 infected liver transplant patients
Charles et al., 2004 (8) MRSA bacteremic patients (n = 53); retrospective 5 (9) 5 (100): 1 (2.1%) (P < 0.01) Persistent bacteremia and fever for >7 days 1 (20): 17 (35) (P = 0.7) hVISA associated with high-bacterial-load infections (P = 0.001) and initial low VANf levels (P = 0.006)
Howden et al., 2004 (28) hVISA confirmed bacteremic patients (n = 25); retrospective 25 (100) 19 (76): 0 Persistent bacteremia or positive sterile-site culture (>7 days and 21 days of therapy, respectively) 7 (33): 0
Khosrovaneh et al., 2004 (31) Persistent and recurrent MRSA bacteremic patients (n = 21); retrospective 3 (13) Not stated No data Paired isolates tested with no hVISA phenotype detected in the initial blood isolate
Maor et al., 2007 (38) hVISA confirmed bacteremic patients (n = 264); retrospective 16 (6) 7 (44): 0 Persistent bacteremia of >7 days 12 (75): 0
Neoh et al., 2007 (42) Adequately treated (VAN for >5 days with trough levels of >10 μg/ml) MRSA bacteremic patients (n = 20); retrospective 2 (10) 2 (100): 5 (27) (P < 0.01) Persistence or worsening of symptoms and infection-related mortality 2 (100): 8 (44) hVISA associated with greater no. of febrile days (P < 0.01) and increased no. of days for CRPg to decrease by >30% of maximum value (P < 0.01)
Fong et al., 2009 (16) Persistent MRSA infection (>7 days of culture positivity) (n = 56)c; retrospective 3 (5) 56 days for hVISA/VISA vs 46 days for VSSA (P < 0.01); 9/9 (100): 21/26 (80) bacteremic patientsd Duration of bacteremia (in days); persistent bacteremia for >7 daysd 5 (50): 19 (63) (P = 0.48) hVISA/VISA associated with bone/joint (P < 0.01) and prosthesis (P = 0.04) infections and increased length of hospital stay (P < 0.01)
Maor et al., 2009 (37) MRSA bacteremic patients (n = 250); retrospective 27 (12) 12 days for hVISA vs 2 days for VSSA (P < 0.01) Duration of bacteremia (in days) 14 (51): 103 (46) (P = 0.6) hVISA associated with infective endocarditis (P = 0.007) and osteomyelitis (P = 0.006)
Horne et al., 2009 (24) Consecutive clinical MRSA isolates (n = 117); prospective 59 (50) 10 (38): 11 (26) (P = 0.08) Unresolved signs or symptoms of infection following standard therapy or recurrence of infection within 1 mo of cessation of therapy 12 (21): 11 (20) (P = 0.93) hVISA associated with lower rate of infection (P < 0.003) and bacteremia (P < 0.001)
Bae et al., 2009 (4) MRSA infective endocarditis cases from the ICEe cohort (n = 65); prospective 19 (29) 13 (68): 17 (37) (P = 0.029) Persistent bacteremia of >3 days despite active antibiotic treatment 8 (42): 16 (35) (P = 0.59) hVISA associated with congestive cardiac failure (P = 0.033) and older patients (P = 0.037)
Musta et al., 2009 (41) MRSA bacteremic patients (n = 489); retrospective 71 (17) 20 (47): 101 (42) (P = 0.5) Persistent bacteremia of >7 days and/or a metastatic infection 14 (43): 43 (27) (P = 0.5)
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a

For details of detection methods, see Table 1.

b

NS, not significant.

c

Of the 56 patients who met the case definition, 10 cases (3 of hVISA infection and 7 of VISA infection) and 30 randomly assigned controls were selected.

d

Data obtained by personal communication.

e

ICE, International Collaboration on Endocarditis.

f

VAN, vancomycin.

g

CRP, C-reactive protein.

FIG. 1.

FIG. 1.

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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.

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.

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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

▿

Published ahead of print on 15 November 2010.

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