Clostridium difficile, a spore forming

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1 Infectious Diseases Probiotics for Clostridium difficile Associated Diarrhea: Focus on Lactobacillus rhamnosus GG and Saccharomyces boulardii Marisel Segarra-Newnham Author information provided at the end of the text. OBJECTIVE: To review the literature on the use of probiotics to treat or prevent recurrences of Clostridium difficile associated diarrhea (CDAD) by replacing normal gastric flora. DATA SOURCES: PubMed (1970 March 2007) was searched using the terms probiotics, Clostridium difficile, colitis, diarrhea, prevention, and treatment. STUDY SELECTION AND DATA EXTRACTION: Case reports, case series, and clinical trials describing the use of probiotics in the treatment or prevention of recurrences of CDAD as primary outcome were included. DATA SYNTHESIS: A variety of controlled trials, case series, and case reports have evaluated probiotics to treat first or recurrent episodes of CDAD. In addition, a meta-analysis has been conducted to try to determine the role of probiotics in CDAD. In general, most case series and case reports have shown favorable results with Lactobacillus rhamnosus GG or Saccharomyces boulardii. However, other reports have shown lack of benefit. The meta-analysis showed that these probiotics may be useful in treating or preventing recurrences of CDAD. Nonetheless, the heterogeneity of the studies makes definite conclusions difficult. In addition, several cases of bacteremia or fungemia associated with probiotic use have been reported, particularly in the last decade. Patients most commonly affected by these complications are immunosuppressed. Unfortunately, these are also the patients more likely to have severe CDAD or are at risk for recurrences. CONCLUSIONS: Additional experience with and study of probiotics are warranted due to numerous unanswered questions. Given the potential for complications in debilitated and immunosuppressed patients, the risks may outweigh benefits, and rational antibiotic use may be a better option to prevent a first episode or recurrence of CDAD. KEY WORDS: Clostridium difficile diarrhea, Lactobacillus, probiotics, Saccharomyces. Ann Pharmacother 2007;41: Published Online, 26 Jun 2007, DOI /aph.1K110 THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREDIT ACPE UNIVERSAL PROGRAM NUMBER: H01 A For Our Patients summary of this article is available at See also page Clostridium difficile, a spore forming gram-positive anaerobe, can cause disease with severity ranging from mild diarrhea to life-threatening pseudomembranous colitis and toxic megacolon. 1 It is the leading identified cause of nosocomial diarrhea. 1,2 The organism produces 2 toxins: enterotoxin A and cytotoxin B. 3 Patients with C. difficile associated diarrhea (CDAD) are usually older, with multiple comorbidities and a history of hospitalizations and antibiotic exposure. 2,4-7 The incidence of antibiotic-associated diarrhea (AAD) is estimated at 5 40% depending on the population and antibiotic studied. 3,8,9 ADD is the result of disruption of normal fecal flora; it usually occurs during antibiotic therapy, but may occur up to 6 weeks after therapy is completed. 3,8 About 20 50% of AAD cases are due to C. difficile. 1,3,8-11 CDAD can result in increased morbidity, costs, and hospital stay. 3,8 Duration of antibiotic exposure is a risk factor for both AAD and CDAD. 8 An estimated 20% of patients have recurrent CDAD (RCDAD), usually within the first 2 months of the initial episode. 3,5,12 Patients who have had more than 2 episodes of CDAD have a 50 65% chance of having additional episodes. 13 Fortunately, patients have not shown progressively worsening episodes. Nonetheless, up to 60% of cases have reinfection with a different C. difficile strain instead of relapse; therefore, reexposure to antibiotics should be minimized. 2,5 Treatment of minor infections, particularly in the first 2 months after the initial CDAD episode, should be avoided. 14 Over 90% of patients with the first RCDAD episode respond to a second 2 week course of the same an The Annals of Pharmacotherapy 2007 July/August, Volume 41

2 tibiotic they previously responded to, typically metronidazole. 15,16 Subsequent relapses are treated with oral vancomycin. 5 A recent review covers the current and future treatments for CDAD in detail. 16 Among the agents that have been studied for CDAD are probiotics. A probiotic is defined by the World Health Organization as a live microorganism which when administered in adequate doses confers a benefit on the host. 17 These organisms compete for nutrients, stimulate the immune system, inhibit mucosal adherence, may produce antimicrobial substances, and provide colonization resistance to C. difficile. 10,18,19 Colonization resistance is defined as the ability to inhibit colonization and subsequent infection by opportunistic pathogens such as C. difficile. 13 Sales in the US of probiotics for a variety of indications are in the billions of dollars per year. 20 Data Source A literature search was completed using PubMed (1970 March 2007) for case reports, case series, or clinical studies of probiotics used as treatment of CDAD. References from relevant articles were reviewed for possible inclusion. Search terms were Clostridium difficile, antibiotic associated colitis, probiotics, Lactobacillus, Saccharomyces, diarrhea, prevention, and treatment. Only reports or studies that evaluated CDAD as primary outcome are included. While some studies have evaluated the role of probiotics in preventing AAD, no study has evaluated their role in preventing the first episode of CDAD; therefore, this indication was not specifically reviewed. The main probiotics reported in the literature are Lactobacillus rhamnosus GG and Saccharomyces boulardii. Other agents, such as a mixture of probiotics (Lactobacillus acidophilus and Bifidobacterium bifidum) 21 or Lactobacillus plantarum 299v 22 have been studied; however, the data are very limited and these agents are not included in this review. LACTOBACILLUS Lactobacillus organisms are part of the normal flora in the gastrointestinal and female genital tracts. 23 Most commonly used as a probiotic is Lactobacillus rhamnosus GG (LGG), which is an L. casei species variant. 24,25 LGG is commercially available as a dietary supplement (Culturelle) from ConAgra Functional Foods. 26 LGG can colonize the GI tract and resists gastric acid. 27 LGG has shown positive results for RCDAD in case series with adults and children. 27,28 However, only one randomized pilot study has been conducted. 29 These reports are summarized in Table 1. CASE SERIES In the first literature report on LGG, Gorbach et al. 28 reviewed 5 cases of patients with RCDAD. Patients had up to 5 relapses over 2 10 months and reported no recurrences 4 months to 4 years after treatment with LGG. Four patients responded (defined as termination of diarrhea and no further relapses) to an initial course of LGG, and the fifth responded after a second course of LGG. LGG has also been used in pediatric patients with RC- DAD. A report of 4 children (mean age 34 mo) with 3 5 episodes of CDAD each, followed for a median of 9.5 months, showed all patients responding clinically to a 2 week course. 27 PILOT STUDY In a pilot study, patients (average age 78 y; median of 1 previous CDAD episode) were treated with LGG or placebo and were followed for 39 days after treatment was completed. 29 The recurrence rate was not significantly different between the groups (8 pts. [37.5%] with LGG vs 6 pts. [14.3%] with placebo). However, 67% of patients received additional antibiotics unrelated to CDAD treatment for unknown indications. Statistical significance was probably difficult to reach given the small sample size and the confounding variable of additional antibiotics. Based on this limited information, LGG should be studied further before recommendations for use can be provided. Although LGG appears to be safe, there have been reports of bacteremia complicating probiotic use. Table 1. Summary of Reports and Study of LGG Pts. Reference Dosing Regimen (N) Population Results Case reports Gorbach (1987) organisms daily for 7 10 days 5 RCDAD 4 pts. responded to 1st course; 1 pt. responded to 2nd course Biller (1995) mg bid for 2 wk 4 RCDAD, pediatrics all responded within 5 7 days Pilot study, randomized and blinded Lawrence (2005) mg or placebo bid for duration 15 RCDAD 3/8 pts. in LGG group vs of antibiotics for C. difficile plus 21 days after 1/7 pts. in placebo group responded LGG = Lactobacillus rhamnosus GG; RCDAD = recurrent Clostridium difficile associated diarrhea. The Annals of Pharmacotherapy 2007 July/August, Volume

3 M Segarra-Newnham COMPLICATIONS LGG bacteremia is uncommon but there have been reports of its occurrence in premature babies and immunosuppressed patients Some clinicians believe that LGG could be classified as an opportunistic organism and that increased isolation recently may be due to increased awareness of infection potential. 33 A review of 45 bacteremia cases over a 15 year period ending in 1994 showed that most cases were nosocomial. 32 There was no indication whether any patient received LGG as a probiotic. Sixty percent of patients had polymicrobial bacteremia. L. casei was identified in 10 of 12 (83%) cases that were identified to the species level. Forty-eight percent of the bacteremia episodes occurred in the intensive care unit setting, 40% of the patients had underlying malignancy, and 24% had received hyperalimentation. Three patients were post solidorgan transplant; 2 patients had endocarditis. Microbiologic cure was 98% (42/45); follow-up cultures were not performed in 3 patients. Twenty-two patients (49%) died during hospitalization, but only 1 death was directly attributable to bacteremia. However, at 1 year, only 31% of patients were still alive, highlighting the severity of their illness. In the authors opinions, when Lactobacillus bacteremia occurs, it is a marker of serious illness and poor long-term prognosis. 32 This finding appears to have been confirmed in a recent large review of Lactobacillus infections. 23 Several cases of bacteremia and other infections have been reported in patients treated with the probiotic LGG (Table 2) A liver abscess, caused by L. rhamnosus and unable to be distinguished from LGG, was reported in a woman taking 500 ml of LGG daily. 34 The patient recovered with surgical drainage and treatment with ciprofloxacin and clindamycin. Additional bacteremia cases have been reported in children, where contamination of a central venous catheter (CVC) was believed to be the possible mode of transmission. 35 A man with mitral valve prolapse developed LGG mitral valve endocarditis after chewing the contents of LGG capsules because he found them too large to swallow. 36 A blood isolate similar to the isolate in the capsules was confirmed by spectrometry and sensitivities. Additional bacteremia cases have been reported in premature babies with short-gut syndrome who were receiving LGG. 37,38 A review of 25 LGG bacteremia cases at a hospital in Finland reported 11 (44%) cases possibly related to probiotic use. 39 The risk factors for bacteremia were immunosuppression, prolonged hospitalization, and prior surgery. The first 2 risk factors are also seen in patients with RCDAD. 4-7 Average age of the patients was 61 years, and 2 patients had polymicrobial infections. No further information regarding specific cases, such as duration of or indication for probiotic use, was provided. Two additional reports have been published from Finland, where a large increase in the use of probiotics was seen in the mid-1990s through the 2000s. LGG has been added to dairy products in Finland routinely since The initial review, from 1989 to 1992, reported on 8 Lactobacillus isolates. Five of these patients were post organ transplant or had metastatic cancer. None of the cases appeared to have been related directly to the use of probiotics; however, patient-specific information was not available. The authors concluded that reports of bacteremia have not increased although consumption of probiotics had increased dramatically. 41 A follow-up report from 1995 to 2000 also found no change in the rate of 0.3 bacteremia cases per inhabitants. 40 Ninety cases were reported during the study period, with 37 isolates identified as LGG; however, there was no information provided on patients use of probiotics or dairy product consumption. SACCHAROMYCES BOULARDII S. boulardii has been studied in 2 controlled trials for RCDAD. 12,42 This probiotic is commercially available as Table 2. Case Reports of Complications from LGG Probiotic Use Reference Age/Sex Risk Factors Infection Comments/Outcome Rautio (1999) y/f took LGG for 4 mo for abdominal discomfort liver abscess responsed after 6 wk hospitalization Mackay (1999) y/m chewed LGG capsules for a healthy gut endocarditis responded to 6 wk of treatment Land (2004) mo/m CVC, given LGG for diarrhea via feeding tube bacteremia responded to 6 wk of treatment 6 y/f CVC, given LGG for diarrhea via feeding tube bacteremia responded to 10 days of treatment Kunz (2004) 37 3 mo/m premature, short-gut syndrome, intestinal atresia, bacteremia responded to 10 days of treatment and given probiotic via gastrostomy tube, CVC discontinuation of probiotic 1 mo/m premature, short-gut syndrome, given probiotic via bacteremia responded to 10 days of treatment and gastrostomy tube to prevent bacterial overgrowth, discontinuation of probiotic CVC DeGroote (2005) mo/m premature, CVC, given LGG for rotavirus diarrhea bacteremia responded to CVC removal and 7 days via gastrostomy tube, short-gut syndrome of treatment CVC = central venous catheter; LGG = Lactobacillus rhamnosus GG The Annals of Pharmacotherapy 2007 July/August, Volume 41

4 Probiotics for C. difficile Associated Diarrhea Florastor (Biocodex, Inc., Creswell, OR) 26 Although there has been controversy surrounding species differentiation between S. boulardii and S. cerevisiae (Brewer s yeast), most authors believe that this is no longer an issue and that these species are the same In Europe, both preparations are registered under the name S. cerevisiae, although there are 2 different control strains available. 43,44,46 S. boulardii has been used in Europe for decades to treat diarrhea. 48 All case reports involving S. boulardii have described patients with RCDAD as discussed below. 49,50 The reports and trials are presented in Table 3. RCDAD REPORTS Kimmey et al. 49 published a case report of a 67-year-old woman using S. boulardii to prevent RCDAD. The patient experienced 8 documented CDAD recurrences over 8 months. The patient was given S. boulardii after failing a 4 week vancomycin tapering regimen. She received another vancomycin taper plus the probiotic until semiformed stools developed. She took the probiotic for 2 additional months, followed by a 10 day tapering regimen. The total probiotic treatment period was about 90 days. An open trial evaluated 13 patients with an average of 3.6 recurrences. 50 Patients received vancomycin 250 mg 4 times daily for 10 days and S. boulardii for 30 days. The treatment duration was based on physician preference: 11 patients received days of treatment, 1 patient received 74 days, and another received 98 days of treatment, resulting in an average duration of 40 days. Success was defined as no diarrhea while taking the probiotic S. boulardii. Patients reported that the average number of bowel movements decreased from 4.5 to 2.4 (p = 0.03) with S. boulardii. Seven patients were contacted a median of 6 days after completing the probiotic, and none reported diarrhea. Nonetheless, there was no indication of previous time frame of episodes, and follow up in a small subsample of patients may be considered too short to determine the significance of the finding. STUDIES In a double-blind controlled study, patients with active CDAD were randomized to receive S. boulardii or placebo. Patients with AIDS or those receiving cancer chemotherapy or antifungals were excluded. Diarrhea was defined as 3 or more watery stools for 2 days and a positive C. difficile toxin or culture. Stool frequency was self-reported. The patients average age was 58 years. Sixty patients had at least one previous episode of CDAD. Overall, failure of the probiotic in preventing another CDAD episode was significantly less than failure with the placebo. The adverse effects reported were increased thirst and constipation. No benefit was seen for patients with their first CDAD episode, while there was a statistically significantly lower rate of RCDAD in the subgroup of patients with a mean of 3.2 previous CDAD episodes (34.6% vs 64.7%, respectively; p = 0.04). Given the wide 95% confidence interval (2.3 to 50.6) seen in decreasing risk for RC- DAD, it is problematic to say that there is a clinical benefit. 11 Evaluation of outcomes was not controlled for time since last episode or hospital length of stay. In addition, the marginal benefit (p = 0.05) was confined to the subgroup with previous CDAD episodes. Surawicz et al. 12 conducted an exploratory trial in adults. In the original epidemiologic study, 5 patients who received high-dose (2 g/day) vancomycin (n = 85) with S. boulardii had a lower rate of RCDAD compared with patients who received placebo (16.7% vs 50%, respectively; p = 0.05). Patients receiving low-dose (500 mg/day) oral vancomycin (n = 32) with S. boulardii had a similar rate of RCDAD compared with those receiving placebo (51.1% vs 44.7%, respectively), as did patients receiving metro- Table 3. Summary of Reports and Studies with Saccharomyces Pts. Reference Dosing Regimen (N) Population Results Report Kimmey (1990) mg bid for 90 days with taper 1 RCDAD no further episodes at 18 mo Open trial Surawicz (1989) mg bid started on day 5 of oral 13 RCDAD no further recurrences in 11 pts. vancomycin and continued for 30 days Randomized, blinded trials McFarland (1994) mg bid for 4 wk combined with antibiotics 124 CDAD recurrence 26.3% (probiotic) vs 44.8% (placebo); for C. difficile for at least 4 days and for 4 wk p = 0.05; benefit confined to RCDAD group after (n = 60) Surawicz (2000) mg bid started on day 7 of high-dose 32 RCDAD recurrence 16.7% (probiotic) vs 50% (placebo); vancomycin and continued for 28 days p = 0.05; subgroup report of observational study CDAD = Clostridium difficile associated diarrhea; RCDAD = recurrent CDAD. The Annals of Pharmacotherapy 2007 July/August, Volume

5 M Segarra-Newnham nidazole (n = 53) with S. boulardii versus placebo (48.2% vs 50%, respectively). The epidemiologic study did not mention the use of a probiotic. 5 The report published in focused on patients receiving the high-dose vancomycin combined with S. boulardii regimen. These subjects had more severe CDAD, at least one previous CDAD episode, and were more likely to have colitis or fecal white cells. These were likely reasons that the group self-selected for the high-dose group, as the original study was an observational trial designed to review the epidemiology of CDAD. Patients were treated for CDAD according to the preference of their private physicians and were then referred to the authors of the study for follow-up and randomization to receive a probiotic or placebo. Definitions of self-reported diarrhea were similar to the ones used in the study above. 42 The success rate with S. boulardii was barely statistically significant (p = 0.05; 95% CI 0.3 to 62), 11 which appears to indicate no significant difference. There was no adjustment based on the number of previous CDAD episodes. In addition, patients were not randomized according to CDAD treatment dose. It is possible that the statistical difference was due to the high-dose vancomycin patients being inherently different from patients in the other 2 groups. COMPLICATIONS While S. boulardii may be believed to be nonpathogenic fungi, 47 almost 40 cases of fungemia possibly related to use of this probiotic have been reported in the literature, the majority in the past decade (Table 4). 45,51-66 An outbreak in 3 roommates in an intensive care unit (ICU) in Italy was recently reported. 51 Patients had S. cerevisiae subtype boulardii fungemia believed to have been acquired from patients receiving treatment with a probiotic. All 3 patients had a CVC and were receiving enteral nutrition. An additional incomplete report was that of a 35- year-old woman included in the publication, but it is not known whether she received a probiotic. Nearby patients may have received the probiotic powder to prevent AAD. However, none of the patients reported in the outbreak was receiving it. After the first 2 cases, probiotic use in the ICU was stopped for 3 months and then reintroduced. With the third episode diagnosed about a month after reintroduction of probiotics, the use of S. boulardii was stopped. The timing of the fourth infection was not clear. Possible transmission was believed to have been airborne, with contamination of the CVC as the entry site. It is uncertain from the information presented what the timing of the infections was and why the patients who were infected were not receiving the probiotic, although this practice was reported as standard for patients in the intensive care unit who were receiving antibiotics, which all 3 patients were. The duration of probiotic use in the patients who received it was not reported. At least 12 additional cases of possible CVC contamination or nosocomial transmission of fungemia have been reported In 4 cases of S. boulardii fungemia, contamination of the CVC may have had a role. 52 One patient developed septic shock, and the CVC could have been contaminated when capsules were opened near the patient s bed. The authors showed that contamination of surfaces can be measured up to 30 minutes after opening a packet without gloves and can persist after vigorous hand washing. Recommendations were made to open packets or capsules while wearing gloves and outside the patient s room to avoid surface contamination. A recently reported case involved a patient who may have had a CVC contaminated by healthcare personnel who were also taking care of a patient in a neighboring room who was being treated with S. boulardii. 53 A report from France listed 7 cases of S. boulardii fungemia that occurred over a 52 month period. 54 Six of the patients received S. boulardii packets 1 2 g daily to prevent AAD or diarrhea from enteral feeding. All of the patients were on mechanical ventilation and had CVCs. Three of the patients did not survive their hospital stay, but no death was related to fungemia. The authors recommended that S. boulardii not be used in critically ill patients. A woman who was immunosuppressed due to highdose steroid and cyclophosphamide treatment developed fungemia after RCDAD was treated with metronidazole and S. boulardii. 55 The patient had a CVC at the time. DNA fingerprinting of the blood isolate was identical to that of the probiotic preparation. Two additional cases of S. boulardii in immunocompromised patients treated with a probiotic have been reported. 56 A woman being treated for CDAD developed S. cerevisiae fungemia after she received 1 g of S. boulardii per day after failing 10 days of oral metronidazole. The second patient was treated with S. boulardii after 15 days of persistent diarrhea while receiving penicillin and antituberculosis treatment. Electrophoresis of the probiotic capsules and the blood isolates showed that S. boulardii and S. cerevisiae were the same. One case of fungemia associated with probiotic administration occurring in a woman with an apparent intact immune system has been reported. 57 The only comorbid condition listed was chronic obstructive pulmonary disease; there was no history of gastrointestinal problems or bowel disease and no mention of steroid treatment before or during hospitalization. It was not specified whether the patient received the probiotics in packets. Stool samples were negative for pathogens, possibly ruling out CDAD. Authors of a literature review of 60 cases of S. cerevisiae fungemia reported 4 cases between 1970 and 1980, 10 between 1981 and 1991, and 46 cases between 1992 and Seventeen patients died (28% mortality rate) The Annals of Pharmacotherapy 2007 July/August, Volume 41

6 Table 4. Case Reports of Fungemia from Saccharomyces boulardii Probiotic Use Pts. Reference (age/sex) Risk Factors Outcome Pletincx (1995) 58 1 y/f CVC, pneumonia, diarrhea treated with probiotic responded to fluconazole Probiotics for C. difficile Associated Diarrhea Bassetti (1998) y/f CVC, on steroids and probiotic for RCDAD episode fever responded 24 h after amphotericin B started Fredenucci (1998) y/m enteral nutrition, diarrhea while on antibiotics for fever responded within 24 h after fluconazole started presumed aspiration pneumonia, treated with packets Niault (1999) y/f probiotic via gastric tube for diarrhea responded after 15 days of fluconazole Cesaro (2000) 60 8 mo/nr leukemia, CVC, given probiotic to prevent AAD, responded after 14 days of amphotericin B receiving fluconazole prophylaxis Perapoch (2000) 61 3 mo/m CVC, congenital cardiopathy, diarrhea treated given lipid amphotericin, responded within 48 h of with probiotic CVC removal NR/F intestinal atresia, CVC, not on probiotic but near responded to lipid amphotericin by day 19, CVC pt. receiving probiotic, appears to be a newborn removed Hennequin (2000) y/m CF, CVC, TPN, multiple antibiotics, given responded after 3 wk of amphotericin B probiotic for better tolerance of nutrition 36 y/m HIV-positive, chemotherapy for lymphoma, responded after 10 days of fluconazole parenteral nutrition, CVC, received probiotic for persistent diarrhea 47 y/m cancer, CVC, given probiotic for diarrhea after responded after 6 wk of fluconazole multiple antibiotic courses 78 y/f dialysis, CVC, enteral nutrition and probiotic no antifungal therapy; no symptoms at the time of positive cultures Rijnders (2000) y/m given probiotic to treat tube feeding associated treated with fluconazole, died 4 wk later; no findings diarrhea; status postneurosurgery for hematoma of yeast infection on autopsy; had colitis of unknown etiology Lherm (2002) y/m CVC, probiotic for diarrhea no treatment after probiotic stopped and CVC changed, died 51 y/f aortic surgery, CVC, probiotic for diarrhea received fluconazole, died 50 y/m CVC, no probiotic responded to fluconazole, CVC culture grew fungi 82 y/f CVC, probiotic for diarrhea no antifungal treatment, survived 75 y/m respiratory failure, CVC, probiotic for diarrhea no antifungal treatment, survived 77 y/m duodenal ulcer, CVC, probiotic for diarrhea received amphotericin B, died 71 y/f stroke, CVC, probiotic for diarrhea no antifungal treatment, survived Cassone (2003) y/m enteral nutrition, CVC, roommate receiving probiotic responded to 3 wk of treatment 48 y/m enteral nutrition, CVC, roommate receiving probiotic fever responded after 48 h of treatment 75 y/f enteral nutrition, CVC, roommate receiving probiotic responded to CVC removal and 2 wk of treatment 35 y/f incomplete report unclear Riquelme (2003) y/f ESRD post-kidney pancreas transplant with CDAD responded after 21 days of fluconazole after antibiotic treatment 41 y/m HIV-positive with secondary syphilis and Myco- responded after total amphotericin B dose of 1100 mg bacterium tuberculosis, meningoencephalomyelitis, probiotic for diarrhea Lungarorri (2003) 63 <1 mo/m premature, parenteral nutrition, CVC, on probiotic responded to lipid amphotericin, CVC removed to prevent bacterial overgrowth Henry (2004) y/m cancer, oral mucositis, treated with probiotic for treated with amphotericin B survived diarrhea, CVC Cherafi (2004) y/f colitis, on probiotic for CDAD treated with fluconazole, died Muñoz (2005) y/f CDAD treated with probiotic no treatment given, as follow-up blood cultures were negative, died unexpectedly 15 days later 74 y/f on steroids, developed CDAD after antibiotic treated with fluconazole, died of unrelated infection therapy; given probiotic 12 days later 76 y/f given probiotic for CDAD, which was stopped treated with fluconazole, died several months later of after endocarditis developed a stroke Burkhardt (2005) y/m spastic tetraparesis, gastrostomy, on probiotic responded to voriconazole after failing 7 days of for diarrhea prophylaxis fluconazole Graf (2007) y/f cancer, pt. in neighboring room on probiotic for treated with fluconazole and later voriconazole, CDAD, CVC refused CVC removal, died 2 mo later AAD = antibiotic-associated diarrhea; CDAD = Clostridium difficile associated diarrhea; CF = cystic fibrosis; CVC = central venous catheter; ESRD = end-stage renal disease; NR = not reported; RCDAD = recurrent CDAD; TPN = total parenteral nutrition. The Annals of Pharmacotherapy 2007 July/August, Volume

7 M Segarra-Newnham Twenty-five (42%) cases were potentially related to probiotic use of S. boulardii, including 3 cases in the authors institution. These probiotic-related cases were listed in 13 reports in English and 2 in French; most were reported after the year Of these 25 probiotic-related cases, all patients had a CVC and 16 had a stay in the intensive care unit. Fungemia was detected a median of 10 days after probiotic administration. Treatment consisted of probiotic discontinuation, removal of CVCs, and administration of antifungals. Two additional cases of fungemia occurred in patients who did not appear to have received S. boulardii as a probiotic but had been previously reported in outbreaks. 51,54 Seven more cases were reported to have occurred in patients in the vicinity of a patient receiving S. boulardii. 51,61,67 Nonetheless, one of the reports, which accounted for 3 of the 7 cases, did not mention nearby probiotic use as the potential reason for fungemia. 67 The more recent case of nosocomial transmission was not included in this report. 54 Therefore, it seems that 5 cases may have been related to nosocomial transmission from a nearby patient receiving a probiotic. 51,54,61 A second review of invasive Saccharomyces spp. infection was published in late This report included 92 cases, with 72 reports of fungemia and 83% of cases (n = 76) reported after A total of 37 patients had S. boulardii fungemia (51% of all Saccharomyces fungemias); only 5 (14%) of these patients had no documented probiotic use at the time of infection. One case related to the outbreak previously listed, 54 and the others occurred in patients near patients who were receiving probiotic therapy. 51,61 A favorable outcome was seen in 73% (n = 27) of the patients. In addition to the 33 cases listed in Table 4, there are 3 non-english reports (2 in French and 1 in German) that are discussed in the 2005 review. 68 However, the patient with unclear use of probiotic, reported by Cassone et al., 51 was not included in the review, and 3 cases reported from abstracts cited by Cassone et al. are included in their total. Therefore, it appears that at least 39 cases of fungemia related to probiotic use by a patient or one nearby have been reported in the literature. Six patients received Saccharomyces specifically for CDAD, and most patients were treated with fluconazole. This number may appear small compared with the likely millions of people who have used probiotics for different indications. Nonetheless, it is worrisome given that the patients likely to have this complication are the same debilitated patients at risk for RCDAD. 2,5,8 In considering all of these data, it seems appropriate to avoid use of probiotics in patients with risk factors for sepsis. 26 According to a review of infectious complications from probiotic use, the major risk factors appear to be immunosuppression and premature birth. 30 Minor risk factors may be the presence of a CVC, impaired intestinal barrier (ie, diarrhea), the administration of a probiotic via a J-tube, concomitant administration of a broad-spectrum antibiotic that does not cover the probiotic (which would appear to be counterproductive), using probiotics with high mucosal adhesion, and the presence of cardiac valvular disease (LGG only). 30 Unfortunately, these risk factors would be commonly seen in patients with RCDAD. 2,5,8,68 It appears that the best defense against CDAD is to prevent the first episode with judicious use of antibiotics 13 and good infection control practices in the hospital. 1,5,15 For patients with an initial CDAD episode, it is important to avoid antibiotic reexposure, especially within 2 months. 2,5,14 META-ANALYSES Of 3 published meta-analyses of probiotics, only 1 specifically addressed CDAD. 71 McFarland 71 combined published studies for both AAD prevention and treatment of CDAD up to Of note, this author was involved in several of the studies scrutinized. The author reported that the previous meta-analyses may not be accurate, as some evaluations commonly used for meta-analysis (eg, scattered plots) were not provided. 69,70 Twelve studies, half using S. boulardii and half LGG, with 354 patients, were combined for the analysis. For AAD prevention, probiotics appeared to be more effective for children than for adults. Only studies that reviewed CDAD as a preplanned evaluation, whether as a primary or secondary objective, were included in McFarland s 71 analysis (n = 6). Studies that reported CDAD as post hoc analysis were excluded. For CDAD, only 2 studies described a positive response, all in adults with RCDAD. The pooled relative risk was 0.59 (95% CI 0.41 to 0.85) in favor of probiotics and limited to decreasing RCDAD. Of the 6 studies included in that meta-analysis, I excluded 2 because they used probiotics that have very limited data, as previously listed. 21,22 That leaves 2 studies with LGG 29,72 and 2 with S. boulardii. 12,42 The 2 LGG studies were either reported as preliminary 72 in a journal supplement or as a letter, 29 with very limited information published. Both S. boulardii studies were reviewed above. 12,42 Since no cases of fungemia or bacteremia with the use of probiotics were reported in the studies evaluated, McFarland appeared to dismiss quickly the potential for this severe complication and limits the potential for infection to catheter contamination. However, it should be noted that all of these studies excluded immunosuppressed patients. McFarland believed that 6 8 weeks of treatment with a probiotic is a reasonable duration of therapy, although most studies used shorter duration of treatment. The main concerns with any probiotic meta-analysis are that most studies used different definitions of RCDAD and different probiotic doses. With a lack of standardization for the preparations, it is possible to have unreliable organism concentrations The Annals of Pharmacotherapy 2007 July/August, Volume 41

8 Probiotics for C. difficile Associated Diarrhea Summary Data regarding usefulness of the probiotics LGG and S. boulardii are conflicting. It is possible that probiotics will be shown to have a role in preventing RCDAD. Nonetheless, potential bacteremia and fungemia may outweigh the benefits in immunosuppressed and debilitated patients, who are also the ones at highest risk for RCDAD. Marisel Segarra-Newnham PharmD MPH BCPS (AQ ID), Clinical Pharmacy Specialist, Infectious Diseases, Veterans Affairs Medical Center, Patient Support Service (119), 7305 North Military Trail, West Palm Beach, FL 33410, fax 561/ , marisel.segarranewnham@ va.gov Reprints: Dr. Segarra-Newnham I thank Lisa Aguas PharmD for her help with initial literature searches and evaluation. References 1. Bouza E, Muñoz P, Alonso R. Clinical manifestations, treatment and control of infections caused by Clostridium difficile. Clin Microbiol Infect 2005;11(suppl 4): Aslam S, Hamill RJ, Musher DM. 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Liver abscess due to a Lactobacillus rhamnosus strain indistinguishable from L. rhamnosus strain GG. Clin Infect Dis 1999;28: Land MH, Rouster-Stevens K, Woods CR, Cannon ML, Cnota J, Shetty AK. Lactobacillus sepsis associated with probiotic therapy. Pediatrics 2005;115: DOI /peds Mackay AD, Taylor MB, Kibbler CC, Hamilton-Miller JMT. Lactobacillus endocarditis caused by a probiotic organism. Clin Microbiol Infect 1999;5: Kunz AN, Noel JM, Fairchok MP. Two cases of Lactobacillus bacteremia during probiotic treatment of short gut syndrome. J Pediatr Gastroenterol Nutr 2004;38: DeGroote MA, Frank DN, Dowell E, Glode MP, Pace NR. Lactobacillus rhamnosus GG bacteremia associated with probiotic use in a child with short gut syndrome. Pediatr Infect Dis J 2005;24: DOI /01.inf e6 39. Salminen MK, Rautelin H, Tynkkynen S, et al. Lactobacillus bacteremia, clinical significance, and patient outcome, with special focus on probiotic L. rhamnosus GG. 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9 M Segarra-Newnham 40. Salminen MK, Tynkkynen S, Rautelin H, et al. Lactobacillus bacteremia during a rapid increase in probiotic use of Lactobacillus rhamnosus GG in Finland. Clin Infect Dis 2002;35: Saxelin M, Chuang N-H, Chassy B, et al. Lactobacilli and bacteremia in Southern Finland, Clin Infect Dis 1996;22: McFarland LV, Surawicz CM, Greenberg RN, et al. A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA 1994;271: Erratum 1994;272: Smith D, Metzgar D, Wills C, Fierer J. Fatal Saccharomyces cerevisiae aortic graft infection. J Clin Microbiol 2002;40: Herbrecht R, Nivoix Y. Saccharomyces cerevisiae fungemia: an adverse effect of Saccharomyces boulardii probiotic administration. Clin Infect Dis 2005;40: Muñoz P, Bouza E, Cunca-Estrella M, et al. Saccharomyces cerevisiae fungemia: an emerging infectious disease. Clin Infect Dis 2005;40: McCullough MJ, Clemons KV, McCusker JH, Stevens DA. Species identification and virulence attributes of Saccharomyces boulardii (nom. inval.). J Clin Microbiol 1998;36: McFarland LV. Saccharomyces boulardii is not Saccharomyces cerevisiae (letter). Clin Infect Dis 1996;22: Eddy JT, Stamatakis MK, Makela EH. Saccharomyces boulardii for the treatment of Clostridium-difficile associated colitis. Ann Pharmacother 1997;31: Kimmey MB, Elmer GW, Surawicz CM, McFarland LV. Prevention of further recurrences of Clostridium difficile colitis with Saccharomyces boulardii. Dig Dis Sci 1990;35: Surawicz CM, McFarland LV, Elmer G, Chinn J. Treatment of recurrent Clostridium difficile colitis with vancomycin and Saccharomyces boulardii. Am J Gastroenterol 1989;84: Cassone M, Serra P, Mondello F, et al. Outbreak of Saccharomyces cerevisiae subtype boulardii fungemia in patients neighboring those treated with a probiotic preparation of the organism. J Clin Microbiol 2003;41: DOI /JMC Hennequin C, Kauffmann-Lacroix C, Jobert A, et al. Possible role of catheters in Saccharomyces boulardii fungemia. Eur J Clin Microbiol Infect Dis 2000;19: Graf C, Gavazzi G. Saccharomyces cerevisiae fungemia in an immunocompromised patient not treated with Saccharomyces boulardii preparation (letter). J Infect 2007;54: Epub 20 Mar DOI /j.jinf Lherm T, Monet C, Nougière B, et al. Seven cases of fungemia with Saccharomyces boulardii in critically ill patients. Intensive Care Med 2002;28: DOI /s Bassetti S, Frei R, Zimmerli W. Fungemia with Saccharomyces cerevisiae after treatment with Saccharomyces boulardii. Am J Med 1998;105: Riquelme AJ, Calvo MA, Guzmán AM, et al. Saccharomyces cerevisiae fungemia after Saccharomyces boulardii treatment in immunocompromised patients. J Clin Gastroenterol 2003;36: Niault M, Thomas F, Prost TJ, Ansari FH, Kalfon P. Fungemia due to Saccharomyces species in a patient treated with enteral Saccharomyces boulardii (letter). Clin Infect Dis 1999;28: Pletincx M, Legein J, Vandenplas Y. Fungemia with Saccharomyces boulardii in a 1-year-old girl with protracted diarrhea. J Pediatr Gastroenterol Nutr 1995;21: Fredenucci I, Chomarat M, Boucaud C, Flandrois JP. Saccharomyces boulardii fungemia in a patient receiving ultra-levure therapy. Clin Infect Dis 1998;27: Cesaro S, Chinello P, Rossi L, Zanesco L. Saccharomyces cerevisiae fungemia in a neutropenic patient treated with Saccharomyces boulardii. Support Care Cancer 2000;8: DOI /s Perapoch J, Planes AM, Querol A, et al. Fungemia with Saccharomyces cerevisiae in two newborns, only one of whom had been treated with ultra-levura. Eur J Clin Microbiol Infect Dis 2000;19: DOI /s Rijnders BJA, Van Wijngaerden E, Verwaest C, Peetermans WE. Saccharomyces fungemia complicating Saccharomyces boulardii treatment in a non-immunocompromised host (letter). Intensive Care Med 2000; 26: Lungarorri MS, Mezzetti D, Radicioni M. Methaemoglobinaemia with concurrent blood isolation of Saccharomyces and Candida (letter). Arch Dis Child Fetal Neonatol Ed 2003;88:F Henry S, D Hondt L, Andre M, Holemans X, Canon JL. Saccharomyces cerevisiae fungemia in a head and neck cancer patient. Acta Clin Belg 2004;59: Cherafi S, Robberecht J, Miendje Y. Saccharomyces cerevisiae fungemia in an elderly patient with Clostridium difficile colitis. Acta Clin Belg 2004;59: Burkhardt O, Köhnlein T, Pletz MW, Welte T. Saccharomyces boulardii induced sepsis: successful therapy with voriconazole after treatment failure with fluconazole. Scand J Infect Dis 2005;37: DOI / Fiore NF, Conway JH, West KW, Kleiman MB. Saccharomyces cerevisiae infections in children. Pediatr Infect Dis J 1998;17: Enache-Angoulvant A, Hennequin C. Invasive Saccharomyces infection: a comprehensive review. Clin Infect Dis 2005;41: Cremonini F, Di Caro S, Nista EC, et al. Meta-analysis: the effect of probiotic administration on antibiotic-associated diarrhea. Aliment Pharmacol Ther 2002;16: D Souza AL, Rajkumar C, Cooke J, Bulpitt CJ. Probiotics in the prevention of antibiotic associated diarrhoea: meta-analysis. BMJ 2002;324: 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: Pochapin M. The effect of probiotics on Clostridium difficile diarrhea. Am J Gastroenterol 2000;95(suppl):S11-3. Uso de Probióticos para la Diarrea Asociada a Clostridium difficile: Énfasis en Lactobacillus rhamnosus GG y Saccharomyces boulardii M Segarra-Newnham Ann Pharmacother 2007;41: EXTRACTO OBJETIVO: Revisar la información disponible en la literatura sobre el uso de probióticos para tratar o prevenir recurrencias de diarreas asociadas al Clostridium difficile (CDAD) al reemplazar la flora gastrointestinal. FUENTE DE DATOS: PubMed (enero 1970 marzo 2007). Términos incluidos en la búsqueda incluyeron probióticos, Clostridium difficile, colitis, diarrea, prevención, y tratamiento. SELECCION DE ESTUDIOS Y EXTRACCION DE DATOS: Se incluyeron informes de casos, series de casos y estudios clínicos que describían el uso de probióticos para el tratamiento o prevención de recurrencia de CDAD como el resultado primario. SÍNTESIS DE DATOS: Una variedad de estudios clínicos controlados, series de casos e informes de casos han evaluado el uso de probióticos para tratar el primer episodio o episodios recurrentes de CDAD. Un meta análisis ha sido realizado con el propósito de determinar el papel que juegan de los probióticos en CDAD. En general, la mayoría de las series de casos e informes de casos han demostrado resultados favorables con Lactobacillus rhamnosus GG y Saccharomyces boulardii. Sin embargo, otros informes no han demostrado beneficio. El meta análisis mostró que los probióticos podrían ser útiles en el tratamiento o prevención de recurrencias de CDAD. Sin embargo, la heterogeneidad de los estudios hace difícil llegar conclusiones definitivas. Además, se han informado varios casos de bacteremia o fungemia asociados al uso de probióticos, particularmente en la última década. Los pacientes mayormente afectados por estas complicaciones eran pacientes inmunosuprimidos. Desafortunadamente, estos son los pacientes más propensos a presentar CDAD severa o a mayor riesgo de episodios recurrentes. CONCLUSIONES: Es necesario realizar estudios adicionales con probióticos para contestar las numerosas preguntas existentes. Dado el potencial de complicaciones en pacientes debilitados e inmunosuprimidos, los 1220 The Annals of Pharmacotherapy 2007 July/August, Volume 41