The Vice of VRSA
Abstract & Commentary
Synopsis: The results of genetic analysis of a strain of S aureus with high-level resistance to vancomycin suggest that this resistance was the consequence of genetic transfer from a VRE to an MRSA, each present in and on the unfortunate patient who served as the incubator.
Source: Weigel LM, et al. Genetic analysis of a high-level vancomycin-resistant isolate of Staphylococcus aureus. Science. 2003;302:1569-1571.
A culture taken from an exit-site infection from a hemodialysis catheter of a 40-year-old Michigan woman on June 14, 2002 (see Table 1), resulted in the isolation of a strain of methicillin-resistant Staphylococcus aureus (MRSA) that also had high-level resistance to vancomycin (MIC = 1024 mg/mL). This resistance was due to the expression of the vanA gene, previously only detected in vancomycin-resistant enterococci (VRE). Weigel and colleagues examined this first vancomycin-resistant S aureus (VRSA) in an attempt to reconstruct its genetic history.
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Table 1. |
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Patient Number 1. |
| The 40-year-old woman from whom these isolates were obtained had diabetes mellitus and end-stage renal disease for which she was receiving chronic hemodialysis. She had had a series of infections, including a chronic foot ulcer. In March 2001, MSSA was isolated from an amputation wound, while 2 months later MRSA and vancomycin-susceptible Enterococcus faecalis were isolated from a foot ulcer. In attempts to treat the latter, during the first months of 2002, she had received the following antibiotics: vancomycin, gentamicin, ampicillin/sulbactam, piperacillin/tazobactam, levofloxacin, clindamycin, cefazolin, trimethoprim/sulfamethoxazole, tobramycin, and metronidazole. In April she received vancomycin and rifampin for treatment of MRSA bacteremia associated with an abscess of an AV graft. She then developed a series of infections at the exit site of temporary hemodialysis catheters, the third of which yielded VRSA. Culture of plantar ulcers at that time contained VREF and VRSA. The VRSA cleared after treatment with
trimethoprim/sulfamethoxazole.
Source: MMWR Morbid Mortal Wkly Rep. 2002;51:565-567. |
The organism was confirmed to be S aureus by genetic sequencing, and pulsed-field gel electrophoresis (PFGE) demonstrated it to belong to the most commonly identified pulsed-field type in US hospitals, designated USA100. Vancomycin resistance was confirmed by PCR as being vanA-mediated. The VRSA was also resistant to aminoglycosides, ß-lactams, fluoroquinolones, macrolides, rifampin, and tetracycline but was susceptible to linezolid, quinupristin/dalfopristin, and trimethoprim/sulfamethoxazole.
The VRSA contained a single 57.9 kb plasmid (pLW1043). Two other isolates from the same patient, an MRSA and a VRE, were also examined. The antibiogram of the VRSA and MRSA isolates differed only in the resistance of the former to vancomycin and teicoplanin, and the 2 isolates both belonged to the same pulsed-field type, USA100. The MRSA contained a single 47 kb plasmid (pAM829), while the VRE contained 2 plasmids, 45 kb and 95 kb in size. Restriction analysis demonstrated that the plasmids from the VRSA and the MRSA were very similar, although the VRSA plasmid was 11 kb larger (the approximate size of Tn1546). Hybridization experiments localized vanA to a 7.1 kb fragment on the VRSA and VRE plasmids but absent in that of the MRSA. Study of the the fragment common to both was consistent with its identity with the VanA coding region of Tn1546, the prototypical Van encoding transposon element found on plasmids in VRE.
These data were interpreted to indicate that the MRSA plasmid had acquired Tn1546, converting the organism to a VRSA. It was felt likely that conjugative transfer of the VRE plasmid to the MRSA had been followed by excision of Tn1546 from that plasmid and its subsequent integration into the preexisting MRSA plasmid. Direct transduction was an alternative possibility.
Comment by Stan Deresinski, MD, FACP
The first report of an S aureus isolate with reduced susceptibility to vancomycin appeared in 1997. That strain had an MIC of 8 mg/mL; only a small number of strains with similar MICs of 8-16 mg/mL have been isolated since.1 By current US CDC criteria (see Table 2), such strains are designated as "vancomycin-intermediate S aureus (VISA)." More commonly detected, and a possible cause of failure of vancomycin therapy, is heteroresistance. All strains of VISA are morphologically altered, with a thicker than normal cell wall, and the thickness of the cell wall correlates with the vancomycin MIC.2 Resistance to vancomycin, which is lost on serial passage, is apparently the result of altered murein monomers with increased affinity for vancomycin, together with either increased monomer synthesis or reduced cell wall turnover, the consequence of which is sequestration of vancomycin preventing its interaction with its target.3
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Table 2. |
S aureus Vancomycin Susceptibility Classification
Category MIC (mg/mL) Susceptible = 4 Intermediate (VISA, GISA) 8-16 Resistant (VRSA) = 32 Heteroresistant = 4 with resistant subpopulations Source: Fridkin SK. Clin Infect Dis. 2001;32:1018-1025.VRSA is a totally different story, with stable high-level resistance to vancomycin as a consequence of an MRSA having acquired a vanA gene from an enterococcus in an individual coinfected with MRSA and VRE. A second vanA-containing VRSA, isolated in culture from a Pennsylvania man in September 2002, presumably had acquired this resistance gene in a similar manner. Both VRSA strains belong to pulsed-field type USA100, which represents 44% of S aureus isolated in the United States and is typically multidrug resistant. To date, all but one US VISA also belong to USA100.4
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Table 3. |
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History of S aureus Resistance |
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| Year Reported | Reduced Susceptibility to | Associated Gene | Mechanism | Designation |
| 1948 | penicillin | bla | Hydrolysis of b-lactam ring | MSSA |
| 1961 | methicillin | mecA | Altered target* | MRSA |
| 1997 | vancomycin | None | Excess, altered target | VISA |
| 2002 | vancomycin | VanA* | Altered target** | VRSA |
| *VanA was first detected in E faecium in 1988. | ||||
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**Replacement of alanine with lactate in the disaccharide pentapeptide cell wall precursors. |
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This second VRSA strain is also multidrug resistant but, like the first VRSA, retains susceptibility to trimethoprim/sulfamethoxazole, linezolid, and quinupristin/dalfopristin. It is of interest that this isolate is also susceptible to the investigational glycopeptides, oritavancin and dalbavancin, or to daptomycin.5 Mupirocin was active but was only bacteriostatic. The 2 VRSA-infected patients were successfully treated with trimethoprim/sulfamethoxazole.
There was no evidence of spread of either of these VRSA strains to other individuals, and no additional strains have appeared. But you can bet VRSA will be back.
Dr. Deresinski, MD, FACP Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center.
References
1. Hiramatsu K, et al. Dissemination in Japanese hospitals of strains of Staphylococcus aureus heterogeneously resistant to vancomycin. Lancet. 1997;350: 1670-1673.
2. Cui L, et al. Cell wall thickening is a common feature of vancomycin resistance in Staphylococcus aureus. J Clin Microbiol. 2003;41:5-14.
3. Goldstein FW, Kitzis MD. Vancomycin-resistant Staphylococcus aureus: No apocalypse now. Clin Microbiol Infect. 2003;9:761-765.
4. McDougal LK, et al. Pulsed-field gel electrophoresis typing of oxacillin-resistant Staphylococcus aureus isolates from the United States: Establishing a national database. J Clin Microbiol. 2003;41:5113-5120.
5. Bozdogan B, et al. Antibacterial susceptibility of a vancomycin-resistant Staphylococcus aureus strain isolated at the Hershey Medical Center. J Antimicrob Chemother. 2003;52:864-868.
The results of genetic analysis of a strain of S aureus with high-level resistance to vancomycin suggest that this resistance was the consequence of genetic transfer from a VRE to an MRSA, each present in and on the unfortunate patient who served as the incubator.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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