vancomycin-intermediate and vancomycin-resistant staphylococcus aureus infections

Vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus infections

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Print | BackVancomycin-intermediate and vancomycin-resistant Staphylococcus aureus infectionsAuthorFranklin D Lowy, MDSection EditorDaniel J Sexton, MDDeputy EditorElinor L Baron, MD, DTMHDisclosuresAll topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Jun 2013. | This topic last updated: Oct 19, 2012.

INTRODUCTION — The emergence of S. aureus with diminished vancomycin susceptibility was anticipatedwhen vancomycin-resistant enterococci (VRE) were initially described in the late 1980s [1,2]. The expectedmechanism of vancomycin resistance in S. aureus was plasmid-mediated transfer of the vanA gene clusterfrom VRE. It was a surprise, therefore, when the first reported case of diminished vancomycin susceptibilityin a clinical isolate of S. aureus in 1997 was mediated not via acquisition of vanA by a strain of methicillin-resistant S. aureus (MRSA), but by an unusually thickened cell wall containing dipeptides capable of bindingvancomycin, thereby reducing availability of the drug for intracellular target molecules [3-8]. This was thefirst observation of vancomycin-intermediate S. aureus (VISA). The predicted mechanism of vanA geneplasmid-mediated transfer from enterococci to S. aureus was later observed for the first time in 2002; thiswas the first description of vancomycin-resistant S. aureus (VRSA) [9,10].

Issues related to the mechanism, epidemiology, laboratory definitions, treatment and prevention of S.aureus with reduced susceptibility to vancomycin will be reviewed here. Issues related to MRSA arediscussed separately. (See related topics).

DEFINITIONS — Both the Clinical and Laboratory Standards Institute (CLSI) and the United States Foodand Drug Administration (FDA) have established the following vancomycin minimal inhibitory concentrationinterpretive criteria for S. aureus. The definitions have been modified in response to increasing reports ofvancomycin treatment failure in infections due to strains with elevated MICs (2 mcg/mL), as well as to flagthose isolates that are likely to be heteroresistant; the definitions prior to 2006 are noted in parentheses[11-13]. (See 'Heteroresistance' below.)

Vancomycin susceptible — ≤2 mcg/mL (≤4 mcg/mL)Vancomycin intermediate (VISA) — 4 to 8 mcg/mL (8 to 16 mcg/mL)Vancomycin resistant (VRSA) — ≥16 mcg/mL (≥32 mcg/mL)

The acronyms for vancomycin-intermediate S. aureus (VISA), glycopeptide-intermediate S. aureus (GISA)and vancomycin-resistant S. aureus (VRSA) are derived from these criteria. VISA and GISA refer to thesame susceptibility cutoff. The term VISA is more commonly used, although the term GISA may be moreaccurate since early reports indicated that most of these strains also had intermediate resistance to theglycopeptide teicoplanin.

Repeated isolation of S. aureus from normally sterile sites despite seemingly appropriate therapy for longerthan 7 days should prompt consideration of infection with a strain of S. aureus with reduced susceptibility tovancomycin, even if the MIC of the original isolate was within the susceptible range [13-16].

Reduced vancomycin susceptibility can occur in S. aureus irrespective of background methicillin susceptibilityand may result in increased tolerance to several classes of antibiotics [17]. (See 'Treatment' below.)

VISA

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Mechanism — Reduced susceptibility to vancomycin in vancomycin-intermediate S. aureus (VISA) isolates isdue to the synthesis of an unusually thickened cell wall containing dipeptides (D-Ala-D-Ala) capable ofbinding vancomycin, thereby reducing availability of the drug for intracellular target molecules [3-8,18-20].

The genetic basis for these cell wall alterations is not fully understood. Several studies have identifiedmutations in selected genes, including vraR, graRS, and walRK, that appear to contribute to thedevelopment of resistance [21-24]. The group II polymorphism at the accessory gene regulator (agr) locusis present in some VISA strains (as well as some MRSA strains) [20,25].

VISA strains may have developed from preexisting MRSA strains in the presence of vancomycin; this wassuggested by the similarity between pulse-field gel electrophoresis patterns of the MRSA and subsequentVISA strains isolated from individual patients [26-31]. This course of events may have resulted from failureto eradicate the initial MRSA strain or subsequent reinfection with the same strain.

Epidemiology — Several VISA strains associated with clinical infection have been described [3,26-30,32,33].The first reported case was observed in 1997 in Japan and occurred in a four-month-old with a surgical siteinfection. This original vancomycin-intermediate S. aureus (VISA) strain was designated Mu50; itsvancomycin MIC was 8 mcg/mL [3]. The patient was successfully treated with amoxicillin-clavulanate plusgentamicin. However, the first infection with VISA appears to have occurred in 1995 in France, in a 2-year-old with leukemia and central catheter-associated bacteremia; management was successful with surgicaldrainage and quinupristin-dalfopristin [33].

Subsequently, clinical infections with similar strains have been reported in the United States and around theworld [26-29,32,34,35]. Features common to many of the United States cases included ongoing or recentdialysis, MRSA bacteremia related to central venous catheter or prosthetic graft material, and prolongedvancomycin exposure (6 to 18 weeks) in the three to six months preceding infection [26,28-30]. Contactinvestigation for two patients with VISA infection (including 177 contacts) yielded no VISA carriers [26].

Most published studies show a correlation between rising MIC values to vancomycin and a poorer clinicaloutcome as measured by treatment failure or mortality [36]. A study comparing outcomes among patientswith MSSA and MRSA bacteremia has raised additional questions concerning the basis for the poorer clinicaloutcomes [37]. Patients with S. aureus bacteremia caused by strains with vancomycin MIC (by Etest) >1.5µg/ml had a poorer outcome than those infected with strains having an MIC of ≤1.5 µg/ml. Notably, thisoutcome was independent of the methicillin susceptibility of the isolate and whether the patients weretreated with vancomycin or a beta-lactam. This observation suggests that there may be structuraldifferences in the strains with higher vancomycin MICs, or other host factors.

Infection with S. aureus with vancomycin MICs ≥4 mcg/mL is rare, although the incidence is difficult toestimate given the rarity of infection and challenges related to laboratory detection. Surveillance data fromthe United States and Europe indicate that S. aureus isolates with vancomycin MICs ≥4 mcg/mL representless than 0.3 percent of MIC values [13]. In a CDC study of 630 clinical isolates from 33 United Stateshospitals, no strains of VISA were identified, but two isolates demonstrated heteroresistance [38].

Heteroresistance — Heteroresistant vancomycin-intermediate S. aureus (hVISA) refers to VISA strains inwhich subpopulations display variable rather than uniform susceptibility to vancomycin [3,31].Heteroresistant strains of S. aureus contain subpopulations of bacteria with vancomycin MICs in theintermediate range, but the vancomycin MIC for the entire population of the strain remains within thesusceptible range [31]. Like VISA strains, hVISA populations withstand vancomycin by means of anunusually thickened cell wall. (See "Overview of antibacterial susceptibility testing", section on'Heteroresistance'.)

The prototype heteroresistant strain was S. aureus Mu3, a clinical isolate recovered from a Japanese patientwith staphylococcal pneumonia [31]. The reported frequency of heteroresistance is variable. Most studiesdescribe a frequency of 0.5 to 1.5 percent, but frequencies as high as 20 percent have been reported inJapan [13,31,39].

The relevance of heteroresistance to clinical vancomycin failure is still not fully understood [32]. However,



there are several reports of vancomycin failure and persistent infection due to hVISA [40-42]. In a reviewof 65 patients with endocarditis due to MRSA, 19 isolates (29 percent) exhibited the hVISA phenotype bypopulation analysis profiling [42,43]. Patients with these isolates were more likely to have persistentbacteremia (68 versus 37 percent) and heart failure (47 versus 19 percent) [42].

There is no practical, validated laboratory test for accurate routine detection of heteroresistant S. aureus. Asa result, the CLSI lowered the intermediate vancomycin MIC breakpoint to 4 mcg/mL (as described below)in order to flag those isolates that are likely to be heteroresistant and/or clinically refractory to vancomycintherapy [13]. (See "Overview of antibacterial susceptibility testing", section on 'Heteroresistance'.)

VRSA

Mechanism — The mechanism of vancomycin resistance in vancomycin-resistant S. aureus (VRSA) isplasmid-mediated transfer of the vanA gene cluster from enterococci with vancomycin resistance (via mobilegenetic element Tn1546) [44-46]. Resistance in VRSA isolates is due to the synthesis of an alternative cellwall terminal peptide (D-ala-D-lac), rather than the normal terminal peptide (D-ala-D-ala). Vancomycin isunable to bind to the former peptide. Expression of the vanA genes is only initiated by exposure tovancomycin so that there is limited effect on the fitness of the isolate (in contrast with the vancomycin-intermediate S. aureus [VISA] strains).

Epidemiology — At least 12 patients with infection due vancomycin-resistant S. aureus (VRSA) have beenidentified in the United States:

The first isolate of VRSA was reported in 2002 from a patient in Michigan with diabetes, peripheralartery disease, and chronic renal failure on hemodialysis [9]. The isolate grew from both a catheterexit site swab specimen and from a chronic foot ulcer that appeared newly infected. The MIC was1024 mcg/mL. A strain of vancomycin-resistant Enterococcus faecalis (VRE) was also cultured fromthe ulcer, and DNA sequencing demonstrated that the vanA genes in the staphylococcus andenterococcus isolates were identical [47]. Contact investigation for this patient (including 547 people)yielded no VRSA carriers.The second isolate of VRSA was reported in 2002 in Pennsylvania [48,49]. The isolate was identifiedfrom a patient with a chronic foot ulcer undergoing evaluation for possible osteomyelitis. The MIC bythe broth dilution method was 32 mcg/mL. The foot ulcer culture also demonstrated VRE, althoughthe patient had not received vancomycin [50].The third isolate of VRSA was reported in 2004 in New York [51]. It grew from a urine cultureobtained from a patient in a long-term care facility; the MIC by the broth dilution method was 64mcg/mL.

After the first three isolates were reported, four additional cases of VRSA were described in Michigan in2005-2006 [52]. Because co-colonization with methicillin-resistant S. aureus (MRSA) and VRE is common,development of further VRSA strains is likely [53,54]. A comparative genomic analysis of the 12 reportedVRSA isolates concluded that they represent separate events in which the plasmid containing thevancomycin resistant transposon was acquired. There did not appear to be evidence of clonal disseminationof a single VRSA strain [55].

LABORATORY TESTING — Confirmatory MIC testing should be performed on S. aureus isolates for whichthe vancomycin MIC is ≥2 mcg/mL. Laboratory detection of S. aureus with reduced susceptibility tovancomycin may require special inquiry with the microbiology laboratory about susceptibility testingmethods [56]. An MIC susceptibility testing method (such as broth microdilution, agar dilution, or agar-gradient diffusion [E-test]) must be used for detection of S. aureus with reduced susceptibility tovancomycin; disk diffusion and automated methods are not sufficient [57-60]. A full 24-hour incubationperiod should be used with all methods.

A routine approach to S. aureus susceptibility testing should be tailored to the clinical scope of a particularlaboratory [38,61]. The most accurate method for detecting heteroresistant subpopulations is withperformance of population analysis profiles [43]. Additional susceptibility testing is warranted in patientswith repeated isolates of S. aureus from normally sterile sites despite seemingly appropriate therapy for



longer than seven days. Isolates should also be sent to the state public health laboratory or the Centers forDisease Control and Prevention for confirmatory evaluation when S. aureus with reduced susceptibility issuspected.

TREATMENT — The observation of repeated isolates of S. aureus from normally sterile sites despiteseemingly appropriate therapy for longer than seven days should prompt consideration of infection with astrain of S. aureus with reduced susceptibility to vancomycin, even if the MIC is within the susceptible range[13-16]. (See 'Heteroresistance' above.)

Vancomycin failure appears more likely for patients with infection due to S. aureus isolates with avancomycin MIC >0.5 mcg/mL than those with an MIC ≤0.5 mcg/mL. This was illustrated in a retrospectivestudy of 30 patients with methicillin-resistant S. aureus (MRSA) bacteremia refractory to vancomycintherapy [14]. The frequency of successful therapy for 23 patients whose isolates had an MIC of 1 or 2mcg/mL was much lower than for the 9 patients with an isolate with an MIC ≤0.5 mcg/mL (9.5 versus 55.6percent, respectively).

Antibiotic selection — The optimal antimicrobial regimen for S. aureus with reduced susceptibility tovancomycin is unknown [62]. An appropriate approach is treatment with at least one antimicrobial to whichthe organism is known to be susceptible by in vitro testing, particularly for isolates with vancomycin MIC >2mcg/mL [32,63-66]. These isolates are frequently susceptible to the alternative antistaphylococcal agentssuch as daptomycin, linezolid, telavancin, ceftaroline, minocycline, or quinupristin-dalfopristin [64-68].There are now several reports of isolates with reduced susceptibility to vancomycin also having reducedsusceptibility to daptomycin. The clinical relevance of this observation remains uncertain [69]. There arelimited data regarding the efficacy of tigecycline, especially in the setting of bacteremia. Vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA) isolates have demonstratedvariable susceptibility to chloramphenicol, rifampin, and trimethoprim-sulfamethoxazole [3,26-30,33,58,70,71]. Even if reported as susceptible, quinolones should not be used for the treatment of theseinfections due to the risk of resistance emerging during therapy.

Increasing the dose of vancomycin may not safely overcome its poor activity or limited tissue penetration[62,72]. This was illustrated in a study of 95 cases of MRSA infection (including 51 due to strains with anMIC ≥2 mcg/mL) with two target vancomycin trough groups (≥15 or <15 mcg/mL) [72]. The patients withinfection due to strains with MIC ≥2 mcg/mL had a significantly lower treatment response than patientswith an MIC <2 mcg/mL (62 versus 85 percent) and a trend toward increased mortality (24 versus 10percent). Nephrotoxicity occurred only in the group with the goal vancomycin trough ≥15 mcg/mL (12versus 0 percent in the group with goal trough <15 mcg/mL), but was predicted by concomitant therapywith other nephrotoxic agents. (See "Vancomycin dosing and serum concentration monitoring in adults".)

Using vancomycin in combination with a second antistaphylococcal antibiotic may not improve itstherapeutic efficacy [62,73,74]. As an example, treatment with vancomycin and rifampin compared withvancomycin alone in a randomized trial of 42 patients with MRSA endocarditis was associated with apossible prolongation of bacteremia (median nine versus seven days) [73]. There are limited data on theefficacy on combination therapy with vancomycin and an aminoglycoside [75].

For patients with persistent MRSA bacteremia in the setting of vancomycin treatment failure, the optimalapproach is uncertain. Treatment with high dose daptomycin (10 mg/kg/day) in combination with anotheragent (such as gentamicin 1 mg/kg IV every eight hours, rifampin 600 mg PO/IV daily or 300 to 450 mgPO/IV twice daily, linezolid 600 mg PO/IV twice daily, or trimethoprim-sulfamethoxazole 5 mg/kg IV twicedaily) may be considered [66]. In addition, the combination of daptomycin with a beta-lactam has beenshown to be effective in several cases of refractory S. aureus bacteremia [76]. The in vitro bactericidalactivity of daptomycin was enhanced by increased binding to the cytoplasmic membrane in the presence ofthe anti-staphylococcal beta-lactam.

Experimental data suggest that beta-lactams and vancomycin may be synergistic against selected VISAisolates; these observations are of potential clinical interest but require further evaluation [77,78].

Duration of therapy — The duration of therapy depends upon the site of infection and should parallel the



duration of therapy for MRSA infections. In addition, treatment must include removal of implicated sourcesof infection such as central venous catheters; depending on individual patient circumstances, surgicaldebridement and/or removal of prosthetic material may also be required. (See "Treatment of invasivemethicillin-resistant Staphylococcus aureus infections in adults" and "Treatment of Staphylococcus aureusbacteremia in adults", section on 'Duration of therapy'.)

PREVENTION — As with methicillin-resistant S. aureus (MRSA), S. aureus strains with reduced susceptibilityto vancomycin are transmissible between individuals. The first report of an outbreak due to a singlevancomycin-intermediate S. aureus (VISA) strain involved 21 ICU patients [79]. Severe infection (eg,pneumonia, bacteremia, endocarditis) was diagnosed in 11 of the 21 patients, and eight patients died.Extensive colonization of the inanimate environment was described. In spite of maximum contactprecautions, the outbreak was not curtailed until additional policies were implemented including restrictedadmissions and twice daily environmental cleaning.

Special efforts to insure compliance with contact precautions and handwashing should be instituted whenpatients are infected or colonized with VISA or vancomycin-resistant S. aureus (VRSA) [80]. In addition,healthcare providers should be vigilant about removing temporary venous catheters when they are nolonger needed and minimizing prolonged empiric antimicrobial therapy whenever possible [16,81].Consultation with infectious disease specialists, hospital epidemiologists, the local health department, andthe CDC is appropriate for optimizing laboratory investigation, patient management and infection controlissues. (See "Prevention and control of methicillin-resistant Staphylococcus aureus in adults" and "Generalprinciples of infection control".)

SUMMARY AND RECOMMENDATIONS

Failure of treatment for methicillin-resistant Staphylococcus aureus (MRSA) infection with vancomycinshould prompt consideration of infection with vancomycin-intermediate S. aureus (VISA), vancomycin-resistant S. aureus (VRSA), or heteroresistant S. aureus strains. Evaluation and management shouldinvolve cooperation between infectious disease specialists, laboratory personnel, and epidemiologists.The Clinical and Laboratory Standards Institute definitions for S. aureus vancomycin minimal inhibitoryconcentrations are as follows (see 'Definitions' above):

Vancomycin susceptible — ≤2 mcg/mLVancomycin intermediate (VISA) — 4 to 8 mcg/mLVancomycin resistant (VRSA) — ≥16 mcg/mL

The mechanisms of resistance for VRSA involve vanA gene plasmid-mediated transfer from enterococcito S. aureus. For VISA strains, the mechanism involves the binding of vancomycin to bacterial cell walldipeptide to reduce drug availability for intracellular targets. (See 'Mechanism' above and 'Mechanism'above.)Heteroresistant strains of S. aureus contain subpopulations of bacteria with vancomycin MICs in theintermediate range, but the vancomycin MIC for the entire population of the strain is within thesusceptible range. There is not yet a practical, validated laboratory test for accurate routine detectionof heteroresistant S. aureus. (See 'Heteroresistance' above.)An MIC susceptibility testing method (such as broth microdilution, agar dilution, or agar-gradientdiffusion) must be used for detection of S. aureus with reduced susceptibility to vancomycin; diskdiffusion or automated methods are not sufficient. (See 'Laboratory testing' above.)We suggest treatment with at least one antimicrobial agent to which the organism is susceptible(Grade 2C). (See 'Treatment' above.)Infection control measures should be implemented as for MRSA. (See 'Prevention' above.)

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