Reply to Fabre et. al L. Clifford McDonald, 1 Stuart Johnson, 2,3 Johan S. Bakken, 4 Kevin W. Garey, 5 Ciaran Kelly, 6 Dale N. Gerding, 2 1 Centers for Disease Control and Prevention, Atlanta, Georgia; 2 Edward Hines Jr Veterans Administration Hospital, Hines, and 3 Loyola University Medical Center, Maywood, Illinois; 4 St Luke s Hospital, Duluth, Minnesota; 5 University of Houston College of Pharmacy, Texas; and 6 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts Corresponding author: L. Clifford McDonald, MD Centers for Disease Control and Prevention 1600 Clifton Road, MS A35 Atlanta GA, 30333 Cmcdonald1@cdc.gov Reply to author- Fabre et al. pose an important question about the evidence in support of the recommendation to move metronidazole to a second line status and whether it is likely to result in net benefit or harm to patients [1]. The evidence supporting our recommendation to relegate metronidazole to second-line therapy of nonsevere CDI in settings where access to vancomycin or fidaxomicin is limited was of high quality. We analyzed five prospective, randomized, controlled trials that showed metronidazole inferior to vancomycin for initial cure as well as sustained response for all patients, not just patients with severe disease [2]. Additional data of lesser quality also Published by Oxford University Press for the Infectious Diseases Society of America 2018. This work is written by (a) US Government employee(s) and is in the public domain in the US.
support the conclusion that metronidazole is an inferior therapy for CDI, including slower time to response [3], relatively poor response overall [4] and retrospective data showing inferior response even in patients with mildto-moderate disease [5]. The more recent study mentioned by the authors [6] was also a retrospective study that looked at recurrence and 30-day mortality as outcomes; despite propensity matching, the possibility of unmeasured confounding persists (i.e. large sample sizes do not overcome systematic bias); and there has never been a suggestion that vancomycin is superior to metronidazole for preventing recurrence as confirmed in this study. Thirty day mortality for all patients treated with vancomycin vs metronidazole was significantly lower, albeit with most of the reduced mortality in patients with severe CDI. In both the Zar et al.[7] and Johnson et al.[8] prospective, randomized, controlled trials, vancomycin trended toward superiority in the mild disease subgroups and a multivariate analysis by Johnson et al. found vancomycin to be superior overall, independent of disease severity. This suggests a continuous, consistent benefit of vancomycin over metronidazole across a spectrum of disease severity, albeit a smaller measurable effect on outcomes that are more uncommon in mild disease. These data, combined with the poor pharmacokinetic properties of the drug leading to low concentrations of the drug in stool [9] suggest that metronidazole is not an optimal drug for treating this enteric infection. Although cost has been an important practical consideration for selection of CDI treatments, our recommendations were based on relative efficacy of the agents. Availability of an FDA-approved oral solution (https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208910s000lbl.pdf ) and lower acquisition costs for generic capsules should improve access to vancomycin. Both oral metronidazole and vancomycin disrupt the microbiome and there is not consensus that one promotes overgrowth of vancomycin- resistant enterococci more than the other does [10]. Although the previous CDI guidelines recommended metronidazole for patients with mild-to-moderate CDI, those criteria are still not validated and not standardized, suggesting caution for using "mild CDI" as an indication for metronidazole. In addition, these recommendations appear difficult to
follow, possibly from ambiguity in severity classification, resulting in poor outcomes when metronidazole is used for what in retrospect is likely severe disease [6, 11].
Disclaimer. The findings and conclusions in this report are those of the author(s), and do not necessarily represent the official position of the CDC or the US Department of Veterans Affairs. Potential Conflicts: Dr. Kelly reports grants from NIH NIAID R01 AI116596, grants from Institut Merieux Research grant, during the conduct of the study; personal fees from Facile Therapeutics, personal fees from First Light Biosciences, personal fees from Finch, personal fees from Merck, personal fees from Seres Health, personal fees from Vedanta, personal fees from Artugen, personal fees from Matrivax, outside the submitted work. Dr. Johnson reports personal fees from Bio-K+, personal fees from Synthetic Biologics, personal fees from CutisPharma, outside the submitted work. Dr. Gerding reports personal fees from Merck, personal fees from Rebiotix, personal fees from Summit, personal fees from Da Volterra, personal fees from MGB BioPharma, personal fees from Pfizer, personal fees from Sanofi Pasteur, personal fees from Actelion, grants from Seres, outside the submitted work; In addition, Dr. Gerding has a patent Treatment and Prevention of CDI issued. Dr. Garey reports consultancy fees from Biomerieux, Merck & Co, Summit Pharmaceuticals. Grants from Merck & Co, Summit Pharmaceuticals, and Techlab. Presentation fees from Biomerieux and Merck & Co. All other authors declare no conflicts. References 1. Fabre VD, K; Avdic, E; Cosgrove, S.E. Role of metronidazole in mild Clostridium difficile infections. Clinical Infectious Diseases 2018. 2. McDonald LC, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis 2018; 66(7): e1-e48. 3. Wilcox MH, Howe R. Diarrhoea caused by Clostridium difficile: response time for treatment with metronidazole and vancomycin. J Antimicrob Chemother 1995; 36(4): 673-9. 4. Musher DM, Aslam S, Logan N, et al. Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole. Clin Infect Dis 2005; 40(11): 1586-90. 5. Siegfried J, Dubrovskaya Y, Flagiello T, et al. Initial Therapy for Mild to Moderate Clostridium difficile Infection: Exploring the Role of Oral Metronidazole Versus Vancomycin in 168 Hospitalized Patients. Infectious Diseases in Clinical Practice 2016; 24(4): 210-6.
6. Stevens VW, Nelson RE, Schwab-Daugherty EM, et al. Comparative Effectiveness of Vancomycin and Metronidazole for the Prevention of Recurrence and Death in Patients With Clostridium difficile Infection. JAMA Intern Med 2017; 177(4): 546-53. 7. Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis 2007; 45(3): 302-7. 8. Johnson S, Louie TJ, Gerding DN, et al. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis 2014; 59(3): 345-54. 9. Johnson S, Homann SR, Bettin KM, et al. Treatment of asymptomatic Clostridium difficile carriers (fecal excretors) with vancomycin or metronidazole. A randomized, placebo-controlled trial. Ann Intern Med 1992; 117(4): 297-302. 10. Al-Nassir WN, Sethi AK, Li Y, Pultz MJ, Riggs MM, Donskey CJ. Both oral metronidazole and oral vancomycin promote persistent overgrowth of vancomycin-resistant enterococci during treatment of Clostridium difficile-associated disease. Antimicrob Agents Chemother 2008; 52(7): 2403-6. 11. Patel I, Wungjiranirun M, Theethira T, et al. Lack of adherence to SHEA-IDSA treatment guidelines for Clostridium difficile infection is associated with increased mortality. J Antimicrob Chemother 2017; 72(2): 574-81.