Role of Metronidazole in Mild Clostridium difficile Infections

To the Editor—We commend the authors of the “Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America,” published in Clinical Infectious Diseases earlier this year [1]. We concur with the authors that vancomycin (VAN) should be first-line therapy for severe C. difficile infection (CDI) based on robust clinical data. We are curious why the authors have excluded metronidazole (MTZ) from the preferred treatment options for initial nonsevere CDI cases for adult patients (scored as weak recommendation, high-quality evidence). In the 2010 guidelines [2], the authors cited the randomized, double-blind, controlled trial study by Zar et al [3] that showed no difference in clinical cure or recurrence between MTZ and VAN for mild CDI, as the basis for recommending MTZ as first-line therapy for initial mild CDI (scored as strong recommendation, good quality of evidence) [2]. In the current update, the authors cite good-quality studies assessing the efficacy of MTZ vs VAN [3, 4] for CDI but do not report that the difference in better outcomes associated with VAN is consistently driven by severe CDI cases. In the Johnson et al and Zar et al trials, there was no difference in mortality, CDI recurrence, or clinical cure between MTZ and VAN for mild CDI cases [3, 4] (Table 1). The authors discuss MTZ for mild CDI cases only in the setting of a 2016 single-center retrospective study that showed a lower treatment response with MTZ compared to VAN among patients with non-NAP1 strain CDI [5]. The subjective criteria for treatment response, differences in patient population between the MTZ and VAN groups, and lack of alternative causes of diarrhea limit interpretation of these results. The 2017 guideline update is based on literature published during 2009–2016; hence, the study by Stevens et al, a large multicenter propensity score-matched study of >4000 patients who demonstrated no difference in recurrence or mortality between MTZ and VAN for mild CDI cases [6], was not included. Studies Comparing Metronidazole Versus Vancomycin for Mild Clostridium difficile Infection Within the Last 10 Years Percentages given in parenthesis represent MTZ vs VAN. Abbreviations: BM, bowel movement; CDI, Clostridium difficile infection; EIA, enzyme immunoassay; ICU, intensive care unit; IDSA, Infectious Diseases Society of America; MTZ, metronidazole; NA, not assessed; NR, not reported; PCR, polymerase chain reaction; PO, orally; SHEA, Society for Healthcare Epidemiology of America; VAN, vancomycin; WBC, white blood cell count. aClinical cure definitions: Zar study: Resolution of diarrhea at day 6 plus negative toxin assay; Johnson study: Resolution of diarrhea and absence of severe abdominal discomfort due to CDI for >2 consecutive days including day 10; Siegfried study: Improvement in CDI signs and symptoms (decrease in number of bowel movements, formed stool consistency, resolution of fever, and abdominal tenderness) by day 10 of therapy; Le study: Resolution of diarrhea on or before day 6 of therapy. Studies Comparing Metronidazole Versus Vancomycin for Mild Clostridium difficile Infection Within the Last 10 Years Percentages given in parenthesis represent MTZ vs VAN. Abbreviations: BM, bowel movement; CDI, Clostridium difficile infection; EIA, enzyme immunoassay; ICU, intensive care unit; IDSA, Infectious Diseases Society of America; MTZ, metronidazole; NA, not assessed; NR, not reported; PCR, polymerase chain reaction; PO, orally; SHEA, Society for Healthcare Epidemiology of America; VAN, vancomycin; WBC, white blood cell count. aClinical cure definitions: Zar study: Resolution of diarrhea at day 6 plus negative toxin assay; Johnson study: Resolution of diarrhea and absence of severe abdominal discomfort due to CDI for >2 consecutive days including day 10; Siegfried study: Improvement in CDI signs and symptoms (decrease in number of bowel movements, formed stool consistency, resolution of fever, and abdominal tenderness) by day 10 of therapy; Le study: Resolution of diarrhea on or before day 6 of therapy. Additionally, while the authors acknowledge neuropathy and nausea as adverse events associated with MTZ, only “minimally absorbed” is noted for VAN. We believe that it would have been reasonable to describe the impact VAN has on the human gut flora including depletion of protective bacteria and selective pressure on vancomycin susceptibility in enterococci [7]. Determinants of strength of recommendations for the 2017 update include (1) quality of evidence; (2) the patient’s values and preferences; (3) resources and cost; and (4) balance between benefits, harm, and burdens [1]. Applying these determinants to MTZ, we find high-quality evidence to support its use in mild CDI cases, lower cost compared to VAN, and less association with colonization/development of drug-resistant organisms compared to VAN. In summary, since the 2010 guidelines that included one randomized controlled trial to support MTZ in mild CDI cases, there have been 2 additional well-designed, large-size studies supporting this recommendation [4, 6]. We believe there is sufficient evidence to consider MTZ as a first-line option for mild CDI cases in patients with low risk for complications. Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.