Abstract
Background
Probiotics are live microorganisms consisting of non‐pathogenic yeast and bacteria that are believed to restore the microbial balance of the gastrointestinal tract altered by infection with Clostridium difficile (C. difficile).
Objectives
To assess the efficacy of probiotics in the treatment of antibiotic associated C. difficile colitis.
Search methods
The databases MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and Cochrane IBD/FBD Specialized Trials register were searched to locate all published reports from 1966 to 2007.
Selection criteria
Randomized, prospective studies using probiotics alone or in conjunction with conventional antibiotics for the treatment of documented C. difficile colitis were eligible for inclusion.
Data collection and analysis
Data extraction and analysis was done independently by two authors.
Main results
Four studies met the inclusion criteria and were included in the review. The four studies examined the use of probiotics in conjunction with conventional antibiotics (vancomycin or metronidazole) for the treatment of recurrence or an initial episode of C. difficile colitis in adults. The studies were small in size and had methodological problems. A statistically significant benefit for probiotics combined with antibiotics was found in one study. McFarland 1994 found that patients receiving S. boulardii were significantly less likely than patients receiving placebo to experience recurrence of C. difficile diarrhea (RR 0.59; 95% CI 0.35 to 0.98). No benefit of probiotics treatment was found in the other studies.
Authors' conclusions
There is insufficient evidence to recommend probiotic therapy as an adjunct to antibiotic therapy for C. difficile colitis. There is no evidence to support the use of probiotics alone in the treatment of C. difficile colitis.
Keywords: Humans; Clostridioides difficile; Anti‐Bacterial Agents; Anti‐Bacterial Agents/therapeutic use; Enterocolitis, Pseudomembranous; Enterocolitis, Pseudomembranous/therapy; Lacticaseibacillus rhamnosus; Lactobacillus plantarum; Probiotics; Probiotics/therapeutic use; Randomized Controlled Trials as Topic; Saccharomyces
Plain language summary
Probiotics for treatment of Clostridium difficile ‐associated colitis in adults
Clostridium difficile (C. difficile) is a bacterium that attaches itself to the gut wall and is responsible for causing severe diarrhea and sometimes death in patients who have undergone antibiotic therapy for unrelated diseases. Antibiotics tend to wipe out the "good" or protective bacteria in the gut which allows colonization with C. difficile. Probiotics are bacteria and yeasts that resemble the protective bacteria of the gut and have been used in several studies to treat C. difficile infection. Unfortunately, these small studies do not provide enough evidence to support the use of probiotics for treating C. difficile infection.
Background
The administration of antibiotics is known to be associated with the development of diarrhea in patients. Erythromycin and the clavulanate in amoxicillin‐clavulanate cause diarrhea by accelerating gastrointestinal motility (Bartlett 2002). Other antibiotics are thought to cause diarrhea by reducing the number of fecal anaerobes, thereby decreasing carbohydrate digestion and absorption, leading to an osmotic diarrhea (Bartlett 2002). Nearly 15% of hospitalized patients receiving beta‐lactam antibiotics develop diarrhea (McFarland 1995; McFarland 1995). Clostridium difficile (C. difficile) infection of the colon is another cause of antibiotic‐associated diarrhea that is thought to be caused by an overgrowth of native or newly acquired C. difficile (Fekety 1993). C. difficile is implicated in 20 to 30% of patients with antibiotic‐associated diarrhea, in 50 to 70% of those with antibiotic‐associated colitis and in more than 90% of those with antibiotic‐associated pseudomembranous colitis (Bartlett 1980; Bartlett 1990; Bartlett 1990; George 1982; Kelly 1994). Approximately 5% of asymptomatic healthy adults carry low concentrations of C. difficile in their colon, and the growth of these bacteria has been shown in vitro to be held in check by normal gut flora (Fekety 1993). The exact mechanism by which C. difficile overgrowth occurs is still unclear, but it can occur with the administration of oral, parenteral or topical antibiotics (Fekety 1993; Thomas 2003). Colonization with C. difficile usually occurs after ingestion of spores. These spores are able to tolerate the acidic environment of the stomach and attach to the gut, producing cytotoxic and enterotoxic effects. Patients can acquire C. difficile colitis within several days of initiation of antibiotic therapy to months after termination of the offending agent. The patients affected by C. difficile colitis vary from inpatient and outpatient settings, to those receiving chemotherapeutic agents and those who acquire it spontaneously. Conventional treatment includes vancomycin or metronidazole for ten days. However, recurrence occurs in 10 to 25% of cases (Moyenuddin 2002; Bartlett 2002; Bricker 2005). The incidence of C. difficile‐associated diarrhea (CDAD) ranges from 1 in 100 to 1 in 1,000 hospital discharges, depending on the antibiotic prescribing habits of the hospital (Ho 1996; Lai 1997; Manian 1995). Additionally, the incidence may change over time at the same hospital as it did in one study from approximately 1 in 300 to 1 in 100 hospital discharges (Olson 1994).
The consequences of CDAD can be severe. Seventy nine deaths due to CDAD were reported in Quebec in 2003 (Pindera 2004). At one academic medical center over a three‐year period, 21 of 710 cases (3%) of C. difficile colitis required intensive care unit admission or died as a result of their infection (Rubin 1995). These deaths were associated with co‐morbid conditions such as malignancy, COPD or renal failure and therapies such as immunosuppressive drugs, antiperistaltic medications or the prior administration of clindamycin (McFarland 1995). At another university hospital the morbidity of C. difficile infection was higher and 24 of 157 patients (15.3%) with C. difficile colitis died from their infection (Morris 2002). The economic consequences of C. difficile infection can also be severe, with one report finding a mean cost of $10,970 (US$) per patient for the treatment of the infection and its complications (McFarland 1999). Of all these reports, those from Quebec are the most worrisome, and subsequent reports of mortality rates in that province are much higher than previous reports (Pepin 2005). This may be related to the appearance of a new variant of C. difficile, which is capable of secreting much higher amounts of toxin A & B and greater resistance to standard antibiotic therapy (Louie 2005). This new variant results in a greater incidence in hospitalized patients (McDonald 2005), a greater need for urgent colectomy for toxic colitis and a mortality rate reported to be as high as 37% of incident cases (Pepin 2005). This variant, ribotype 027, has been reported in Quebec, the USA, and Europe (Louie 2005, Laurence 2006). The emergence of this highly virulent bacterium adds an urgency to the identification of effective therapy.
It is important to explain the terms used in conjunction with C. difficile infection, as the studies analyzed in this review involve various descriptions of C. difficile disease. CDAD occurs in a patient with diarrhea that has tested positive for C. difficile toxin and/or positive stool culture of C. difficile. C. difficile colitis involves a stool test positive for the organism and signs of mucosal inflammation seen on endoscopy. Pseudomembranous colitis refers to the actual presence of pseudomembranes seen on endoscopy. These terms are extensively overlapping, but not necessarily synonymous, as many patients with antibiotic‐associated diarrhea do not undergo the endoscopy and biopsy necessary for the diagnosis of colitis or the endoscopy and visualization of pseudomembranes. This systematic review will use the term CDAD for all forms of symptomatic C. difficile infection for its analysis.
Probiotics are live microorganisms or microbial mixtures administered to "improve the patient's microbial balance", a rather ill defined term applied particularly to the environment of the gastrointestinal tract and the vagina (Elmer 2001). They consist of non‐pathogenic yeast and bacteria such as Saccharomyces boulardii, Lactobacillus rhamnosus GG and Lactobacillus acidophilus and are found in cultured and fermented foods including yogurt, buttermilk, cheese and sauerkraut. The proposed mechanisms of action of probiotics include inhibition of pathogen adhesion, blocking production of microbial toxins, stimulation of the immune system and restoration of colonization resistance (which is the ability of normal microflora to prevent colonization by pathogenic organisms). None of these mechanisms has been established in efficacy studies, particularly in the case of CDAD. Although adverse effects from treatment with probiotics are rare, special consideration has been given to immunocompromised and severely debilitated patients as these high‐risk groups are often prone to opportunistic infections even with benign organisms (Elmer 2001).
Objectives
To assess the efficacy of probiotics for the treatment of Clostridium difficile colitis.
Methods
Criteria for considering studies for this review
Types of studies
Randomized, controlled trials using probiotics alone or in conjunction with conventional antibiotics for the treatment of documented C. difficile colitis.
Types of participants
Participants were patients with documented CDAD. This includes patients with symptomatic diarrhea, those with stool positive C. difficile cytotoxin or positive culture for C. difficile, those with current or recent prior exposure to antibiotics, and those with absence of other pathogens in stool. Patients under 18 years of age were excluded from this study.
Types of interventions
Studies comparing probiotics alone or in combination with traditional antibiotic therapy (metronidazole or vancomycin) for treatment of current or recurrent infection with C. difficile were included. Studies using probiotics for the prevention of C. difficile disease were excluded.
Types of outcome measures
The main outcome measures are resolution of diarrhea and negative stool C. difficile cytotoxin assay or culture. Secondary outcomes include recurrence of diarrhea, mortality, length of hospital stay and adverse events.
Search methods for identification of studies
MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and the Cochrane IBD/FBD Specialized Trials register were searched using the following terms: antibiotic‐associated diarrhea, C. difficile infection, probiotics, randomized trials. English language was not a restriction in the search. The online search was used to locate all published reports from 1966 to July 2007.
Data collection and analysis
Study selection Two authors examined all citations and abstracts derived from the electronic search strategy and independently selected trials to be included in the review. Full reports of potentially relevant trials were retrieved. Reviewers were not blind to the names of trials' authors, institutions or journals. Any disagreement about trial inclusion was resolved by discussion.
Data extraction A data extraction form was developed and used to extract and record information on the results of the included studies. Results were compared between reviewers and differences of opinion settled by discussion. Where data may have been collected but not reported, further information was sought from the trials' investigators.
Quality assessment The methodological quality of eligible trials was assessed independently by each author in terms of quality of random allocation concealment, number of withdrawals and dropouts, whether data were analyzed on an intention‐to‐treat basis, and whether the participants and the outcome assessors were blind to the treatment provided. Where the method of allocation concealment was not clearly reported, the trials' authors were contacted for clarification. Studies were excluded if they were not randomized or if they made comparisons other than those specified.
Data 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 for each study. When appropriate, the results of included studies were to be combined for each outcome. For dichotomous outcomes, a pooled RR and 95% CI were to be calculated using a fixed effects model.
Results
Description of studies
The initial search identified six studies which met the selection criteria. Two studies were subsequently excluded (Elmer 1999; Pochapin 2000). The Pochapin 2000 study was published as an abstract, and it did not contain experimental detail or a complete patient group. Attempts to reach the author to supply further information revealed that the study had been discontinued due to lack of efficacy. Elmer 1999 was excluded because the outcomes were not clinically relevant. The primary outcome was the concentration of S. boulardii in stool specimens. The study was subsequently published with complete outcome data (Surawicz 2000). The included studies (Surawicz 2000; Wullt 2003; Lawrence 2005) examined the use of probiotics used in conjunction with conventional antibiotics (vancomycin or metronidazole) for the treatment of an initial episode or recurrent C. difficile infection.
The McFarland 1994 study was conducted using a randomized, double‐blind, placebo‐controlled, parallel group design. One hundred and forty‐seven outpatients with active C. difficile diarrhea (CDD), some with primary disease and some with recurrent disease, were enrolled. Twenty‐three patients were excluded after entry because they were ineligible, leaving 124 patients in the study. Reasons for exclusion include negative C difficile assay (n = 10), failure to return enrollment forms (n = 6), receipt of exclusion drugs (n = 4), diagnosis of inflammatory bowel disease (n = 1), no current diarrhea (n = 1) and starting the study drug before the antibiotic (n = 1). All participants were treated with vancomycin or metronidazole. Dosages of antibiotics and duration of treatment were at the discretion of each patient's physician. Patients were randomized to Saccharomyces boulardii (1 g/day; 3 x 1010 colony forming units; n = 57) or identical placebo (n = 67) for 4 weeks. Diarrhea cessation was defined as a return to normal bowel frequency (< 3 loose or watery stools per day for at least 48 hours), negative C. difficile assay (culture or toxin) or endoscopic evidence of cure. This is the only study to report mortality. Five patients died during the study. One patient in the S. boulardii group died from pneumonia. Four placebo patients died due to Staphylococcus sepsis, respiratory arrest, cardiac arrest, and prostate cancer.
The Surawicz 2000 study was a randomized double‐blind placebo controlled trial of the treatment of adult patients with recurrent C. difficile associated disease. Recurrent C. difficile disease was defined as > 1 previous episodes diarrhea that was positive for C. difficile and that had initially responded to antibiotic treatment. Two hundred and nine outpatients were initially enrolled; 41 did not meet the definition of recurrent C difficile disease or failed to fulfill eligibility criteria leaving 168 patients in the study. Treatment options included a 10 day orally administered course of high dose vancomycin (2 g/day; n = 32), low dose vancomycin (500 mg/day; n = 85) or metronidazole (1 g/day; n = 53). Choice of antibiotic as well as dosages were left to the discretion of the primary care physician, although those patients with severe CDD were given the higher dose of vancomycin. The study report focuses on high dose vancomycin because the lower dose of vancomycin and metronidazole were found to be ineffective. Patients in the high dose vancomycin group were randomized to oral S. boulardii (1 g/day; n = 18) or placebo (n = 14) for 28 days beginning on day 7 of antibiotic treatment. Diarrhea cessation was defined as a return to normal bowel frequency (< 3 loose or watery stools per day for at least 48 hours). Patients were considered treatment failures if they developed a subsequent episode of C. difficile‐positive diarrhea after the antibiotics were discontinued and before the end of the 2 month follow‐up.
The Wullt 2003 study recruited 29 patients with recurrent C. difficile infection (both inpatients and outpatients), of whom 21 were analyzed. Participants were given oral metronidazole 400 mg three times daily for ten days in combination with either Lactobacillus plantarum 299v (5 x 1010 colony forming units per day; n = 12) or placebo (n = 9) once daily for 38 days. Clinical cure was defined as cessation of diarrhea within 5 to 10 days of initiation of treatment. Bacteriological cure was defined as a negative assay for C. difficile toxin on days 11 to 13.
In the Lawrence 2005 study 15 patients with recurrent CDAD were randomized to receive Lactobacillus rhamnosis GG (LGG) (2.8 x 1011 colony forming units; one capsule orally twice daily, n = 8) or placebo (n = 7) in conjunction with antibiotics as chosen by the primary clinician (metronidazole and/or vancomycin) for the duration of antibiotic therapy and for an additional 21 days. The primary outcome was recurrence of CDAD within 60 days of completing antibiotic therapy.
Length of hospital stay was not reported, and two of the studies may have included outpatients (McFarland 1994; Surawicz 2000).
Risk of bias in included studies
Problems with quality occur in each included study.
In the McFarland 1994 study allocation concealment was adequate, withdrawals and dropouts were adequately described, and the procedures for double blinding were well described and appropriate. Withdrawals and dropouts were treated as treatment failures and an intention to treat analysis was used. However, patients with both recurrent and primary CDAD are included in the study. Antibiotic therapy was not randomly applied. The duration and dosing of metronidazole or vancomycin was varied in an unspecified number of patients during therapy. The authors did not specify when randomization occurred.
Allocation concealment was adequate in the Surawicz 2000 study and the procedures used for double blinding were appropriate. Antibiotic therapy was not randomly applied. No rationale was provided for starting probiotic therapy on day 7 of antibiotic therapy.
In the Wullt 2003 study allocation concealment was adequate and withdrawals and dropouts were adequately described. The drop‐out rate was high (28%). An intention to treat analysis was not used. Wullt 2003 is the only study to use a standardized regimen for antibiotic therapy.
The details of the experimental protocol are not presented in detail in the Lawrence 2005 study. Procedures used for allocation concealment and blinding are unclear. The type of antibiotic and duration and dosing of antibiotic therapy are not adequately described. An intention to treat analysis was reported.
Effects of interventions
: Data were not pooled for analysis because of variations in recruitment criteria, the type of probiotic used, high drop out rates and variations in concommitant antibiotic therapy. Forest plots are grouped by probiotic type.
In the McFarland 1994 study patients who received S. boulardii and antibiotic were significantly more likely than the placebo group to respond to therapy. The patients in the active treatment group were significantly more likely than placebo patients to experience cessation of diarrhea (RR 1.33; 95% CI 1.02 to 1.74) and were significantly less likely to experience recurrence of diarrhea after cessation of antibiotic therapy (RR 0.59; 95% CI 0.35 to 0.98). Patients with recurrent C. difficile receiving S. boulardii were more likely than the placebo patients to respond to therapy. However, in those with initial episode of C. difficile, there were equal failure rates of treatment in both groups (McFarland 1994).
Only the group receiving S. boulardii and high dose vancomycin showed a decreased frequency of recurrent CDD in the Surawicz 2000 study (RR 0.33; 95% CI 0.10 to 1.06). There was no significant change in outcome with S. boulardii versus placebo in the low dose vancomycin or metronidazole groups.
Wullt 2003 performed the only study testing the benefit of L. plantarum. This study compared probiotic plus antibiotic to antibiotic alone. No statistically significant benefit was seen analyzing cure of initial disease (RR 0.93; 95% CI 0.73 to 1.19), recurrence (RR 0.55; 95% CI 0.22 to 1.35) or cure by stool assay (RR 0.75; 0.41 to 1.36). Lawrence 2005 found no significant benefit for therapy with LGG (RR 2.63; 95% CI 0.35 to 19.85).
Wullt 2003 reported no adverse events associated with L. plantarum treatment. The occurrence of adverse events was reported in the other three studies (Lawrence 2005; McFarland 1994; Surawicz 2000). Surawicz 2000 reported that there were no statistically significant differences in the number or type of adverse events in patients treated with S boulardii or placebo, and that no adverse events occurred during the four week follow‐up period. McFarland 1994 reported a statistically significant increase in thirst (P = 0.02) and constipation (P = 0.03) in patients receiving S boulardii compared to placebo. Lawrence 2005 reported mild gastrointestinal upset with bloating (25%) and flatulence (37.5%) in patients treated with LGG.
Discussion
McFarland 1994 provides weak support for the use of probiotics (S. boulardii) in combination with antibiotics for the treatment of C. difficile disease. The Surawicz 2000 study reported a positive benefit for S. boulardii used in conjunction with high dose vancomycin. However, with such a small sample size a definitive conclusion cannot be drawn from this study. No benefit was seen in the other studies. The included trials were small in size and probably would have lacked the power to detect a statistically significant difference between probiotic and placebo should such a difference exist. Furthermore, the considerable clinical heterogeneity related to antibiotic use and initial disease state cited above are such that no recommendation can be made concerning probiotic therapy for established CDAD. There has been growing interest in probiotic prophylaxis in patients receiving antibiotics (Hickson 2007). The efficacy of this intervention should be examined in a properly designed and adequately powered randomized controlled trial.
Authors' conclusions
Implications for practice.
There is insufficient evidence to recommend probiotic therapy as an adjunct to antibiotic therapy for CDAD. There is no evidence to support the use of probiotics alone in the treatment of CDAD.
Implications for research.
A systematic review of antibiotic therapy for CDAD questions the efficacy of any established antibiotic therapy for CDAD as the appropriate placebo controlled trials have not been conducted (Nelson 2007). The same is true for probiotics. Studies in which probiotic preparations are used without antibiotic therapy would be of interest, since concomitant antibiotic therapy may effect the bioavailability of probiotics. The quality issues outlined in this review should be addressed in any future randomized controlled trials.
What's new
| Date | Event | Description |
|---|---|---|
| 6 May 2008 | Amended | Converted to new review format. |
History
Protocol first published: Issue 1, 2004 Review first published: Issue 1, 2008
| Date | Event | Description |
|---|---|---|
| 25 October 2007 | New citation required and conclusions have changed | Substantive amendment |
Acknowledgements
Funding for the IBD/FBD Review Group (October 1, 2005 ‐ September 30, 2010) has been provided by the Canadian Institutes of Health Research (CIHR) Knowledge Translation Branch; the Canadian Agency for Drugs and Technologies in Health (CADTH); and the CIHR Institutes of Health Services and Policy Research; Musculoskeletal Health and Arthritis; Gender and Health; Human Development, Child and Youth Health; Nutrition, Metabolism and Diabetes; and Infection and Immunity.
Miss Ila Stewart has provided support for the IBD/FBD Review Group through the Olive Stewart Fund.
Data and analyses
Comparison 1. S.boulardii versus placebo.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Cessation of diarrhea | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 Patients with initial or recurrent disease | 1 | 124 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.33 [1.02, 1.74] |
| 1.2 Patients with recurrent disease | 1 | 32 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.67 [0.95, 2.93] |
| 2 Recurrence of diarrhea | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 Patients with initial or recurrent disease | 1 | 124 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.59 [0.35, 0.98] |
| 2.2 Patients with recurrent disease | 1 | 32 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.10, 1.06] |
1.1. Analysis.
Comparison 1 S.boulardii versus placebo, Outcome 1 Cessation of diarrhea.
1.2. Analysis.
Comparison 1 S.boulardii versus placebo, Outcome 2 Recurrence of diarrhea.
Comparison 2. L. plantarum versus placebo.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Cessation of diarrhea | 1 | 21 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.73, 1.19] |
| 2 Recurrence of diarrhea | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.55 [0.22, 1.35] |
| 3 Bacteriological cure | 1 | 21 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.41, 1.36] |
2.1. Analysis.
Comparison 2 L. plantarum versus placebo, Outcome 1 Cessation of diarrhea.
2.2. Analysis.
Comparison 2 L. plantarum versus placebo, Outcome 2 Recurrence of diarrhea.
2.3. Analysis.
Comparison 2 L. plantarum versus placebo, Outcome 3 Bacteriological cure.
Comparison 3. Lactobacillus rhamnosus GG versus placebo.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Recurrent CDAD | 1 | 15 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.63 [0.35, 19.85] |
3.1. Analysis.
Comparison 3 Lactobacillus rhamnosus GG versus placebo, Outcome 1 Recurrent CDAD.
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Lawrence 2005.
| Methods | Randomized , double‐blind, placebo controlled trial | |
| Participants | Adult patients with recurrent CDAD (n = 15) | |
| Interventions | Patients received metronidazole or vancomycin or both and were randomized to LGG (one capsule bid; n = 8) or placebo (n = 7) for 28 days | |
| Outcomes | Recurrent CDAD within 60 days of completing antibiotics | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Unclear risk | B ‐ Unclear |
McFarland 1994.
| Methods | Randomized , double‐blind, placebo controlled trial | |
| Participants | Adult patients with recurrent or initial episode of C. difficile associated disease. 147 patients were enrolled, 124 patients were eligible | |
| Interventions | Patients received vancomycin or metronidazole and were randomized to S. boulardii (1 g/day) or placebo for 4 weeks | |
| Outcomes | Recurrence of active C. difficile associated disease | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Low risk | A ‐ Adequate |
Surawicz 2000.
| Methods | Randomized , double‐blind, placebo controlled trial | |
| Participants | Adult patients with recurrent C. difficile disease. 209 patients were enrolled, 168 patients were eligible | |
| Interventions | Patients received high dose vancomycin (2g/day), low dose vancomycin (500 mg/day) or metronidazole (1g/day) and were randomized to S. boulardii (1 g/day ; n = 57) or identical placebo (n = 67) for 28 days beginning on day 7of antibiotic therapy | |
| Outcomes | Recurrence of C. difficile disease | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Low risk | A ‐ Adequate |
Wullt 2003.
| Methods | Randomized , double‐blind, placebo controlled trial | |
| Participants | Adult patients with recurrent C. difficile associated diarrhea. 29 patients were enrolled | |
| Interventions | Patients received metronidazole (400 mg tid) for 10 days and were randomized to L. plantarum (n = 12) or placebo (n = 9) once per day for 38 days | |
| Outcomes | Clinical recurrence until day 70 | |
| Notes | 8 drop outs in study | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Low risk | A ‐ Adequate |
CDAD = Clostridium difficile associated disease LGG = Lactobacillus rhamnosus GG C. difficile = Clostridium difficile S. boulardii = Saccharomyces boulardii L. plantarum = Lactobacillus plantarum 299v
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Elmer 1999 | Outcome of study did not mention number of successfully treated C. difficile cases, but rather focused on the concentration of S. boulardii in stool specimens |
| Pochapin 2000 | Trial discontinued due to lack of efficacy. Author not available for contact. |
Declarations of interest
None known.
Edited (no change to conclusions)
References
References to studies included in this review
Lawrence 2005 {published data only}
- Lawrence SJ, Korzenik JR, Mundy LM. Probiotics for recurrent Clostridium difficile disease. J Med Microb. 2005;54(Pt 9):905‐6. [DOI] [PubMed] [Google Scholar]
McFarland 1994 {published data only}
- McFarland LV, Surawicz CM, Greenberg RN, Fekety R, Elmer GW, Moyer KA, et al. A randomized placebo‐controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA 1994;271(24):1913‐8. [PubMed] [Google Scholar]
Surawicz 2000 {published data only}
- Surawicz CM, McFarland LV, Greenberg RN, Rubin M, Fekety R, Mulligan ME, et al. The search for a better treatment for recurrent Clostridium difficile disease: use of high‐dose vancomycin combine with Saccharomyces boulardii. Clin Infect Dis 2000;31(4):1012‐7. [DOI] [PubMed] [Google Scholar]
Wullt 2003 {published data only}
- Wullt M, Hagslatt ML, Odenholt I. Lactobacillus plantarum 299v for the treatment of recurrent Clostridium difficile‐associated diarrhoea: a double‐blind, placebo‐controlled trial. Scand J Infect Dis 2003;35(6‐7):365‐7. [DOI] [PubMed] [Google Scholar]
References to studies excluded from this review
Elmer 1999 {published data only}
- Elmer GW, McFarland LV, Surawicz CM, Danko L, Greenberg RN. Behaviour of Saccharomyces boulardii in recurrent Clostridium difficile disease patients. Aliment Pharmacol Ther 1999;13(12):1663‐8. [DOI] [PubMed] [Google Scholar]
Pochapin 2000 {published data only}
- Pochapin M. The effect of probiotics on Clostridium difficile diarrhea. Am J Gastroenterol 2000;95(1 Suppl):S11‐3. [DOI] [PubMed] [Google Scholar]
Additional references
Bartlett 1980
- Bartlett JG, Taylor NS, Chang T, Dzink J. Clinical and laboratory observations in Clostridium difficile colitis. Am J Clin Nutr 1980;33(11 Suppl):2521‐6. [DOI] [PubMed] [Google Scholar]
Bartlett 1990
- Bartlett JG. Clostridium difficile: clinical considerations. Rev Infect Dis 1990;12(Suppl 2):S243‐51. [DOI] [PubMed] [Google Scholar]
Bartlett 2002
- Bartlett JG. Clinical practice. Antibiotic‐associated diarrhea. N Engl J Med 2002;346(5):334‐9. [DOI] [PubMed] [Google Scholar]
Bricker 2005
- Bricker E, Garg R, Nelson R, Loza A, Novak T, Hansen J. Antibiotic treatment for Clostridium difficile‐associated diarreha in adults. Cochrane Database of Systematic Reviews 2005, Issue 1. [DOI] [PubMed] [Google Scholar]
Elmer 2001
- Elmer GW. Probiotics: "living drugs". Am J Health Syst Pharm 2001;58(12):1101‐9. [DOI] [PubMed] [Google Scholar]
Fekety 1993
- Fekety R, Shah AB. Diagnosis and treatment of Clostridium difficile colitis. JAMA 1993;269(1):71‐5. [MEDLINE: ] [PubMed] [Google Scholar]
George 1982
- George WL, Rolfe RD, Finegold SM. Clostridium difficile and its cytotoxin in feces of patients with antimicrobial agent‐associated diarrhea and miscellaneous conditions. J Clin Microbiol 1982;15(6):1049‐53. [DOI] [PMC free article] [PubMed] [Google Scholar]
Hickson 2007
- Hickson M, D'Souza AL, Muthu N, Rogers TR, Want S, Rajkumar C, et al. Use of probiotic Lactobacillus preparation to prevent dairrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ 2007;335(7610):80. [DOI] [PMC free article] [PubMed] [Google Scholar]
Ho 1996
- Ho M, Yang D, Wyle FA, Mulligan ME. Increased incidence of Clostridium difficile‐associated diarrhea following decreased restriction of antibiotic use. Clin Infect Dis 1996;23(Suppl 1):S102‐6. [DOI] [PubMed] [Google Scholar]
Kelly 1994
- Kelly CP, Pothoulakis C, LaMont JT. Clostridium difficile colitis. N Engl J Med 1994;330(4):257‐62. [DOI] [PubMed] [Google Scholar]
Lai 1997
- Lai KK, Melvin ZS, Menard MJ, Kotilainen HR, Baker S. Clostridium difficile‐associated diarrhea: epidemiology, risk factors, and infection control. Infect Control Hosp Epidemiol 1997;18(9):628‐32. [DOI] [PubMed] [Google Scholar]
Laurence 2006
- Laurence J. Deaths from "dirty hospital bug" double in five years. The Independant 26 May, 2006:11.
Louie 2005
- Louie TJ. How should we respond to the highly toxogenic NAP1/ribotype 027 strain of Clostridium difficile?. Can Med Assoc J 2005;173(9):1049‐50. [DOI] [PMC free article] [PubMed] [Google Scholar]
Manian 1995
- Manian FA, Meyer L. CDAD rates. Infect Control Hosp Epidemiol 1995;16(2):63‐5. [DOI] [PubMed] [Google Scholar]
McDonald 2005
- McDonald LC, Killgore GE, Thompson A, Owens RC Jr, Kazakova SV, Sambol SP, et al. An epidemic, toxin gene‐variant strain of Clostridium difficile. N Engl J Med 2005;353(23):2433‐41. [DOI] [PubMed] [Google Scholar]
McFarland 1995
- McFarland LV, Surawicz CM, Greenberg RN, Elmer GW, Moyer KA, Melcher SA, et al. Prevention of beta‐lactam‐associated diarrhea by Saccharomyces boulardii compared with placebo. Am J Gastroenterol 1995;90(3):439‐48. [PubMed] [Google Scholar]
McFarland 1999
- McFarland LV, Surawicz CM, Rubin M, Fekety R, Elmer GW, Greenberg RN. Recurrent Clostridium difficile disease: epidemiology and clinical characteristics. Infect Control Hosp Epidemiol 1999;20(1):43‐50. [DOI] [PubMed] [Google Scholar]
Morris 2002
- Morris AM, Jobe BA, Stoney M, Sheppard BC, Deveney CW, Deveney KE. Clostridium difficile colitis: an increasingly aggressive iatrogenic disease?. Arch Surg 2002;137(10):1096‐100. [DOI] [PubMed] [Google Scholar]
Moyenuddin 2002
- Moyenuddin M, Williamson JC, Ohl CA. Clostridium difficile‐associated diarrhea: current strategies for diagnosis and therapy. Curr Gastroenterol Rep 2002;4(4):279‐86. [DOI] [PubMed] [Google Scholar]
Nelson 2007
- Nelson R. Antibiotic treatment for Clostridium difficile‐associated diarrhea in adults. Cochrane Database of Systematic Reviews 2007, Issue 3. [DOI] [PubMed] [Google Scholar]
Olson 1994
- Olson MM, Shanholtzer CJ, Lee JT Jr, Gerding DN. Ten years of prospective Clostridium difficile‐associated disease surveillance and treatment at the Minneapolis VA Medical Center, 1982‐1991. Infect Control Hosp Epidemiol 1994;15(6):371‐81. [DOI] [PubMed] [Google Scholar]
Pepin 2005
- Pepin J, Valiquette L, Cossette B. Mortality attributable to nosocomial Clostridium difficile‐associated disease during an epidemic caused by a hypervirulent strain in Quebec. CMAJ 2005;173(9):1037‐42. [DOI] [PMC free article] [PubMed] [Google Scholar]
Pindera 2004
- Pindera L. Quebec to report on Clostridium difficile in 2005. Can Med Assoc. J. 2004;171(7):715. [DOI] [PMC free article] [PubMed] [Google Scholar]
Rubin 1995
- Rubin MS, Bodenstein LE, Kent KC. Severe Clostridium difficile colitis. Dis Colon Rectum 1995;38(4):350‐4. [DOI] [PubMed] [Google Scholar]
Thomas 2003
- Thomas C, Stevenson M, Riley TV. Antibiotics and hospital‐acquired Clostridium difficile associated diarrhoea: a systematic review. J Antimicrob Chemother 2003;51(6):1339‐50. [DOI] [PubMed] [Google Scholar]