To our knowledge, no previous published studies have directly compared VRE overgrowth and acquisition during treatment of CDAD with metronidazole versus vancomycin. Among patients with preexisting VRE colonization, we found that both drugs promoted similar high-concentration colonization that persisted during the course of therapy and decreased after discontinuation of treatment. Among patients with negative cultures prior to initiation of therapy, new detection of VRE colonization was uncommon in both therapy groups. These findings do not support our hypothesis that oral vancomycin may promote VRE to a greater degree than oral metronidazole and suggest that factors other than promotion of VRE should be the primary considerations in choosing oral vancomycin or metronidazole for treatment of CDAD.
Because multiple genes are necessary to generate vancomycin resistance in enterococci, acquisition of VRE colonization does not occur through mutations in susceptible enterococci in the intestinal tract (4
). Rather, selective pressure exerted by oral vancomycin may facilitate the exogenous acquisition of VRE or the transfer of vancomycin resistance genes from other organisms to E. faecium
in the intestinal tract (12
). Although we evaluated a limited number of patients for new detection of VRE colonization, our data provide some reassurance that this occurrence may be relatively uncommon during oral vancomycin therapy, even in centers with a high prevalence of VRE. Salgado et al. (19
) previously reported that no new acquisition of VRE colonization was detected among 20 patients who received 23 courses of oral vancomycin for CDAD in a medical center with a low prevalence of VRE. In addition, we have demonstrated no de novo emergence of VRE in more than 100 mice treated with oral vancomycin in drinking water (5
; unpublished data). The previous studies that did find high rates of acquisition of VRE in humans during oral vancomycin treatment were conducted in Europe and may have been confounded that the fact that the food supply was contaminated with VRE of animal origin (7
). Finally, it should be noted that the transfer of vancomycin resistance genes in the intestinal tract may occur in the absence of vancomycin selective pressure (12
Our study has some limitations. The study was observational; however, the characteristics of the groups were similar. Because vancomycin is often prescribed for more severe CDAD cases, any bias due to patient selection should have favored the metronidazole group. The number of patients with negative cultures for VRE at initiation of CDAD therapy was low, and therefore additional studies are needed to further assess the risk for new detection of VRE during CDAD treatment, which was a secondary aim of our study. It is possible that a difference between the study groups would have been detected if there had been a longer follow-up period. However, the mean concentration of VRE decreased significantly by days 21 to 25 (i.e., approximately 2 weeks after completion of CDAD therapy) in both treatment groups. In addition, patients were monitored for the duration of their stay in the acute care facility, and therefore the absence of long-term follow-up reflects the fact that most subjects were discharged during or within 1 to 2 weeks of completing CDAD treatment. Because all of the patients were treated for CDAD, it is possible that some of the persistent VRE overgrowth may have been attributable to the previous antibiotics that caused the CDAD. However, our findings from two previous observational studies demonstrate that the concentrations of VRE in the stools of colonized patients decreases significantly by 1 to 2 weeks after discontinuation of treatment with a wide range of different anti-anaerobic antibiotic regimens (2
). Finally, the effects of the agents on the indigenous microflora were not assessed. However, previous studies have confirmed that oral metronidazole and vancomycin cause significant disruption of the intestinal microflora, including Bacteroides
In summary, we found that both oral vancomycin and oral metronidazole treatment of CDAD was associated with persistent overgrowth of preexisting VRE stool colonization. In contrast, the concentration of VRE in stool of colonized patients decreased significantly by 1 to 2 weeks after discontinuation of treatment with anti-anaerobic antibiotics (2
). Among patients with negative cultures prior to initiation of therapy, new detection of VRE colonization was uncommon in both therapy groups. These findings suggest that factors other than promotion of VRE should be the primary considerations in choosing oral vancomycin or metronidazole for treatment of CDAD. In addition, our findings highlight the importance of developing new treatments for CDAD that are less likely to disrupt the intestinal microflora and promote overgrowth of healthcare-associated pathogens.