Evidence

The guideline authors removed metronidazole from a first-line recommendation after analyzing five prospective, randomized, controlled trials showing metronidazole was inferior to vancomycin for initial cure as well as sustained response for all patients, not just patients with severe disease⁽¹⁾.

Additional data suggested slower time to response⁽²⁾, poor response overall⁽³⁾ and retrospective data showed inferior response even in patients with mild to moderate disease⁽⁴⁾.

In a VA dataset there was no difference in recurrence rates between vancomycin and metronidazole but the increased failure rate associated with metronidazole was associated with an increased 30-day mortality⁽⁵⁾. This data was mostly swayed by patients with severe disease.

An additional prospective, randomized controlled trial found vancomycin to be superior overall despite disease severity⁽⁶⁾.

The poor pharmacokinetics of metronidazole may be partially to blame for this⁽⁷⁾⁽⁸⁾. The mean concentration of metronidazole in the colon ranges from <0.25 to 9.5 mcg/g of stool; higher concentrations when the colon is inflamed. The minimum inhibitory concentration of 90% of C. difficile isolates is 2 or less⁽⁷⁾. Considering the concentration of metronidazole is reduced as the colonic inflammation subsides it is not surprising that treatment of metronidazole may not fair as well.

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. Bolton RP, Culshaw MA. Faecal metronidazole concentrations during oral and intravenous therapy for antibiotic associated colitis due to Clostridium difficile. Gut 1986;10:1169-72.

9. Garey K. Solving the mysteries of C. difficile infection. Society of Infectious Diseases Pharmacist Annual Meeting. San Diego, CA. Oct 2017. Lecture.