By Stan Deresinski, MD, FACP, FIDSA, FESCMID

Clinical Professor of Medicine, Stanford University

Dr. Deresinski reports no financial relationships relevant to this field of study.

SYNOPSIS: The combination of oral vancomycin and intravenous metronidazole is not superior to vancomycin alone in the treatment of fulminant infection due to Clostridioides difficile.

SOURCE: Wang Y, Schluger A, Li J, et al. Does addition of intravenous metronidazole to oral vancomycin improve outcomes in Clostridioides difficile infection? Clin Infect Dis 2019 Nov 12. doi: 10.1093/cid/ciz1115. [Epub ahead of print].

Wang and colleagues retrospectively examined the outcomes of adults with Clostridioides difficile infection (CDI) hospitalized over a number of years at Columbia University Medical Center and at Brigham and Women’s Hospital who were treated with oral vancomycin alone or with intravenous metronidazole. The diagnoses were made using polymerase chain reaction (PCR) to detect toxin gene. Of the 2,114 total patients, 1,121 received monotherapy and 993 received the combination. At baseline, the latter had more laboratory abnormalities and were more likely to be in the ICU, to have megacolon, and to have fulminant rather than non-fulminant disease.

Based on Society for Healthcare Epidemiology of America/Infectious Diseases Society of America (SHEA/IDSA) criteria, CDI was non-severe in 34% of patients, severe in 41%, and fulminant in 25%. Not unexpectedly, when compared to the lesser classes, fulminant disease was associated with an increased risk of death. Death or colectomy at 90 days (the primary endpoint of the study) occurred in 23% of the entire cohort, with death in 21%, colectomy in 2%, and CDI recurrence in 11%.

After adjustment, multivariate analysis found that combination therapy relative to monotherapy with vancomycin did not affect the primary outcome (adjusted odds ratio [aOR], 1.07; 95% confidence interval [CI], 0.79-1.45) or 90-day mortality alone. Stratification by disease severity did not significantly change this result, nor did restricting the analysis to ICU patients alone. Dual therapy did not reduce the incidence of CDI recurrence.


The current IDSA CDI guidelines recommend the co-administration of oral vancomycin and IV metronidazole for patients with fulminant CDI, defined as the presence of hypotension, shock, ileus, and/or megacolon.1 This recommendation is based on published literature, the entire corpus of which is contradictory, however. This very large study by Wand and colleagues found no evidence of benefit from the addition of IV metronidazole to oral vancomycin for the treatment of fulminant CDI. It might be argued that orally administered vancomycin may not reach its target in patients with ileus, but published data contradict this.2 At the same time, IV metronidazole achieves only quite low concentrations in the colon.

It also should be noted that, even if the combination were beneficial, its use in this study (and probably at most hospitals) far outstrips the IDSA criteria for its use in fulminant infection. Thus, in this report, dual therapy was administered to 47% of patients despite the fact that only 25% had fulminant infection.

One issue with this study that bedevils all studies of CDI is the variable laboratory methodology for diagnosis. In this study, the diagnosis required only a loose stool and a positive PCR test, so that it is likely that many of the patients in the cohort did not have true CDI, but were only colonized. 


  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:e1-e48.
  2. Gonzales M, Pepin J, Frost EH, et al. Faecal pharmacokinetics of orally administered vancomycin in patients with suspected Clostridium difficile infection. BMC Infect Dis 2010;10:363.