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VRE—Still Here, Still a Problem
Vancomycin-resistant enterococci (VRE), could be considered the “Rodney Dangerfields” of the microbial world. They often get little respect from infection preventionists or physicians even though enterococci overall are the third most common cause of healthcare-associated infections, according to the 2006–2007 National Healthcare Safety Network (NHSN) data.1 VRE including isolates of Enterococcus faecium, Enterococcus faecalis, and occasional other species of enterococci, for which the vancomycin minimum inhibitory concentrations (MICs) are less than 32 µg/mL,2 continue to spread and cause outbreaks among hospitalized patients throughout the world. The strains of VRE that should be considered for infection control interventions are those with acquired vancomycin resistance (predominantly involving vanA, vanB, or vanD genes) and exclude the intrinsically, vanC-mediated, vancomycin-resistant species of Enterococcus gallinarum and Enterococcus casseliflavus, which demonstrate low-level resistance (vancomycin MICs usually in the 4–16 µg/mL range). Other vancomycin resistance genes (e.g., vanE and vanG) remain very rare among enterococci and have not been associated with outbreaks of disease.3 Grounds for Concern
When VRE became a concern for clinicians and infection preventionists in the 1990s, it was primarily because the strains were untreatable. Clinicians had to resort to giving continuous infusions of antimicrobial agents, trying to identify potential synergism with combinations of less active agents, and a number of other creative approaches when confronted with serious VRE infections. Patients were offered a potential reprieve from the scourge of VRE with the approval of quinupristin-dalfopristin, linezolid, and daptomycin in the late 1990s and early 2000s. These drugs proved to be effective for treatment of enterococcal infections, although side effects, particularly with quinupristin-dalfopristin, were commonplace. The reprieve was short-lived. Even in 2007, VRE were already showing signs of developing resistance to linezolid and other antimicrobial agents, making multi-drug resistant VRE a therapeutic and infection control issue once again.4 Estimating IncidenceUnfortunately, there are no national surveillance data on overall number of VRE infections in U.S. hospitals. However, Reik et al. used national survey data from hospital discharges in conjunction with national antimicrobial resistance survey data to make estimates about the number of enterococcal and VRE infections nationwide.5 Because of the inexact nature of hospital coding, Reik and colleagues made both conservative and liberal estimates using Group D streptococcal codes (i.e., the historical designation for organisms now called “Enterococcus species”), versus those codes plus a percentage of infections at various body sites (i.e., blood, urine, and wounds) based on an extensive literature review. These investigators estimated conservatively, based on ICD-9 patient diagnosis codes, that there were 20,931 VRE infections out of a total of 125,134 enterococcal infections in 2004 in U.S. hospitals. By adding on percentages of blood, urinary tract, and wound infections, in addition to the numbers of Group D streptococci reported, the liberal estimate jumped to 85,586 VRE infections out of a total 521,285 enterococcal infections— a fourfold increase in the apparent incidence. Considerations for ControlWhy is it that some hospitals put considerable effort into controlling VRE and others do not? One reason is the nature of patients in the institution. Bone marrow and stem cell transplant patients are at high risk for colonization and infection with antimicrobial-resistant pathogens, and particularly with VRE. Thus transplant centers are especially concerned. Calderwood and colleagues suggested that 30% of transplant patients who are colonized with VRE will develop overt infection. Thus, active surveillance for VRE in this patient population has particular value.6 Huang et al. also studied enterococcal carriage through an active surveillance program using bacterial culture techniques. Surveillance cultures to detect VRE were performed on patients on admission and weekly thereafter while they were inpatients. Results of the cultures increased the identification of VRE-colonized patients by 2.2–17.0 -fold on admission and by 3.3–15.4 -fold in the subsequent weeks in comparison with the identification of colonized or infected patients only through routine cultures ordered for diagnostic purposes.7 VRE colonization and infection is also an issue for pediatric patients. Milstone and colleagues reported that the use of weekly surveillance cultures increased the number of VRE carriers detected in their pediatric intensive care unit by 350%.8 Screening ChallengesScreening for VRE is not as easy as screening for MRSA. Unfortunately, the vanA and vanB vancomycin resistance genes are usually located on transmissible plasmids or conjugal transposons, i.e., mobile genetic elements that move among several species of enterococci, and, in the case of vanB, can also be present in the anaerobic flora that inhabit the human gastrointestinal tract. Molecular tests to detect the vanA and vanB vancomycin resistance genes don’t specifically link those genes to an enterococcal host bacterium the way the mecA gene is linked to the S. aureus chromosome (i.e., via orfX, a genetic linker sequence) in MRSA. Several studies have shown that detection of vanA is highly associated with recovery of a vanA-containing Enterococcus species from stool.9, 10 However, the same cannot be said for vanB genes, which are widely distributed among anaerobic bacteria.11–14 Interestingly, according to Australian researchers, the vanB gene in one strain of Clostridium symbiosum was located on a mobile genetic element that was transferable to both E. faecium and E. faecalis in the digestive tracts of germ-free mice.15
Does finding a transmissible vancomycin resistance gene outside of enterococci diminish or actually enhance the value of the vanB test? Given the possibility of transfer of vancomycin resistance to a co-colonizing gut Enterococcus in a time of increasing enterococcal resistance to the few effective antibiotics left for treating this microbe, the debate takes on
new urgency. References
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Enterococci are the second most common cause of central-line associated bloodstream infections, the third most common cause of urinary tract infections, and the third most common cause of surgical site infections and device-associated infections. In fact, the number of VRE device-associated infections is equal to the number of device-associated methicillin-resistant Staphylococcus aureus (MRSA) infections.