By Stan Deresinski, MD, FACP, FIDSA

Clinical Professor of Medicine, Stanford University

SYNOPSIS: These studies indicate that the addition of intravenously administered metronidazole in the treatment of severe Clostridioides difficile infection is unwarranted.

SOURCES: 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 2020;71:2414-2420.

Vega AD, Heil EL, Blackman AL, et al. Evaluation of addition of intravenous metronidazole to oral vancomycin therapy in critically ill patients with non-fulminant severe Clostridioides difficile infection. Pharmacotherapy 2020;40:398-407.

Wang and colleagues performed a retrospective study at two centers designed to examine the relative benefit of the addition of intravenously administered metronidazole to orally administered vancomycin in adult inpatients with Clostridioides difficile infection (CDI). Treatment must have been initiated within a four-day window (two days before or after) of a positive test for C. difficile. The primary outcome was a composite of the occurrence of death or colectomy within the 90 days after the positive test.

The total cohort consisted of 2,114 patients: 1,121 who received vancomycin monotherapy and 993 who received combination therapy. Using the Infectious Diseases Society of America (IDSA) criteria, CDI was classified as non-severe in 34%, severe in 41%, and fulminant in 25% (hypotension accounted for this designation in most cases). As expected, those who received combination treatment had a greater severity of illness.

The primary outcome occurred in 23% of the entire cohort, with death in 1% and colectomy in 22%. In addition, recurrence subsequently occurred in 11% of survivors. In a crude analysis, death occurred significantly more frequently in those who received vancomycin alone. However, with adjustment for disease severity, there was no association between combination therapy and 90-day death or colectomy (adjusted odds ratio, 1.07; 95% confidence interval [CI], 0.79 to 1.45). Neither stratifying by severity (fulminant vs. non-fulminant) nor restricting the analysis to intensive care unit (ICU) patients changed the finding of a lack of significant relative benefit from combination therapy.

In a smaller study, Vega and colleagues examined the cases of 138 ICU patients with severe but non-fulminant CDI, 60 (43.5%) of whom received combination therapy. Although overall mortality proved to be higher in those receiving both drugs, the 30-day mortality rate in the monotherapy arm (12.8%) did not significantly differ from that in the group that received combination therapy (18.3%; P = 0.371). A subset analysis with matching by APACHE-II score also found no significant difference.


Current IDSA/Society for Healthcare Epidemiology of American (SHEA) guidelines (which are under revision) call for the addition of intravenous (IV) metronidazole to oral vancomycin in the treatment of patients with fulminant CDI as defined by the presence of hypotension, ileus, or megacolon. In contrast to earlier studies on which this recommendation rested, the results of more recent studies have been inconclusive or negative with regard to the benefit of such combination therapy.

Wang et al pointed out that vancomycin, to which C. difficile is very rarely resistant, achieves enormous concentration in the fecal stream, even in the presence of ileus. In contrast, the metronidazole concentration achieved after IV administration is quite modest. Furthermore, the efficacy of metronidazole given alone is minimal, and its presence likely adds little or nothing to vancomycin.

The authors concluded that the use of combination therapy “merits reconsideration.” I think they are being overly polite. Let’s wait and see what IDSA/SHEA say.