Development of Reduced Vancomycin Susceptibility in Methicillin-Susceptible Staphylococcus aureus
CID
Development of Reduced Vancomycin Susceptibility in Methicillin-Susceptible Staphylococcus aureus
Satish K. Pillai () 0 1 2
Christine Wennersten 1 2
Lata Venkataraman 1 2
George M. Eliopoulos 0 1 2
Robert C. Moellering 1
Jr 0 1 2
Adolf W. Karchmer 0 1 2
0 Harvard Medical School , Boston, Massachusetts
1 Received 2 February 2009; accepted 28 May 2009; electronically published 21 September 2009. Center, Div of Infectious Diseases , 110 Francis St, Suite GB, Boston, MA 02215
2 Division of Infectious Diseases , Beth Israel Deaconess Medical Center
Background. Most cases of reduced vancomycin susceptibility in Staphylococcus aureus reported in the literature have been in methicillin-resistant strains. We report the development of reduced vancomycin susceptibility in a series of clonally related, methicillin-susceptible S. aureus (MSSA) clinical isolates. This isogenic series permitted us to determine whether the evolution of reduced vancomycin susceptibility in MSSA is similar to that seen in MRSA. Methods. Differences in vancomycin population analysis profiles; chemical autolysis; vancomycin, oxacillin, and daptomycin minimum inhibitory concentrations; and bactericidal activities were examined. Results. Progressive vancomycin resistance correlated with increasing daptomycin nonsusceptibility. Chemical autolysis and the bactericidal activity of vancomycin, oxacillin, and daptomycin were reduced in the final, vancomycin-intermediate S. aureus isolate, compared with the vancomycin-susceptible MSSA progenitor. Conclusions. Clinicians should recognize that reduced vancomycin susceptibility can occur in S. aureus irrespective of background methicillin susceptibility and that development of intermediate vancomycin susceptibility in MSSA may result in increased tolerance to several classes of anti-staphylococcal antibiotics.
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Methicillin-resistant Staphylococcus aureus (MRSA) is a
major cause of community and nosocomial infections.
Treatment with vancomycin has been the standard of
care for serious MRSA infection for 140 years. However,
over the past decade there have been reports of
vancomycin treatment failures for MRSA infection [1–3].
True vancomycin-resistant S. aureus (VRSA; defined as
a minimum inhibitory concentration [MIC] of 16
mg/mL [4]), which is associated with the incorporation
of the enterococcal vanA cassette into S. aureus, has
been reported only sporadically [5]. In addition to
VRSA, reduced vancomycin susceptibility (RVS) is seen
among vancomycin-intermediate S. aureus (VISA; MIC
of 4–8 mg/mL) and hetero-VISA (susceptible to
vancomycin by routine susceptibility testing, but
containing resistant subpopulations with MICs 4 mg/mL) [4,
6]. Development of hetero-VISA and/or VISA does not
involve incorporation of the vanA cassette, is associated
with altered expression of multiple regulatory genetic
elements, and is phenotypically characterized by
increased cell wall thickness, altered cell wall
penicillinbinding protein profiles, and reduced rates of cell wall
autolysis [7–13]. Decreasing vancomycin susceptibility
is a predictor of failing vancomycin therapy [2, 3, 14].
Most reported cases of hetero-VISA and VISA have
arisen from MRSA progenitors. There are few detailed
reports of RVS in methicillin-susceptible isolates [15–
17]. In fact, in some of these cases the
methicillinsusceptible S. aureus (MSSA) with RVS may have arisen
from MRSA backgrounds. For instance, in 1 report of
MSSA-RVS, molecular investigation revealed the
presence of the genetic element conveying
methicillin-resistance, mecA, and the authors demonstrated an
inverse correlation between oxacillin and vancomycin
MICs in the series of S. aureus isolates recovered from
the index patient [15]. A similar inverse correlation
between oxacillin and vancomycin MICs has been
reported in other mecA-positive S. aureus isolates [18].
In another case, the source patient harbored genetically
related methicillin-resistant and methicillin-susceptible
Table 1. Antibiotic Susceptibility Results (Agar and Macro-Broth Dilution) for Study
Isolates
Minimum inhibitory concentration, mg/mL
Vancomycin (agar)
Oxacillin (agar)
Daptomycin (broth)
VISA, and the authors postulated that the
methicillin-susceptible VISA arose from deletion of the mecA element [16].
BobinDebruex et al [17] described the clinical recovery of a
mecAnegative, methicillin-susceptible hetero-VISA isolate; however,
there was no vancomycin-susceptible progenitor to serve as a
comparator.
In this study, we investigated a series of clinical MSSA isolates
recovered from a patient who experienced vancomycin therapy
failure (case 12 in Table 1 from reference [6]). Briefly, a patient
with an infected foot ulcer initially completed a 2-week course
of antibiotic therapy with oxacilllin for MSSA bacteremia
without evidence of remote sites of infection. The patient,
complaining of back pain, returned 3 weeks after the original
bacteremia and was found to have vertebral osteomyelitis, fo (...truncated)