Title:
Antibiotic treatment for Clostridium difficile-associated diarrhea in adults.

Abstract:
Clostridium difficile is recognized as a frequent cause of antibiotic-associated diarrhea and colitis.
The aim of this review is to investigate the efficacy of antibiotic therapy for C. difficile-associated diarrhea (CDAD).
MEDLINE (1966 to March 24, 2010), EMBASE (1980 to March 24, 2010), Cochrane Central Register of Controlled Trials and the Cochrane IBD/FBD 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".
Only randomized, controlled trials assessing antibiotic treatment for CDAD were included in the review. The following outcomes were sought: initial resolution of diarrhea; initial conversion of stool to cytotoxin and/or culture negative; recurrence of diarrhea; recurrence of fecal evidence of CDAD; patient response to cessation of prior antibiotic therapy; emergent surgery; and death.
Three authors independently assessed abstracts and full text articles for inclusion. The risk of bias was independently rated by two authors. For dichotomous outcomes, relative risks (RR) and 95% confidence intervals (CI) were derived from each study and summary statistics obtained when appropriate, using a fixed effects model, except where significant heterogeneity was detected, at which time a random effects model was used.
Fifteen studies (total of 1152 participants) with CDAD were included. Nine different antibiotics were investigated: vancomycin, metronidazole, fusidic acid, nitazoxanide, teicoplanin, rifampin, rifaximin, bacitracin and fidaxomicin (OPT-80). Most of the studies were active comparator studies comparing vancomycin with other antibiotics. The risk of bias was rated as high for 12 of 15 included studies. Patients with severe CDAD were often excluded from the included studies. In the only placebo-controlled trial vancomycin was found to be superior to placebo for treatment of CDAD for initial symptomatic cure. Initial symptomatic cure was achieved in 41% of vancomycin patients compared to 4% of placebo patients (1 study; 44 patients; RR 9.00; 95% CI 1.24 to 65.16). Vancomycin was significantly superior to placebo for initial bacteriologic response. Initial bacteriologic response was achieved in 45% of vancomycin patients compared to 4% of placebo patients (1 study; 44 patients; RR 10.00; 95% CI 1.40 to 71.62). The results of this study should be interpreted with caution due to the small number of patients and high risk of bias. No statistically significant differences in efficacy were found between vancomycin and metronidazole, vancomycin and fusidic acid, vancomycin and nitazoxanide, or vancomycin and rifaximin. No statistically significant differences in efficacy were found between metronidazole and nitazoxanide or metronidazole and fusidic acid. Vancomycin was significantly superior to bacitracin for initial bacteriologic response. Initial bacteriologic response was achieved in 48% of vancomycin patients compared to 25% of bacitracin patients (2 studies; 104 patients; RR 0.52; 95% CI 0.31 to 0.86). Teicoplanin, an antibiotic of limited availability and great cost, was significantly superior to vancomycin for initial bacteriologic response and cure. Initial bacteriologic response was achieved in 62% of vancomycin patients compared to 87% of teicoplanin patients (2 studies; 110 patients; RR 1.43; 95% CI 1.14 to 1.81). Bacteriologic cure was achieved in 45% of vancomycin patients compared to 82% of teicoplanin patients (2 studies; 110 patients; RR 1.82; 95% CI 1.19 to 2.78). These results should be interpreted with caution due to the small number of patients and the high risk of bias in the two studies in the pooled analysis. Teicoplanin was significantly superior to metronidazole for initial bacteriologic response. Initial bacteriologic response was achieved in 71% of metronidazole patients compared to 93% of teicoplanin patients (1 study; 59 patients; RR 0.76; 95% CI 0.60 to 0.98). This result should be interpreted with caution due to the small number of patients and high risk of bias in the study. Only one study investigated synergistic antibiotic combination, metronidazole and rifampin, and no advantage was demonstrated for the drug combination. This result should be interpreted with caution due to the small number of patients and high risk of bias in the study. Adverse events including surgery and death occurred infrequently in the included studies. There was a total of 18 deaths among 1152 patients in this systematic review. Among the studies that commented on the cause of mortality the deaths were attributed to underlying disease rather than CDAD or antibiotic treatment. One study reported a partial colectomy after failed CDAD treatment.
Current evidence leads to uncertainty whether mild CDAD needs to be treated. The studies provide little evidence for antibiotic treatment of severe CDAD as many studies excluded these patients. Considering the two goals of therapy: improvement of the patient's clinical condition and prevention of spread of C. difficile infection to other patients, one should choose the antibiotic that brings both symptomatic cure and bacteriologic cure. A recommendation to achieve these goals cannot be made because of the small numbers of patients in the included studies and the high risk of bias in these studies, especially related to dropouts. Most of the active comparator studies found no statistically significant difference in efficacy between vancomycin and other antibiotics including metronidazole, fusidic acid, nitazoxanide or rifaximin. Teicoplanin may be an attractive choice but for its limited availability (Teicoplanin is not available in the USA) and great cost relative to the other options. More research of antibiotic treatment and other treatment modalities of CDAD is required.