“A Comparison of Vancomycin and Metronidazole for the Treatment of Clostridium difficile-Associated Diarrhea, Stratified by Disease Severity”
Clin Infect Dis. 2007 Aug 1;45(3):302-7. [free full text]
Clostridium difficile-associated diarrhea (CDAD) is a common nosocomial illness that is increasing in incidence, severity, and recurrence. This trial, initiated in 1994, sought to investigate whether metronidazole PO or vancomycin PO was the superior initial treatment strategy in both mild and more severe disease.
Population: patients with diarrhea (3+ non-formed stools within 24hrs) and either stool C. difficile toxin A positivity within 48hrs after study entry or pseudomembranous colitis per endoscopy
(Patients were dropped from the study if the toxin A assay resulted negative.)
Notable exclusion criteria: prior failure of CDAD to respond to either study drug or treatment with either study drug during the previous 14 days.
Stratification: Prior to treatment randomization, patients were stratified to groups of either mild (0-1 points) or severe (≥2 points) CDAD.
- One point: age > 60, T > 38.3º C, albumin < 2.5 mg/dL, WBC >15k within 48hrs of enrollment
- Two points: endoscopic evidence of pseudomembranous colitis or treatment in the ICU
Intervention: vancomycin liquid 125mg QID and placebo tablet QID x 10 days
Comparison: metronidazole 250mg PO QID and “an unpleasantly-flavored” placebo liquid QID x 10 days
- Cure = resolution of diarrhea by day 6 of tx and negative toxin A assay at 6 and 10 days
- Treatment failure = persistence of diarrhea and/or positive toxin A assay after 6 days, the need for colectomy, or death after 5 days of therapy
- Relapse = recurrence of CDAD by day 21 after initial cure
172 patients were randomized. 90 had mild disease, and 82 had severe disease. 22 patients withdrew from the study prior to completion of 10 days of therapy. This study analyzed only the 150 patients who completed the trial (81 with mild disease, 69 with severe disease). Within severity groups, there were no differences in baseline characteristics among the two treatment groups.
Among patients with mild disease, 37 of 41 (90%) metronidazole patients were cured and 39 of 40 (98%) vancomycin patients were cured (p = 0.36). Among patients with severe disease, 29 of 38 (76%) metronidazole patients were cured and 69 of 71 (97%) vancomycin patients were cured (p = 0.02).
Among patients with mild disease, 3 of 37 (8%) metronidazole patients relapsed and 2 of 39 (5%) of vancomycin patients relapsed (p = 0.67). Among patients with severe disease, 6 of 29 (21%) of metronidazole patients relapsed and 3 of 30 (10%) of vancomycin patients relapsed (p = 0.30).
Patients with mild CDAD had similar cure rates (> 90%) with oral metronidazole and oral vancomycin, however, patients with severe disease had higher cure rates with vancomycin than with oral metronidazole.
This randomized, placebo-controlled trial was the first trial comparing oral metronidazole and vancomycin in CDAD that was blinded and that stratified patients by disease severity.
The authors hypothesize that “a potential mechanism for our observation that metronidazole performs less well in patients with severe disease is that the drug is delivered from the bloodstream through the inflamed colonic mucosa, and stool concentrations decrease as disease resolves.”
Study limitations include single-center design, low N, high dropout rates, lack of intention-to-treat analysis, and slow recruitment (1994-2002). The slow recruitment and long duration of the trial is particularly notable, given that the organism itself, disease prevalence in community settings, host factors, and disease-inciting antibiotic regimens shifted significantly over this extended period.
At the time of publication of this study (2007), the CDC was not recommending vancomycin as first-line therapy for CDAD (for fear of spread of VRE).
Following this study, the 2010 update to the IDSA/SHEA guidelines for the treatment of CDAD recommended metronidazole PO for the initial treatment of mild-to-moderate CDAD, vancomycin 125mg PO QID for the initial treatment of severe CDAD, and vancomycin + metronidazole IV for severe, complicated CDAD.
However, both the disease and the evidence base for its treatment have evolved over the past 8 years. In March 2018, an update to the IDSA/SHEA guidelines was published. As a departure from prior recommendations, vancomycin 125mg PO QID (or fidaxomicin 200mg PO BID) x10 days is now the first-line treatment for non-severe C. diff. See Table 1 of these updated guidelines for a summary of pertinent definitions and treatment regimens.
1. Wiki Journal Club
2. 2 Minute Medicine
3. “Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA).”
4. “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 Mar 19;66(7).
Summary by Duncan F. Moore, MD