Abstract
We retrospectively evaluated 410 patients with coinfection or cocolonization due to vancomycin-resistant (VR) enterococcus (VRE) and methicillin-resistant Staphylococcus aureus (MRSA). The prevalence rate was 19.8%. Risk factors included isolation of VR Enterococcus faecalis and use of linezolid or clindamycin. Inc18-like vanA plasmids were found in 7% of VR E. faecalis isolates and none of the VR E. faecium isolates.
The emergence of vancomycin resistance in Staphylococcus aureus, with 7 of 9 cases worldwide from southeast Michigan (12, 13), is alarming. The isolation of enterococci containing the vanA gene identical to those of vancomycin-resistant (VR) S. aureus (VRSA) strains suggests that the vanA-mediated resistance was due to the transfer of an Inc18-type plasmid from VRE containing traA and repR genes to S. aureus (3, 5). Accordingly, isolation of both VRE and methicillin-resistant S. aureus (MRSA) may be one of the foremost risk factors for the development of VRSA. The National Healthcare Safety Network report for 2006-2007 identified VRE and MRSA as the two most common antimicrobial-resistant pathogens associated with health care-associated infections (8). Our study aimed to evaluate risk factors and epidemiology of colonization or infection with both VRE and MRSA. We also investigated the occurrence of traA and repR genes among VRE isolates to gain information on its potential role as a resistance mechanism for VRSA.
Microbiology records from a 900-bed tertiary-care facility in urban Detroit, MI, from January 2005 through December 2007 were reviewed for data from patients who had at least one culture positive for VRE. Cocolonization or coinfection with MRSA was defined as the isolation of at least one culture positive for MRSA within 14 days from the date of VRE isolation. Data from October to December 2007 included MRSA surveillance cultures. In vitro susceptibilities were determined by the clinical microbiology laboratory (4). PCR analysis was performed to detect the presence of traA and repR genes among VRE isolates (17). Through retrospective chart review, clinical patient characteristics were collected. Statistical comparisons employed t tests, Wilcoxon rank sum tests, and chi-square or Fisher exact tests where appropriate. Multivariate analysis used a stepwise logistic regression model.
Four hundred ten patients were identified to have VRE, 57 (13.9%) had VR Enterococcus faecalis, 272 (66.3%) had VR E. faecium, and 81 (19.8%) had both VRE and MRSA. Clinical characteristics of patients with VRE alone and patients cocolonized or coinfected with VRE and MRSA are shown in Table 1. Table 2 lists the sources of the isolates, with skin or wounds being more significantly common for patients with both VRE and MRSA than for patients with VRE alone. VR E. faecalis rather than VR E. faecium was most commonly associated with cocolonization or coinfection with MRSA (35% versus 17.3%). The independent risk factors for VRE-MRSA cocolonization or coinfection are shown in Table 3 and include isolation of VR E. faecalis and prior receipt of linezolid or clindamycin in the last 90 days. traA and repR genes were found in 4 (7.02%) of the 57 VR E. faecalis isolates, and these genes were not found among VR E. faecium isolates. The 4 VR E. faecalis isolates were taken from blood (n = 2), the urinary tract (n = 1), and a surgical site (n = 1).
TABLE 1.
Clinical characteristics of patients with VRE and patients with both VRE and MRSA
| Variablea | Patients with VRE (n = 329) | Patients with VRE and MRSA (n = 81) | P valueb |
|---|---|---|---|
| Mean ± SD | |||
| Age (yr) | 63.2 ± 16.5 | 64.5 ± 15.1 | 0.511 |
| Length of stay in hospital (days) | 23.7 ± 29.1 | 26.7 ± 34.3 | 0.267 |
| No. (%) of patients | |||
| Male | 141 (42.9) | 39 (48.1) | 0.390 |
| Prior hospitalization | 264 (80.2) | 60 (75.0) | 0.300 |
| Prior ICU stay | 72 (21.9) | 21 (26.6) | 0.371 |
| Prior surgery | 147 (44.8) | 23 (28.8) | 0.009* |
| Nursing home stay | 78 (23.8) | 24 (30.0) | 0.249 |
| Wound care clinic visits | 12 (3.7) | 2 (2.5) | 1.000 |
| Central venous catheter for >72 h | 81 (24.6) | 7 (8.8) | 0.002* |
| Indwelling Foley catheter | 24 (7.3) | 6 (7.5) | 0.950 |
| Chronic wound or ulcer | 89 (27.1) | 15 (18.8) | 0.123 |
| Myocardial infarct | 63 (19.1) | 19 (23.8) | 0.357 |
| Congestive heart failure | 69 (21.0) | 18 (22.5) | 0.765 |
| Chronic obstructive pulmonary disease | 41 (12.5) | 16 (20) | 0.085 |
| Peripheral vascular disease | 32 (9.8) | 7 (8.8) | 0.784 |
| Cerebrovascular accident | 51 (15.5) | 11 (13.8) | 0.695 |
| Connective tissue disease | 51 (15.5) | 2 (2.5) | 0.002* |
| Gastrointestinal ulcer bleeding | 25 (7.6) | 5 (6.3) | 0.678 |
| Dementia | 35 (10.7) | 6 (7.5) | 0.394 |
| Intravenous drug use | 17 (5.2) | 4 (5.0) | 1.000 |
| Chemotherapy | 30 (9.2) | 0 (0.0) | 0.005* |
| Corticosteroids | 14 (4.3) | 1 (1.3) | 0.322 |
| HIV infection | 6 (1.8) | 0 (0.0) | 0.603 |
| Neutropenia | 2 (0.6) | 0 (0.0) | 1.000 |
| Leukemia | 11 (3.4) | 2 (2.5) | 1.000 |
| Solid tumor | 75 (22.9) | 11 (13.6) | 0.066 |
| Transplant recipient | 29 (8.8) | 4 (5.0) | 0.261 |
| Diabetes with end organ damage | 45 (13.7) | 0 (0.0) | <0.001* |
| Acute renal failure | 32 (12.4) | 13 (100.0) | <0.001* |
| Chronic kidney disease | 107 (32.7) | 19 (23.8) | 0.120 |
| Prior antibiotic use in last 90 days | |||
| Vancomycin | 123 (37.6) | 31 (38.3) | 0.913 |
| Linezolid | 12 (3.7) | 7 (8.6) | 0.074 |
| Daptomycin | 1 (0.3) | 1 (1.2) | 0.359 |
| Trimethoprim-sulfamethoxazole | 40 (12.2) | 4 (4.9) | 0.060 |
| Tetracycline | 5 (1.5) | 0 (0.0) | 0.588 |
| Penicillins | 19 (5.8) | 4 (4.9) | 1.000 |
| Beta-lactams | 71 (21.8) | 8 (9.9) | 0.015* |
| Cephalosporin | 87 (26.7) | 13 (16.0) | 0.047* |
| Carbapenem | 28 (8.6) | 5 (6.2) | 0.480 |
| Metronidazole | 37 (11.3) | 4 (4.9) | 0.087 |
| Clindamycin | 7 (2.2) | 5 (6.2) | 0.070 |
| Fluoroquinolone | 94 (28.7) | 13 (16.0) | 0.021* |
| Aminoglycoside | 41 (12.6) | 4 (4.9) | 0.049* |
| No antibacterial use | 46 (14.1) | 30 (37.5) | <0.001* |
ICU, intensive care unit.
*, significant value.
TABLE 2.
Infection sources of patients with VRE and patients with both VRE and MRSA
| Variable | No. (%) of patients with: |
P valuea | |
|---|---|---|---|
| VRE (n = 329) | VRE and MRSA (n = 81) | ||
| VR E. faecalis present | 57 (17.3) | 28 (35.0) | <0.001* |
| Source | |||
| Catheter | 37 (11.3) | 0 (0.0) | 0.001* |
| Endocarditis | 3 (0.9) | 0 (0.0) | 1.000 |
| Skin/wound | 48 (14.6) | 20 (24.7) | 0.029* |
| Intra-abdominal | 32 (9.8) | 4 (4.9) | 0.166 |
| Respiratory | 5 (1.5) | 1 (1.2) | 1.000 |
| Urinary tract | 163 (49.5) | 42 (51.9) | 0.710 |
| Bacteremia | 83 (25.3) | 22 (27.2) | 0.732 |
| Undetermined | 9 (2.8) | 0 (0.0) | 0.215 |
*, significant value.
TABLE 3.
Independent predictors of cocolonization or coinfection with vancomycin-resistant Enterococcus and methicillin-resistant Staphylococcus aureus
| Variablea | P value | Odds ratio | Odds ratio confidence | 95% limit |
|---|---|---|---|---|
| Presence of VR E. faecalis vs VR E. faecium | <0.001 | 3.694 | 1.901 | 7.176 |
| Linezolid | <0.001 | 8.981 | 2.673 | 30.175 |
| Clindamycin | 0.021 | 4.994 | 1.271 | 19.625 |
| Metronidazole | 0.034 | 0.242 | 0.065 | 0.901 |
| No antibacterial use | <0.001 | 6.989 | 3.519 | 13.879 |
| Connective tissue disease | 0.020 | 0.171 | 0.039 | 0.757 |
| CVC > 72 h | 0.002 | 0.246 | 0.101 | 0.599 |
CVC, central venous catheter.
In this study, VRE-MRSA cocolonization or coinfection was common, occurring in 20% of all patients studied. Prior studies on cocolonization or coinfection with VRE and MRSA (1, 6, 7, 9, 11, 15) demonstrated prevalence rates ranging from 2.7% to 28.6% (6, 7, 10, 15). We found the major risk factors for VRE and MRSA cocolonization or coinfection were isolation of VR E. faecalis, rather than E. faecium, and exposure to the antimicrobials linezolid and clindamycin. Earlier studies demonstrated different findings. Furuno et al. (7) showed age, admission to a medical intensive care unit, male gender, and receiving antimicrobial drugs on a previous admission within the preceding year as risk factors; Warren et al. (15) found age, hospitalization during the preceding 6 months, and admission to a long-term-care facility to be risks; and Polgreen et al. (11) reported residency in long-term-care facilities as a risk factor for both MRSA and VRE infections. Though vancomycin resistance was more common among E. faecium isolates, in this study, E. faecalis was independently associated with cocolonization or coinfection with MRSA. This finding has an important implication in a potential role of the organism in relation to VRSA isolation (3, 10). The reason for linezolid and clindamycin being major risk factors is unclear and was not determined by the study. Both antimicrobial agents have anti-MRSA activity, and linezolid has in vitro activity against both enterococci and MRSA. Linezolid and clindamycin also inhibit protein synthesis and toxin production, which may have an impact on a virulence characteristic associated with colonization. With the recent rise in the use of linezolid, further studies are needed to determine a dynamic potential role in an interrelationship between VRE and MRSA. It remains a challenge to completely understand the relationship between the use of a specific agent and resistance and infections with resistant organisms. The Centers for Disease Control and Prevention advocate careful oversight of vancomycin use in the control of multidrug-resistant organisms (2). Given the results of this study, in geographic areas where VRE and MRSA are endemic, additional monitoring and control of the use of linezolid and clindamycin may be of importance.
Our study is unique in determining the incidence of traA and repR genes among VRE in a geographic area known to have VRSA. The vanA VRE plasmid from the first VRSA isolate was identified as an Inc18-like plasmid (5, 16, 17), which was related to the VRE vanA plasmids associated with the latter VRSA cases. The latter plasmids were characterized by the detection of the two Inc18-specific genes traA and repR (14, 17). This study shows that Inc18-like vanA plasmids are rare among vancomycin-resistant E. faecalis and E. faecium isolates. Importantly, all 4 traA- and repR-positive isolates are strains of VR E. faecalis. The four patients resided in southeast Michigan, with ages ranging from 38 to 83 years, had chronic illnesses like diabetes, osteomyelitis, and renal disease on hemodialysis. These are characteristics similar to the 7 Michigan VRSA cases. None of 4 patients was cocolonized or coinfected with MRSA, but 2 had remote S. aureus infections. The potential exchange of genetic information, especially the vanA gene, between and among staphylococci and enterococci remains a challenge concerning infection, prevention, and therapy (9, 12).
Limitations of our study include evaluation in a single hospital located in a metropolitan area. The VRE isolates examined for Inc18-like plasmids all originated in southeast Michigan. Limited data for the prevalence of traA and repR genes from other regions exist. VRE-MRSA coinfection or cocolonization was defined using a 14-day cutoff period, which could have missed subsequent MRSA cultures. As this is a retrospective study which used clinical cultures and surveillance MRSA cultures, we could have underestimated the true proportion of patients colonized with VRE and MRSA among selected patients.
Cocolonization or coinfection with VRE and MRSA was common in this study (20% prevalence). Independent risk factors include isolation of VR E. faecalis rather than E. faecium and prior use of linezolid or clindamycin. traA and repR genes, the roles of which remain unclear in the emergence of VRSA, are infrequent among VRE but were found in E. faecalis isolates. Patients who tested positive for the Inc18-like plasmids share similar characteristics with the VRSA cases. Infection prevention interventions for vancomycin-resistant E. faecalis may need particular attention.
Footnotes
Published ahead of print on 9 December 2009.
REFERENCES
- 1.Benson, L., B. Spraque, J. Campos, and N. Singh. 2007. Epidemiology of infection and colonization with vancomycin-resistant enterococci and frequency of cocolonization with methicillin-resistant Staphylococcus aureus in children. Infect. Control Hosp. Epidemiol. 28:880-882. [DOI] [PubMed] [Google Scholar]
- 2.Centers for Disease Control and Prevention. 1995. Recommendations for preventing the spread of vancomycin resistance. Recommendations of the Hospital Infection Control Practices Advisory Committee (HICPAC). MMWR Morb. Mortal. Wkly. Rep. 44:1-13. [PubMed] [Google Scholar]
- 3.Chang, S., D. M. Sievert, J. C. Hageman, M. L. Boulton, F. C. Tenover, F. C. Downes, S. Shah, J. T. Rudrik, G. R. Pupp, W. J. Brown, D. Cardo, and S. K. Fridkin for the Vancomycin-Resistant Staphylococcus aureus Investigative Team. 2003. Infection with vancomycin-resistant Staphylococcus aureus containing the vanA resistance gene. N. Engl. J. Med. 348:1342-1347. [DOI] [PubMed] [Google Scholar]
- 4.Clinical and Laboratory Standards Institute. 2005. Performance standards for antimicrobial susceptibility testing: 15th informational supplement. Clinical and Laboratory Standards Institute, Wayne, PA.
- 5.Flannagan, S. E., J. W. Chow, S. M. Donabedian, W. J. Brown, M. B. Perri, M. J. Zervos, Y. Ozawa, and D. B. Clewell. 2003. Plasmid content of a vancomycin-resistant Enterococcus faecalis isolate from a patient also colonized by Staphylococcus aureus with a VanA phenotype. Antimicrob. Agents Chemother. 47:3954-3959. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Franchi, D., M. W. Climo, A. H. M. Wong, M. B. Edmond, and R. P. Wenzel. 1999. Seeking vancomycin resistant Staphylococcus aureus among patients with vancomycin-resistant enterococci. Clin. Infect. Dis. 29:1566-1568. [DOI] [PubMed] [Google Scholar]
- 7.Furuno, J. P., E. N. Perencevich, J. A. Johnson, M. Wright, J. C. McGregor, J. G. Morris, Jr., S. M. Strauss, M. Roghman, L. L. Nemoy, H. C. Standiford, J. N. Hebden, and A. D. Harris. 2005. Methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci co-colonization. Emerg. Infect. Dis. 11:1539-1544. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Hidron, A. I., J. R. Edwards, J. Patel, T. C. Horan, D. M. Sievert, D. A. Pollock, and S. K. Fridkin. 2008. Antimicrobial-resistant pathogens associated with healthcare-associated infections: annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006-2007. Infect. Control Hosp. Epidemiol. 16:105-113. [DOI] [PubMed] [Google Scholar]
- 9.McDonald, J. R., J. J. Engemann, K. S. Kaye, and D. J. Sexton. 2004. Co-infection or co-colonization with vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus in a network of community hospitals. Infect. Control Hosp. Epidemiol. 8:622. [DOI] [PubMed] [Google Scholar]
- 10.Noble, W. C., Z. Virani, and R. G. Cree. 1992. Co-transfer of vancomycin and other resistance genes from Enterococcus faecalis NCTC 12201 to Staphylococcus aureus. FEMS Microbiol. Lett. 72:195-198. [DOI] [PubMed] [Google Scholar]
- 11.Polgreen, P. M., S. E. Beekmann, Y. Y. Chen, G. V. Doern, M. A. Pfaller, A. B. Brueggemann, L. A. Herwaldt, and D. J. Diekema. 2006. Epidemiology of methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococcus in a rural state. Infect. Control Hosp. Epidemiol. 27:252-256. [DOI] [PubMed] [Google Scholar]
- 12.Tenover, F. C. 2008. Vancomycin-resistant Staphylococcus aureus: a perfect but geographically limited storm? Clin. Infect. Dis. 46:675-677. [DOI] [PubMed] [Google Scholar]
- 13.Tenover, F. C., and L. C. McDonald. 2005. Vancomycin-resistant staphylococci and enterococci: epidemiology and control. Curr. Opin. Infect. Dis. 18:300-305. [DOI] [PubMed] [Google Scholar]
- 14.Thompson, J. K., and M. A. Collins. 2003. Completed sequence of plasmid pIP501 and origin of spontaneous deletion derivatives. Plasmid 50:28-35. [DOI] [PubMed] [Google Scholar]
- 15.Warren, D. K., A. Nitin, C. Hill, V. J. Fraser, and M. H. Kollef. 2004. Occurrence of co-colonization or co-infection with vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus in a medical intensive care unit. Infect. Control Hosp. Epidemiol. 25:99-104. [DOI] [PubMed] [Google Scholar]
- 16.Weigel, L. M., D. B. Clewell, S. R. Gill, N. C. Clark, L. K. McDougal, S. E. Flannagan, J. F. Kolonay, J. Shetty, G. E. Killgore, and F. Tenover. 2003. Genetic analysis of a high-level vancomycin-resistant isolate of Staphylococcus aureus. Science 302:1569-1571. [DOI] [PubMed] [Google Scholar]
- 17.Zhu, W., N. C. Clark, L. K. McDougal, J. Hageman, L. C. McDonald, and J. B. Patel. 2008. Vancomycin-resistant Staphylococcus aureus isolates associated with Inc18-Like vanA plasmids in Michigan. Antimicrob. Agents Chemother. 52:452-457. [DOI] [PMC free article] [PubMed] [Google Scholar]