Antibiotic therapy for <I>Clostridium difficile-</I>associated diarrhea in adults

Nelson RL, Kelsey P, Leeman H, Meardon N, Patel H, Paul K, Rees R, Taylor B, Wood E, Malakun R

Published Online:

September 7, 2011

Diarrhea may be a side effect of many commonly used antibiotics, and in some cases may be due to overgrowth of a bacterium called Clostridium difficile (C. difficile) in the colon after other bacteria have been killed. The seriousness of C. difficile-associated diarrhea (CDAD) can range from being a nuisance, to a life threatening or even fatal disease. The treatment of CDAD is usually cessation of the initiating antibiotic and immediate administration of a different antibiotic. However each of these steps, cessation of the original antibiotic, immediate retreatment, and the choice of a new antibiotic are poorly supported by currently available evidence. Fifteen studies (total 1152 participants) of antibiotic treatment of CDAD were included in this review. Nine different antibiotics were investigated: vancomycin, metronidazole, fusidic acid, nitazoxanide, teicoplanin, rifampin, rifaximin, bacitracin and fidaxomicin (OPT-80). Most of the studies were compared vancomycin with other antibiotics. Vancomycin was found to be superior to placebo (fake medicine) for improvement of the symptoms of CDAD including resolution of diarrhea. Most of the studies found no statistically significant difference in effectiveness between vancomycin and other antibiotics including metronidazole, fusidic acid, nitazoxanide or rifaximin. Teicoplanin was found to be superior to vancomycin for curing the C. difficile infection. Teicoplanin may be an attractive choice for the treatment of CDAD. However, it is expensive compared to the other antibiotics and is of limited availability. Side effects including surgery and death occurred infrequently in the included studies. There was a total of 18 deaths among 1152 patients in this systematic review. These deaths were attributed to underlying disease rather than CDAD or antibiotic treatment. One study reported a partial colectomy (removal of the diseased part of the colon) after failed CDAD treatment. It is questionable whether mild CDAD needs to be treated. The included studies provide little evidence for antibiotic treatment of severe CDAD as many studies attempted to exclude these patients. Considering the goals of CDAD 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 poor methodological quality of these studies. Over time there have been emerging therapies for the treatment of clostridium difficile such as resins, new biological compounds and probiotics as alternatives to antibiotics. These interventions along with antibiotic therapy for Clostridium difficile-associated diarrhea need further investigation.

Abstract (click to read)

Background:

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

Objectives:

The aim of this review is to investigate the efficacy of antibiotic therapy for C. difficile-associated diarrhea (CDAD).

Search strategy:

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".

Selection criteria:

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.

Data collection and analysis:

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.

Main results:

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.

Authors' conclusions:

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.

This record should be cited as:

Nelson RL, Kelsey P, Leeman H, Meardon N, Patel H, Paul K, Rees R, Taylor B, Wood E, Malakun R. Antibiotic treatment for Clostridium difficile-associated diarrhea in adults. Cochrane Database of Systematic Reviews 2011, Issue 9. Art. No.: CD004610. DOI: 10.1002/14651858.CD004610.pub4

Assessed as up to date:

October 13, 2010

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Primary Review Group:

Inflammatory Bowel Disease and Functional Bowel Disorders Group

Health topics:

Gastroenterology > Diarrhoeal infections > Clostridium difficile

Infectious disease > Diarrhoeal infections > Clostridium difficile

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Antibiotic therapy for <I>Clostridium difficile-</I>associated diarrhea in adults

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