Dual therapy with intravenous (IV) metronidazole and oral vancomycin is not superior to oral vancomycin alone in the treatment of Clostridioides difficile infections (CDI), according to study results published in ClinicalInfectiousDiseases.

CDI is the leading cause of healthcare-associated diarrhea; data from 2011 demonstrated a total annual incidence of 450,000 cases, 29,300 of which were fatal, in the United States. It is important to treat CDI with appropriate antibiotics because of the significant disease burden. Current practice guidelines from the Society for Healthcare Epidemiology of American and Infectious Diseases Society of America recommend that treatment plans should be based on the severity of infection.

Oral vancomycin or fidaxomicin are the recommended treatment for most CDIs. The treatment recommended for fulminant CDI (infection associated with hypotension, shock, ileus, or megacolon) is dual therapy with oral vancomycin and IV metronidazole. Although there has been no evidence supporting a synergistic effect of vancomycin and metronidazole against CDI in vitro, it has been hypothesized that IV metronidazole may have better drug penetration than vancomycin, especially under clinical circumstances such as ileus.

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However, treatment with metronidazole has potential risks, including exacerbating the depletion of gut microbiota, which then leaves patients more vulnerable to colonizing pathogens or CDI recurrence. Metronidazole is also commonly associated with adverse events and drug-drug interactions. Therefore, this 2-center retrospective study compared dual therapy with IV metronidazole and oral vancomycin vs vancomycin monotherapy and assessed the prevalence of use and effectiveness of dual therapy in fulminant and non-fulminant CDI.

A total of 2114 adult inpatients with positive polymerase chain reaction testing for C difficile were included from Columbia University Medical Center in New York City or Brigham and Women’s Hospital in Boston, Massachusetts, from 2010 to 2018. Of the included patients, 25% met the criteria for fulminant CDI due to hypotension. All patients received oral vancomycin within 2 days before or 2 days after testing. Patients who received IV metronidazole within the same period were classified into the dual therapy group. In total, 993 patients received dual therapy and 1121 patients received monotherapy. The primary outcome was death or colectomy within 90 days after the index test. To adjust for CDI severity and other established predictors of CDI outcomes, logistic regression was used. As a secondary outcome, CDI recurrence was examined, adjusting for death as a competing risk.

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In total, 23% of included patients met the primary study outcome. After adjustment for Society for Healthcare Epidemiology of American and Infectious Diseases Society of America delineations of disease severity and other established outcome predictors, results suggested that there was no association between dual therapy and the primary outcome (adjusted odds ratio [aOR], 1.07); this remained true when analyses were restricted to patients with fulminant CDI (aOR, 1.17). Furthermore, dual therapy had no association with CDI recurrence.

Overall, the study authors concluded that, “The recommendation that IV metronidazole be added to oral vancomycin in patients with fulminant CDI merits re-consideration.”


Wang Y, Schluger A, Li J, Gomez-Simmonds A, Salmasian H, Freedberg D. Dose addition of intravenous metronidazole to oral vancomycin improve outcomes in Clostridioides difficile infection? [published online November 12, 2019]. Clin Infect Dis. doi:10.1093/cid/ciz1115/55623046