Abstract and Commentary

VRE: Genetic transfer and a pathogen is born

Synopsis: Vancomycin resistance in Enterococcus faecium may have arisen in commensal gastrointestinal anaerobes, with subsequent transfer of genetic material to the enterococcus. Genetic studies suggest clonal selection of E faecium expressing a putative virulence gene esp.

Sources: Willems RJ, et al. Variant esp gene as a marker of a distinct genetic lineage of vancomycin-resistant Enterococcus faecium spreading in hospital. Lancet 2001;357:853-855.

Stinear TP, et al. Enterococcal vanB resistance locus in anaerobic bacteria in human feces. Lancet 2001; 357:855-856.

Gonzales RD, et al. Infections due to vanco-mycin-resistant Enterococcus faecium resistant to linezolid. Lancet 2001; 357:1,179.

Abstract: A recent report from Australia provides a potential mechanism for the origin of one type of vancomycin resistance in enterococci. While developing a PCR method for rapid detection of enteric carriers of vancomycin-resistant enterococcus (VRE), Stinear and colleagues found the presence of the vanB gene in 13 of 50 human stool specimens that contained no detectable VRE. Using selective culture methodology, they were able to isolate anaerobic bacteria containing the vanB gene from two samples. Upon sequence analysis, one isolate was closely related to Eggerthella lenta, and the other to Clostridium innocuum.

Both isolates were positive by PCR for vanB, and the nucleotide sequence matched that found in the original stool sample. In addition, both isolates had the vanB type of glycopeptide resistance (e.g., resistant to vancomycin but susceptible to teicoplanin). The observations provide evidence that enterococci may have acquired vanB type resistance via gene transfer from commensal anaerobes.

Willems and colleagues in The Netherlands have found evidence of a common origin for Enterococ-cus faecium strains implicated in hospital epidemics. In Europe, hospital outbreaks of vancomycin-resistant Enterococcus faecium (VREF) are relatively infrequent compared to the United States. However, VREF carriage is relatively common among livestock and healthy people. Willems, et al, genotyped VREF faecium isolates from hospital outbreaks
in the United States, the United Kingdom, The Netherlands, and Australia, as well as multiple nonepidemic human and animal strains from various locations. Fifteen of 16 of the epidemic strains contained the esp gene. This gene, which codes for a cell surface protein, is often present in E faecalis strains causing clinical infection. It has been linked to virulence in E faecalis. None of the nonepidemic VREF strains contained the esp gene. The esp gene sequence was highly conserved among the epidemic E faecium isolates and showed substantial genetic divergence from the E faecalis esp gene (24-25 base pairs difference).

Pathogenic potential emerges

Based on the analysis of an additional genetic sequence, the epidemic VREF strains appeared to have a common origin. Willems, et al, postulate that the VREF strains containing the variant esp gene have been present for a considerable period of time, based on the number of mutational differences with the E faecalis esp gene. The pathogenic potential of these strains only became recognized after they had acquired vancomycin resistance.

Gonzales and colleagues reported the isolation of linezolid-resistant VREF from five patients. All five had received prolonged courses of linezolid (21 to 40 days) for the treatment of infection due to linezolid-susceptible VREF prior to isolation of the resistant strains. Linezolid MICs of the resistant strains ranged from 3 ug/mL to 64 ug/mL. Four
of the five isolates were available for typing by pulsed-field gel electrophoresis (PFGE); they were unrelated. The pre- and post-therapy VREF isolates of one of the patients were available for typing. They were closely related, differing by only one band. This indicates that the original, susceptible strain most likely became resistant during linezolid therapy. Gonzales, et al, calculated the frequency of emergence of resistance to linezolid by VREF to be 2.2% in their center. This is substantially higher than the rate of < 1% reported by the manufacturer in the original compassionate release trial.

Commentary by Robert Muder, MD, hospital epidemiologist at the Pittsburgh VA Medical Center.

These reports provide provocative data on the evolution and spread of VREF. It appears that the enterococcal vanB gene may have been acquired via gene transfer from relatively nonpathogenic anaerobes in the human gut. Stinear, et al, were able to find two additional vanB-positive anaerobic isolates from stool samples of chronic dialysis patients. They also note that in Australia, vanB-type resistance is most common. Furthermore, Australian VREF strains show considerable diversity by PFGE, indicating that spread of clonal strains is not a major mechanism of nosocomial VREF acquisition.

In contrast, the report by Willems, et al, may help to explain why clonal dissemination of particular VREF may be associated with hospital outbreaks. The esp gene is a putative virulence factor in E faecalis and has generally not been identified in E faecium. The high degree of genetic difference between the two species’ esp genes indicates that the epidemic strains of E faecium acquired the esp genes some time in the past, and only became widespread after the acquisition of vancomycin resistance. The possible role played by esp in enterococcal virulence is unsettled but deserves further scrutiny.

The development of resistance to linezolid by E faecium is a sobering reminder that the release of a new antimicrobial is nearly always followed by reports of increased resistance to the agent following its use.