Antibiotic treatment for Clostridium difficile-associated diarrhea in adults.

BACKGROUND

Clostridium difficile (C. difficile) is recognized as a frequent cause of antibiotic-associated diarrhea and colitis.

OBJECTIVES

The aim of this review is to establish the efficacy of antibiotic therapy for C. difficile-associated diarrhea (CDAD), to identify the most effective antibiotic treatment for CDAD in adults and to determine the need for stopping the causative antibiotic during therapy.

SEARCH STRATEGY

MEDLINE (1966 to 2003), EMBASE (1980 to 2003), Cochrane Central Database of Controlled Trials and the Cochrane IBD Review Group Specialized Trials Register were searched using the following search terms: "pseudomembranous colitis and randomized trial"; "Clostridium difficile and randomized trial"; "antibiotic associated diarrhea and randomized trial".

SELECTION CRITERIA

Only randomized, controlled trials assessing antibiotic treatment for CDAD were included in the review. Probiotic trials are excluded. The following outcomes were sought: initial resolution of diarrhea; initial conversion of stool to C. difficile cytotoxin and/or stool culture negative; recurrence of diarrhea; recurrence of fecal C. difficile cytotoxin and/or positive stool culture; patient response to cessation of prior antibiotic therapy; sepsis; emergent surgery: fecal diversion or colectomy; and death.

DATA COLLECTION AND ANALYSIS

Data were analyzed using the MetaView statistical package in Review Manager. For dichotomous outcomes, relative risks (RR) and 95% confidence intervals (CI) were derived from each study. When appropriate, the results of included studies were combined for each outcome. For dichotomous outcomes, pooled RR and 95% CI were calculated using a fixed effect model, except where significant heterogeneity was detected, at which time the random effects model was used. Data heterogeneity was calculated using MetaView.

MAIN RESULTS

Of eleven studies identified, two were subsequently excluded because patients were stool positive for C. difficile, but did not have diarrhea or because the study was not a randomized controlled trial. All of the remaining nine studies involved patients with diarrhea who recently received antibiotics for an infection other than C. difficile. The definition of diarrhea ranged from at least two loose stools per day with an associated symptom such as rectal temperature > 38(o)C, to at least six loose stools in 36 hours. In terms of symptomatic cure, metronidazole, bacitracin and fusidic acid were not shown to be less effective than vancomycin. Teicoplanin may be slightly more effective than vancomycin with a relative risk of 1.21 [95% CI 1.00 to 1.46] and a p-value of 0.06. In terms of initial symptomatic resolution, vancomycin is more effective than placebo with a relative risk of 6.75 [95% CI 1.16 to 48.43] and a p-value of 0.03. This result should be interpreted with caution given the small number of patients in this comparison (12 in the vancomycin group and nine in the placebo group) and the poor methodological quality of the trial. Metronidazole, bacitracin, teicoplanin, fusidic acid and rifaximine are as effective as vancomycin for initial symptomatic resolution. The other secondary outcomes measured in this review: surgery, sepsis and death occurred infrequently in all of the studies.

AUTHORS' CONCLUSIONS: Current evidence leads to uncertainty whether mild CDAD needs to be treated. Patients with mild CDAD may resolve their symptoms as quickly without treatment. The only placebo-controlled study shows vancomycin's superior efficacy. However, this result should be treated with caution due to the small number of patients enrolled and the poor methodological quality of the trial. The Johnson study of asymptomatic carriers also shows that placebo is better than vancomycin or metronidazole for eliminating C. difficile in stool during follow-up. If one does decide to treat, then two goals of therapy need to be kept in mind: improvement of the patient's clinical condition and prevention of spread of C. difficile infection to other patients. Given these two considerations, one should choose the antibiotic that brings both symptomatic cure and bacteriologic cure. In this regard, teicoplanin appears to be the best choice because the available evidence suggests that it is better than vancomycin for bacteriologic cure and has borderline superior effectiveness in terms of symptomatic cure. Teicoplanin is not readily available in the United States, which must be taken into account when making treatment decisions in that country.