Vancomycin-Intermediate and Vancomycin-Resistant Staphylococcus Aureus Infections

Vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus infections
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Author
Franklin D Lowy, MD
Section Editor
Daniel J Sexton, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: J un 2013. | This topic last updated: Oct 19, 2012.
INTRODUCTION The emergence of S. aureus with diminished vancomycin susceptibility was anticipated
when vancomycin-resistant enterococci (VRE) were initially described in the late 1980s [1,2]. The expected
mechanism of vancomycin resistance in S. aureus was plasmid-mediated transfer of the vanA gene cluster
from VRE. It was a surprise, therefore, when the first reported case of diminished vancomycin susceptibility
in 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 binding
vancomycin, thereby reducing availability of the drug for intracellular target molecules [3-8]. This was the
first observation of vancomycin-intermediate S. aureus (VISA). The predicted mechanism of vanA gene
plasmid-mediated transfer from enterococci to S. aureus was later observed for the first time in 2002; this
was 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 are
discussed separately. (See related topics).
DEFINITIONS Both the Clinical and Laboratory Standards Institute (CLSI) and the United States Food
and Drug Administration (FDA) have established the following vancomycin minimal inhibitory concentration
interpretive criteria for S. aureus. The definitions have been modified in response to increasing reports of
vancomycin treatment failure in infections due to strains with elevated MICs (2 mcg/mL), as well as to flag
those 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 the
same susceptibility cutoff. The term VISA is more commonly used, although the term GISA may be more
accurate since early reports indicated that most of these strains also had intermediate resistance to the
glycopeptide teicoplanin.
Repeated isolation of S. aureus from normally sterile sites despite seemingly appropriate therapy for longer
than 7 days should prompt consideration of infection with a strain of S. aureus with reduced susceptibility to
vancomycin, 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 susceptibility
and may result in increased tolerance to several classes of antibiotics [17]. (See 'Treatment' below.)
VISA
Mechanism Reduced susceptibility to vancomycin in vancomycin-intermediate S. aureus (VISA) isolates is
due to the synthesis of an unusually thickened cell wall containing dipeptides (D-Ala-D-Ala) capable of
binding 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 identified
mutations in selected genes, including vraR, graRS, and walRK, that appear to contribute to the
development of resistance [21-24]. The group II polymorphism at the accessory gene regulator (agr) locus
is 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 was
suggested by the similarity between pulse-field gel electrophoresis patterns of the MRSA and subsequent
VISA strains isolated from individual patients [26-31]. This course of events may have resulted from failure
to 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 J apan and occurred in a four-month-old with a surgical site
infection. This original vancomycin-intermediate S. aureus (VISA) strain was designated Mu50; its
vancomycin MIC was 8 mcg/mL [3]. The patient was successfully treated with amoxicillin-clavulanate plus
gentamicin. 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 surgical
drainage and quinupristin-dalfopristin [33].
Subsequently, clinical infections with similar strains have been reported in the United States and around the
world [26-29,32,34,35]. Features common to many of the United States cases included ongoing or recent
dialysis, MRSA bacteremia related to central venous catheter or prosthetic graft material, and prolonged
vancomycin exposure (6 to 18 weeks) in the three to six months preceding infection [26,28-30]. Contact
investigation 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 clinical
outcome as measured by treatment failure or mortality [36]. A study comparing outcomes among patients
with MSSA and MRSA bacteremia has raised additional questions concerning the basis for the poorer clinical
outcomes [37]. Patients with S. aureus bacteremia caused by strains with vancomycin MIC (by Etest) >1.5
g/ml had a poorer outcome than those infected with strains having an MIC of 1.5 g/ml. Notably, this
outcome was independent of the methicillin susceptibility of the isolate and whether the patients were
treated with vancomycin or a beta-lactam. This observation suggests that there may be structural
differences 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 to
estimate given the rarity of infection and challenges related to laboratory detection. Surveillance data from
the United States and Europe indicate that S. aureus isolates with vancomycin MICs 4 mcg/mL represent
less than 0.3 percent of MIC values [13]. In a CDC study of 630 clinical isolates from 33 United States
hospitals, no strains of VISA were identified, but two isolates demonstrated heteroresistance [38].
Heteroresistance Heteroresistant vancomycin-intermediate S. aureus (hVISA) refers to VISA strains in
which subpopulations display variable rather than uniform susceptibility to vancomycin [3,31].
Heteroresistant strains of S. aureus contain subpopulations of bacteria with vancomycin MICs in the
intermediate range, but the vancomycin MIC for the entire population of the strain remains within the
susceptible range [31]. Like VISA strains, hVISA populations withstand vancomycin by means of an
unusually 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 J apanese patient
with staphylococcal pneumonia [31]. The reported frequency of heteroresistance is variable. Most studies
describe a frequency of 0.5 to 1.5 percent, but frequencies as high as 20 percent have been reported in
J apan [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 review
of 65 patients with endocarditis due to MRSA, 19 isolates (29 percent) exhibited the hVISA phenotype by
population analysis profiling [42,43]. Patients with these isolates were more likely to have persistent
bacteremia (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. As
a 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 vancomycin
therapy [13]. (See "Overview of antibacterial susceptibility testing", section on 'Heteroresistance'.)
VRSA
Mechanism The mechanism of vancomycin resistance in vancomycin-resistant S. aureus (VRSA) is
plasmid-mediated transfer of the vanA gene cluster from enterococci with vancomycin resistance (via mobile
genetic element Tn1546) [44-46]. Resistance in VRSA isolates is due to the synthesis of an alternative cell
wall terminal peptide (D-ala-D-lac), rather than the normal terminal peptide (D-ala-D-ala). Vancomycin is
unable to bind to the former peptide. Expression of the vanA genes is only initiated by exposure to
vancomycin 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 been
identified in the United States:
The first isolate of VRSA was reported in 2002 from a patient in Michigan with diabetes, peripheral
artery disease, and chronic renal failure on hemodialysis [9]. The isolate grew from both a catheter
exit site swab specimen and from a chronic foot ulcer that appeared newly infected. The MIC was
1024 mcg/mL. A strain of vancomycin-resistant Enterococcus faecalis (VRE) was also cultured from
the ulcer, and DNA sequencing demonstrated that the vanA genes in the staphylococcus and
enterococcus 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 identified
from a patient with a chronic foot ulcer undergoing evaluation for possible osteomyelitis. The MIC by
the broth dilution method was 32 mcg/mL. The foot ulcer culture also demonstrated VRE, although
the patient had not received vancomycin [50].
The third isolate of VRSA was reported in 2004 in New York [51]. It grew from a urine culture
obtained from a patient in a long-term care facility; the MIC by the broth dilution method was 64
mcg/mL.
After the first three isolates were reported, four additional cases of VRSA were described in Michigan in
2005-2006 [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 reported
VRSA isolates concluded that they represent separate events in which the plasmid containing the
vancomycin resistant transposon was acquired. There did not appear to be evidence of clonal dissemination
of a single VRSA strain [55].
LABORATORY TESTING Confirmatory MIC testing should be performed on S. aureus isolates for which
the vancomycin MIC is 2 mcg/mL. Laboratory detection of S. aureus with reduced susceptibility to
vancomycin may require special inquiry with the microbiology laboratory about susceptibility testing
methods [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 to
vancomycin; disk diffusion and automated methods are not sufficient [57-60]. A full 24-hour incubation
period should be used with all methods.
A routine approach to S. aureus susceptibility testing should be tailored to the clinical scope of a particular
laboratory [38,61]. The most accurate method for detecting heteroresistant subpopulations is with
performance of population analysis profiles [43]. Additional susceptibility testing is warranted in patients
with 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 for
Disease Control and Prevention for confirmatory evaluation when S. aureus with reduced susceptibility is
suspected.
TREATMENT The observation of repeated isolates of S. aureus from normally sterile sites despite
seemingly appropriate therapy for longer than seven days should prompt consideration of infection with a
strain 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 a
vancomycin MIC >0.5 mcg/mL than those with an MIC 0.5 mcg/mL. This was illustrated in a retrospective
study of 30 patients with methicillin-resistant S. aureus (MRSA) bacteremia refractory to vancomycin
therapy [14]. The frequency of successful therapy for 23 patients whose isolates had an MIC of 1 or 2
mcg/mL was much lower than for the 9 patients with an isolate with an MIC 0.5 mcg/mL (9.5 versus 55.6
percent, respectively).
Antibiotic selection The optimal antimicrobial regimen for S. aureus with reduced susceptibility to
vancomycin is unknown [62]. An appropriate approach is treatment with at least one antimicrobial to which
the organism is known to be susceptible by in vitro testing, particularly for isolates with vancomycin MIC >2
mcg/mL [32,63-66]. These isolates are frequently susceptible to the alternative antistaphylococcal agents
such 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 reduced
susceptibility to daptomycin. The clinical relevance of this observation remains uncertain [69]. There are
limited 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 demonstrated
variable 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 these
infections 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 an
MIC 2 mcg/mL) with two target vancomycin trough groups (15 or <15 mcg/mL) [72]. The patients with
infection due to strains with MIC 2 mcg/mL had a significantly lower treatment response than patients
with an MIC <2 mcg/mL (62 versus 85 percent) and a trend toward increased mortality (24 versus 10
percent). Nephrotoxicity occurred only in the group with the goal vancomycin trough 15 mcg/mL (12
versus 0 percent in the group with goal trough <15 mcg/mL), but was predicted by concomitant therapy
with other nephrotoxic agents. (See "Vancomycin dosing and serum concentration monitoring in adults".)
Using vancomycin in combination with a second antistaphylococcal antibiotic may not improve its
therapeutic efficacy [62,73,74]. As an example, treatment with vancomycin and rifampin compared with
vancomycin alone in a randomized trial of 42 patients with MRSA endocarditis was associated with a
possible prolongation of bacteremia (median nine versus seven days) [73]. There are limited data on the
efficacy on combination therapy with vancomycin and an aminoglycoside [75].
For patients with persistent MRSA bacteremia in the setting of vancomycin treatment failure, the optimal
approach is uncertain. Treatment with high dose daptomycin (10 mg/kg/day) in combination with another
agent (such as gentamicin 1 mg/kg IV every eight hours, rifampin 600 mg PO/IV daily or 300 to 450 mg
PO/IV twice daily, linezolid 600 mg PO/IV twice daily, or trimethoprim-sulfamethoxazole 5 mg/kg IV twice
daily) may be considered [66]. In addition, the combination of daptomycin with a beta-lactam has been
shown to be effective in several cases of refractory S. aureus bacteremia [76]. The in vitro bactericidal
activity of daptomycin was enhanced by increased binding to the cytoplasmic membrane in the presence of
the anti-staphylococcal beta-lactam.
Experimental data suggest that beta-lactams and vancomycin may be synergistic against selected VISA
isolates; 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 sources
of infection such as central venous catheters; depending on individual patient circumstances, surgical
debridement and/or removal of prosthetic material may also be required. (See "Treatment of invasive
methicillin-resistant Staphylococcus aureus infections in adults" and "Treatment of Staphylococcus aureus
bacteremia in adults", section on 'Duration of therapy'.)
PREVENTION As with methicillin-resistant S. aureus (MRSA), S. aureus strains with reduced susceptibility
to vancomycin are transmissible between individuals. The first report of an outbreak due to a single
vancomycin-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 contact
precautions, the outbreak was not curtailed until additional policies were implemented including restricted
admissions and twice daily environmental cleaning.
Special efforts to insure compliance with contact precautions and handwashing should be instituted when
patients 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 no
longer needed and minimizing prolonged empiric antimicrobial therapy whenever possible [16,81].
Consultation with infectious disease specialists, hospital epidemiologists, the local health department, and
the CDC is appropriate for optimizing laboratory investigation, patient management and infection control
issues. (See "Prevention and control of methicillin-resistant Staphylococcus aureus in adults" and "General
principles of infection control".)
SUMMARY AND RECOMMENDATIONS
Failure of treatment for methicillin-resistant Staphylococcus aureus (MRSA) infection with vancomycin
should prompt consideration of infection with vancomycin-intermediate S. aureus (VISA), vancomycin-
resistant S. aureus (VRSA), or heteroresistant S. aureus strains. Evaluation and management should
involve cooperation between infectious disease specialists, laboratory personnel, and epidemiologists.
The Clinical and Laboratory Standards Institute definitions for S. aureus vancomycin minimal inhibitory
concentrations are as follows (see 'Definitions' above):
Vancomycin susceptible 2 mcg/mL
Vancomycin intermediate (VISA) 4 to 8 mcg/mL
Vancomycin resistant (VRSA) 16 mcg/mL
The mechanisms of resistance for VRSA involve vanA gene plasmid-mediated transfer from enterococci
to S. aureus. For VISA strains, the mechanism involves the binding of vancomycin to bacterial cell wall
dipeptide 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 the
intermediate range, but the vancomycin MIC for the entire population of the strain is within the
susceptible range. There is not yet a practical, validated laboratory test for accurate routine detection
of heteroresistant S. aureus. (See 'Heteroresistance' above.)
An MIC susceptibility testing method (such as broth microdilution, agar dilution, or agar-gradient
diffusion) must be used for detection of S. aureus with reduced susceptibility to vancomycin; disk
diffusion 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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