Title of critically appraised topic: Is probiotic use an effective adjuvant therapy to antibiotics in

Transcription

1 Title of critically appraised topic: Is probiotic use an effective adjuvant therapy to antibiotics in treatment of Clostridium difficile-associated diarrhea? Author: (This copy has been stripped of identifiers) PA program: Matriculation: Expected graduation: Mailing address: Daytime phone: 1

2 Abstract: Objective: The clinical question for this critically appraised topic (CAT) is, For adults treated with antibiotics for Clostridium difficile-associated diarrhea, do probiotic supplements increase successful treatment of the disease, with treatment defined as resolution of diarrhea and a negative C. difficile cytotoxin assay or negative stool culture? A review of the most current evidence was performed to answer this clinical question. Methods: MEDLINE and the Cochrane Database of Systematic Reviews were searched using the key words Clostridium difficile, probiotic*, and diarrhea. Relevant clinical trials, meta-analyses and systematic reviews were assessed, and one Cochrane systematic review was identified as the best available evidence to answer the question. Results: Of the four randomized, double-blinded, placebo-controlled trials reviewed in the Cochrane systematic review, one (n=124) found probiotic supplementation of antibiotic treatment for CDAD with Saccharomyces boulardii to increase the likelihood of cessation of CDAD compared to placebo (RR=1.33; 95% CI ). A second trial (n=168) found no difference in resolution of CDAD between probiotics (S. boulardii) and placebo for treatment of CDAD when paired with three different antibiotic regimens (RR=1.67; 95% CI ). A third trial (n=29) with a standardized regimen of antibiotic treatment found no difference between supplementation with Lactobacillus plantarum and placebo for resolution of CDAD (RR= % CI ). One final study (n=15) examined Lactobacillus rhamnosus GG versus placebo in preventing recurrence of CDAD and found no difference (RR= % CI ). Conclusions: Ultimately, there is not enough evidence to suggest that probiotic supplements as an adjuvant therapy to antibiotic treatment for CDAD are beneficial. There are few quality, randomized, double-blinded, placebo-controlled studies available, and those that are have few patients with no standardized probiotic treament or organism between them. More evidence must be sought before a practice recommendation can be made. 2

3 Clinical Scenario Your 65-year-old male patient is being treated empirically with ceftriaxone and clarithromycin for pneumonia. On day six of treatment, he has a sudden onset of frequent, loose stools, and you confirm through a cytotoxin assay and culture of his stool that he is infected with Clostridium difficile, an enteric pathogen. Clostridium difficile-associated diarrhea (CDAD) requires additional antibiotics, which may place this patient at risk of infection by antibiotic-resistant bacterial strains. Furthermore, CDAD poses an 1% to 2.5% mortality risk. 1 Some of your colleagues have told to you about the benefits of supplementing antibiotic therapy with probiotics to treat CDAD, and you are curious if there is evidence to support this practice. Clinical Question For adults treated with antibiotics for Clostridium difficile-associated diarrhea, do probiotic supplements increase successful treatment of the disease, with treatment defined as resolution of diarrhea and a negative C. difficile cytotoxin assay or negative stool culture? Background Probiotics are live non-pathogenic yeast or bacteria, or mixtures of such, which occur naturally in the human gastrointestinal tract. Probiotic supplements have many proposed mechanisms of action in the gastrointestinal tract, including 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). 2 3

4 Search Criteria and Results MEDLINE and the Cochrane Database of Systematic Reviews were searched using the key words Clostridium difficile, probiotic*, and diarrhea. Results were limited to reviews, metaanalyses, and randomized controlled trials published in English in the last five years. 58 studies were identified. Of these results, 48 studies did not address the clinical question for various reasons: they concerned the pediatric patient population; they addressed other causes of diarrhea; they investigated prebiotics; they provided overviews of treatment for intestinal disorders; or they investigated prevention of CDAD rather than treatment. Of the remaining results, many studies were underpowered due to small patient samples. They also varied greatly by probiotic organisms and treatment regimens for both probiotics and antibiotics. Since meta-analyses and systematic reviews are at the highest level of evidence, these were considered more strongly in evaluation of the evidence. A Cochrane systematic review from 2008 investigated the effectiveness of probiotics as an adjuvant therapy to antibiotics in treating adults with CDAD. 2 This represents the best available evidence to answer the clinical question. One meta-analysis identified six randomized controlled trials through 2006 regarding the treatment of CDAD with probiotics. 3 While it is the largest such meta-analysis to date, the author s interpretations and conclusions are questionable. The author found all six studies to be homogenous enough to combine their data, yet they vary widely by probiotic used, probiotic dosages, antibiotic dosages, and treatment duration. Studies regarding prevention of CDAD were also included in the meta-analysis. Furthermore, the author s analysis of the data does not 4

5 account for the fact that five of the six studies relative risk values have confidence intervals that cross 1. For these reasons, this meta-analysis was excluded from this topic appraisal. Evaluating the Evidence Assessment of the effectiveness of probiotics in treatment of CDAD is challenging. Probiotic products are not FDA-approved medications and may be comprised of various yeast or bacterial organisms in varying doses. Such organisms include species of Lactobacillus bacteria or Saccharomyces yeast. Sources of probiotics include fermented milk, yogurt, or capsular supplements, and no dosage has been determined as a standard for treatment. Furthermore, the definition of CDAD can vary study-to-study, as can the method of detecting C. difficile infection in patients. The 2008 Cochrane systematic review identified four randomized, double-blinded, placebocontrolled trials which investigate the effectiveness of probiotics as an adjuvant therapy to antibiotics in treating adults with CDAD. 2 Studies examined adults with symptomatic diarrhea, a history of current or recent antibiotic use, stool positive for C. difficile cytotoxin or C. difficile culture, and an absence of other pathogenic bacteria in the stool. Interventions of included studies were treatment of either primary or recurrent C. difficile infection with traditional antibiotic therapy (metronidazole or vancomycin) plus either a probiotic therapy or placebo. The criterion for primary outcome was resolution of diarrhea followed by a C. difficile-negative stool culture or stool cytotoxin assay. Studies investigating prevention of CDAD with probiotics were excluded. 5

6 Data from the studies were not pooled because of significant heterogeneity between studies. The antibiotic treatment used in each study was not consistent between studies, nor were the probiotic organisms or doses of colony-forming units used. Time frames for treatment and determination of cure were not set either. Because of these differences, the reviewers chose to evaluate each study independently. One study included in the review investigated 124 patients and found the treatment group (using Saccharomyces boulardii) to be more likely than the placebo group to have resolution of their diarrhea (RR=1.33; 95% CI ). This effect was especially noted in the subgroup of patients with their first C. difficile infection, while no difference was noted between the treatment and placebo groups of those with recurrent infection. The authors adequately described their procedures and used an intention-to-treat analysis, but they failed to randomly allocate or standardize doses for antibiotic treatments and did not describe when and how randomization for probiotic treatment occurred. These variations in treatment may have improperly biased the data. Because of this potential bias, this study does not factor strongly into a clinical decision to use probiotics with antibiotics to treat CDAD. In the largest study of the review (n=168), investigators found no significant decrease in recurrence of CDAD when probiotic treatment (S. boulardii) was paired with high dose vancomycin, low dose vancomycin or metronidazole treatments. Overall, treatment was not significantly different from placebo in resolution of CDAD (RR=1.67; 95% CI ). This study also did not randomly apply antibiotic treatment and opted to begin probiotic treatment one week after antibiotic therapy without justification for this approach. The reviewers incorrectly 6

7 report a significant success of probiotic treatment with high dose vancomycin, even though it is not statistically significant. Regardless, any potential effect may have been due to the potency of the antibiotic rather than a real effect of the probiotic treatment. A third study found no significant difference between treatment (Lactobacillus plantarum) and placebo for cure of CDAD (RR= % CI ). This study standardized its antibiotic regimen, but it failed to use an intention-to-treat analysis despite a high patient drop-out rate. The study only investigated 29 patients, so it may have been underpowered. Thus a type II error may have occurred: the authors may have failed to find a difference between treatment and placebo when one really exists. A fourth trial (n=15) found no significant difference between treatment (L. rhamnosus GG) and placebo for recurrence of CDAD (RR= % CI ). Though this study used an intention-to-treat analysis, the authors failed to adequately explain their experiment, allocation, and blinding procedures. The antibiotics were selected based upon clinician judgment, and their selection methods and dosages were not described. Finally, the outcome investigated was recurrence of CDAD and not resolution of the initial CDAD. This study s evidence is weak for these reasons and its low patient sample size puts it at risk of type II error. Probiotics are not without a risk of adverse effects. One trial in the Cochrane review reported statistically significant increases in thirst and constipation with probiotic use. Another found that 25% of patients treated with probiotics experienced bloating and 37.5% experienced flatulence. 2 7

8 There is a significant scarcity of valid research on the use of probiotics with antibiotics to treat CDAD. Of the randomized, double-blinded, placebo-controlled trials that have been performed, outcomes are inconsistent; and to date, there has been no consensus on use of probiotic organisms, dosages or indications for treatment with probiotics. Ideally, a desirable future study would be a randomized, double-blinded, placebo-controlled study with a large patient sample. The authors would detail their procedures, use proper statistical analyses and standardize the doses and durations of both probiotic and antibiotic therapy. Many obstacles exist in such an endeavor, including variation in acceptable antibiotic therapy and differences in the severity of patients illnesses. Also, ethical standards may dictate that a provider use clinical judgment over trial protocol in the instance of life-threatening cases of CDAD. Clinical Bottom Line At this time, there is not sufficient evidence to suggest the use of probiotic supplements as an adjuvant therapy to traditional antibiotic treatment for Clostridium difficile-associated diarrhea. The standard of care for the patient in this scenario is discontinuation of the antibiotics used to treat the pneumonia, if possible, and initiation of oral metronidazole. For those who have treatment failure or contraindications to metronidazole, oral vancomycin can be used. 1 8

9 References 1. Schroeder MS. Clostridium difficile-associated diarrhea. Am Fam Physician. 2005;71(5): Pillai A, Nelson RL. Probiotics for treatment of Clostridium difficile-associated colitis in adults. Cochrane Database Of Systematic Reviews (Online) [serial online]. 2008;(1):CD Available from: MEDLINE with Full Text, Ipswich, MA. Accessed April 19, McFarland LV. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am J Gastroenterol. 2006;101: