Journal of Clinical Pharmacy and Therapeutics (2008) 33, 663 668 ORIGINAL ARTICLE Feasibility and tolerability of probiotics for prevention of antibiotic-associated diarrhoea in hospitalized US military veterans N. Safdar*à MD MS, R. Barigala*à MD MPH, A.Said à MD MS and L. McKinleyà RN MPH *Section of Infectious Diseases, Department of Medicine, University of Wisconsin Medical School, University of Wisconsin Hospital and Clinics and àwilliam S. Middleton Memorial Veterans Affairs Medical Center, Madison, WI, USA SUMMARY Background: Probiotics may be efficacious for the prevention of antibiotic-associated diarrhoea. The tolerability and acceptability of probiotics in an elderly US veteran population has not been assessed. Purpose: To undertake a randomized trial to determine the tolerability and acceptability of a probiotic, Florajen Ò in an elderly population with multiple comorbidities. Methods: Pilot randomized double-blind trial comparing a probiotic, Florajen Ò to placebo for the prevention of antibiotic-associated diarrhoea in elderly hospitalized patients receiving antibiotics. Results: Forty patients were enrolled and randomized. Antibiotic-associated diarrhoea occurred in 6 16 (37%) in the placebo group and 4 23 (17%) patients in the Florajen Ò group, (RR 1Æ63, 95% CI 0Æ73 3Æ65, P = 0Æ15). Florajen Ò was well tolerated in the study population with no major side effects that necessitated discontinuation. Conclusions: In this pilot study, Florajen Ò was well tolerated in an elderly population, all of whom were taking several other medications. A larger study is needed to determine the effect of Florajen Ò on antibiotic-associated diarrhoea and Clostridium difficile infection. Keywords: antibiotic-associated diarrhoea, probiotics Received 1 May 2008, Accepted 11 August 2008 Correspondence: Dr N. Safdar, h4 511 CSC, 600 Highland avenue, Madison, WI 53792, USA. Tel.: +1 608 263 1545; fax: +1 608 263 4464; e-mail: ns2@medicine.wisc.edu INTRODUCTION Antibiotic-associated diarrhoea (AAD) occurs commonly and is an important cause of morbidity and increased cost in hospitalized patients (1). The frequency of this complication varies with the type of antibiotic used and ranges from 5% to 25% (2). Between 15% and 25% of AAD is caused by Clostridium difficile (3, 4). Perturbation of normal gastrointestinal flora by antibiotics has been proposed to be a cause of AAD. Probiotics, by replenishing the normal gastrointestinal flora may be useful for preventing or treating AAD (5, 6). A number of probiotics have been studied for the prevention of antibiotic-associated diarrhoea (7 10). The results have been conflicting with some studies showing benefit and others finding no benefit (11 13). Most studies have been undertaken in children (14 18). The tolerability and feasibility of probiotics has not been well characterized in hospitalized elderly patients with comorbidities who are receiving antibiotics. We undertook a pilot clinical trial of a commercially available lactobacillus probiotic- Florajen Ò in one such population hospitalized US military veterans receiving antibiotics for proven or presumed infection at a single institution. METHODS Trial design This was a double-blind randomized placebo-controlled trial conducted at a single Veterans Affairs Medical Center in Madison, Wisconsin from November 2003-June 2005. Newly admitted adult Ó 2008 The Authors. Journal compilation Ó 2008 Blackwell Publishing Ltd 663
664 N. Safdar et al. ( 18 years old) inpatients ( 24 h) who were placed on antibiotic therapy for presumed or proven infection on admission and were expected to receive antibiotics for at least 72 h, were eligible for inclusion. Potential subjects were excluded if they were receiving antibiotics on admission, had diarrhoea on enrolment, were taking medications that would interfere with gut motility and peristalsis (such as opiates, loperamide, stool softeners), were unable to provide informed consent, unable to take oral medications and had a history of Clostridium difficile colitis within the last 3 months. The trial was approved by the Institutional Review Board and written informed consent was obtained from all participants prior to enrolment. Following enrolment, subjects were randomized to either Florajen Ò or placebo taken orally. Baseline information was collected, including demographic data, presumed type of infection and type of antibiotic therapy. A randomization schedule was generated by the study coordinator using blocks of four. No stratification was used. The study drug and placebo were stored at the inpatient pharmacy, which dispensed active and placebo capsules according to the randomization schedule. Patients and investigators were unaware of treatment assignment. Intervention After informed consent was obtained, patients were randomized to receive Florajen Ò one capsule three times daily for 14 days after the last dose of antibiotic or matching placebo one capsule three times daily for 14 days after the last dose of antibiotic. Active capsules (Florajen Ò ; American Lifeline, Inc., Baraboo, WI, USA) contained Lactobacillus acidophilus (20 billion CFUs per capsule) in a gelatine capsule. We did not verify the bacterial count in the capsules. Patients were provided enough capsules to complete the 2-week course after the anticipated end of antibiotic treatment and were instructed to keep them refrigerated. Compliance was checked by counting capsules at the first follow-up visit. Study procedures Study drug was started on day one of antibiotic use. During hospitalization, daily assessment of bowel movements and diarrhoea was done by the research team by asking the subject and reviewing the clinical chart. Once the subject was discharged from the hospital and went home, the remainder of the study medication that was still required was given, with written instructions regarding dosage and the stop date. A daily diary to record bowel movements and any adverse effects was filled out for each subject by the investigators while the patient remained hospitalized. Upon discharge, patients filled out the daily diary and either mailed it back or brought it with them for the first follow-up visit. The follow-up visit was coordinated with other follow-up appointments occurring on that day to minimize burden to the subject. Each subject was asked about duration of treatment, side effects and presence or absence of diarrhoea. For those discharged to a care facility with no follow-up scheduled at the VA, the subject was asked to mail the diary to the research team and a telephone follow-up to the care-facility manager was performed after discharge from the hospital. Outcomes This was a pilot study undertaken to determine the feasibility of undertaking a randomized trial of probiotics in a veteran population. Other outcomes that were assessed included antibiotic-associated diarrhoea (the proportion of patients experiencing diarrhoea during the period of study) and C. difficile-associated diarrhoea. We used definitions of diarrhoea that have been employed in other studies of antibiotic-associated diarrhoea and defined diarrhoea if the bowel movement consistency on the Stool Consistency Continuum was listed as 1, 2 or 3 for two or more consecutive days (11). The Stool Consistency Continuum is a tool comprising eight line drawings depicting stools varying from watery to hard. Clostridium difficile-associated diarrhoea was considered to be present if diarrhoea (as determined by a score of 1,2 or 3 for two or more consecutive days) was present and stool was positive for C. difficile toxin. Statistical analysis In this pilot study, patient characteristics were summarized with means and SDs or frequencies and percentages. Comparisons of categorical vari-
Antibiotic-associated diarrhoea 665 ables between study groups were assessed with the chi-squared test or, where applicable, Fishers exact test. Continuous variables were compared between groups using two-sample t-tests. All reported P values were two-sided, and a type I error level of 5% was used. Analyses were intention to treat. All statistical analyses were carried out using SAS (SAS Institute Inc., Cary, NC, USA, 2007). RESULTS Between November 2003 and June 2005, 40 subjects were enrolled and were randomized, 23 to Florajen Ò and 17 to placebo. One subject on placebo withdrew at his request and thus, 23 patients took Florajen Ò and 16 took placebo (Fig. 1). Subjects took the study drug for a mean of 22Æ8 days (SD 9Æ39) in the Florajen Ò group and 24Æ46 days (SD 4Æ83) in the placebo group (P =0Æ72). All except one patient were men. Major comorbid illnesses, were equally distributed in the two groups. Mean age was similar in both groups. Subjects in both groups were taking an average of eight concomitant medications, besides antibiotics. Baseline characteristics of the study population are shown in Table 1. Antibiotic use In the Florajen Ò group, 16 23 (70%) patients received beta-lactams compared with 14 16 (87%) in the placebo group (P =0Æ19). 9 23 (39%) in the Florajen Ò group received fluoroquinolones, compared with 5 16 (31%) in the placebo group (P = 0Æ61). Macrolides were used in 7 23 (39%) patients receiving Florajen Ò and 8 16 receiving placebo (50%) (P =0Æ21). Indications for antibiotics In accordance with the inclusion criteria, all patients received antibiotics for a documented or presumed infection. The indications for antibiotics Assessed for eligibility (n = 560) Enrollment Randomised Excluded (n = 520) Not meeting inclusion criteria (n = 478) Refused to participate (n = 42) Allocated to Florajen (n = 23) Received allocated intervention (n = 23) Allocation Allocated to placebo (n = 17) Received allocated intervention (n = 16) Did not receive allocated intervention (n = 1) Give reasons: subject preference Lost to follow-up (n = 0) Discontinued intervention (n = 0) Follow-up Lost to follow-up (n = 0) Discontinued intervention (n = 0) Fig. 1 Patient enrolment CONSORT flow chart (25). Analysed (n = 23) Excluded from analysis (n = 0) Analysis Analysed (n = 17) Excluded from analysis (n = 0)
666 N. Safdar et al. Table 1. Baseline characteristics of the study participants Variable were: pulmonary infection (12 23, 52% in the Florajen Ò group and 11 16, 68% in the placebo group), urinary tract infection (3 23, 13% in the Florajen Ò group and 1 16, 6% in the placebo group), bacteremia (1 23, 4% in the Florajen Ò group and none in the placebo group), skin and soft tissue infection (7 23, 31% in the Florajen Ò group and 2 16, 12% in the placebo group) and cholangitis (none in the Florajen Ò group and 2 16, 12% in the placebo group). Monitoring of compliance with study medication In the Florajen Ò group, 20 23 (87%) patients took drug for 14 days after antibiotics were stopped. In the placebo group, 14 16 (87%) took drug for 14 days after antibiotics were stopped. Outcomes Florajen Ò, n (%) Placebo, n (%) P-value Male 22 23 (96) 17 17 (100) 0Æ30 Age (SD) 66Æ56 (14Æ53) 72Æ47 (11) 0Æ15 Diabetes 9 23 (39) 7 17 (41) 0Æ47 Lung disease 14 23 (61) 10 16 (62) 0Æ91 Peripheral 7 23 (31) 7 16 (43) 0Æ39 vascular disease Gastroesophageal 10 23 (44) 11 16 (69) 0Æ11 reflux Immunocompromised 7 23 (31) 8 16 (50) 0Æ21 Renal disease 5 23 (22) 3 16 (19) 0Æ38 Proton pump inhibitor use 7 23 (31) 8 16 (50) 0Æ19 AAD occurred in 6 16 (37%) in the placebo group and 4 23 (17%) patients in the Florajen Ò group, (RR 1Æ63, 95% CI 0Æ73 3Æ65, P = 0Æ15). Clostridium difficile toxin was obtained only for seven patients with diarrhoea. It was positive in one and negative in six cases. The one positive case of C. difficile diarrhoea occurred in a patient randomized to placebo. The six negative cases were evenly distributed in the two study groups (Table 2). Adverse effects Patients were questioned daily regarding adverse effects such as nausea, vomiting and abdominal pain. Upon discharge, subjects were asked to keep a log of adverse effects that they had experienced. During hospitalization, charts were reviewed daily to determine the presence of fever. Two subjects in the Florajen Ò group and five in the placebo group reported adverse effects. 2 23 (9%) and 2 16 (12%) had fever in the Florajen Ò and placebo group respectively. However, the fever did not last more than a day in each case and had an alternative explanation in both patients. 0 23 had nausea in the Florajen Ò group and 3 16 (19%) in the placebo group had nausea (P = 0Æ03). DISCUSSION While several trials of probiotics for the prevention of antibiotic-associated diarrhoea have been published, only a few have focused on middle aged and elderly adults (19, 20) but none in the military veteran population. This population with multiple comorbidities and medication use may have greater side effects to probiotics. However, in our study, we found that patients tolerated the probiotic preparation well without major side effects that necessitated discontinuing the medication, despite taking several other concomitant medications. Adverse effects were infrequent and nausea was more common in the placebo group than in the active treatment group. While generally viewed as safe and used widely for a variety of indications, Table 2. Outcomes of study participants Variable Florajen Ò, n (%) Placebo, n (%) RR (95% CI) P-value Antibiotic-associated diarrhoea 4 23 (17) 6 16 (37) 1Æ63 (0Æ73 3Æ65) 0Æ15 C. difficile diarrhoea 0 3 (0) 1 4 (25) 0Æ33 (0Æ009 11Æ33) 0Æ27
Antibiotic-associated diarrhoea 667 some recent case reports have reported the risk of bloodstream infection with the use of probiotics (21). Thus, while our results provide some reassurance as to the tolerability of Florajen Ò in elderly patients with multiple comorbidities, our small sample size precludes conclusions regarding safety. Future studies of probiotics should continue to maintain vigilance when monitoring for adverse effects, particularly in immunocompromised patients. Post-marketing surveillance is also essential to detect rare side effects. Some studies of probiotics for the prevention of AAD have shown that probiotics are efficacious in preventing AAD;(18 20, 22) however, this observation has not been reliably reproduced in several other studies (11, 12). The magnitude of the effect may vary depending upon the type of antibiotic used, the population and the strain and dosage of probiotic employed (6, 10). Gotz et al. administered a combination of lactobacillus acidophilus and lactobacillus helveticus (Lactinex Ò ) or placebo to patients receiving ampicillin and found that the incidence of ampicillin-induced diarrhoea in the placebo group (14%) was significantly greater (P =0Æ03) than in the Lactinex Ò group (0%) (23). However, in a study in children of Lactinex Ò or placebo administered four times a day for 10 days while taking amoxicillin, the investigators found no benefit to Lactinex Ò for the prevention of AAD (12). Other probiotics such as the yeast Saccharomyes boulardii have also been studied for their efficacy in preventing AAD, with conflicting results. In a study from Turkey, 151 hospitalized patients were given S. boulardii twice daily during the course of antibiotic therapy. One percent of the subjects developed AAD in the study group compared with 9% in the placebo group (P <0Æ05) (24). In sharp contrast, a study in elderly hospitalized patients also receiving antibiotics found no benefit in reduction of AAD with S. boulardii administration (13). While we found no difference in the clinical outcomes of antibiotic-associated diarrhoea and C. difficile-associated diarrhoea, ours was a pilot study and did not have adequate power to detect differences in these important outcomes. A larger adequately powered study is needed to examine the efficacy of Florajen Ò for the prevention of antibiotic-associated diarrhoea and C. difficileassociated disease in the veteran population. ACKNOWLEDGEMENTS We thank American Lifeline for providing study medication and placebo. REFERENCES 1. Riley TV (1996) Antibiotic-associated diarrhoea. A costly problem. Pharmacoeconomics, 10, 1 3. 2. Bartlett JG (2002) Clinical practice. Antibiotic-associated diarrhea. New England Journal of Medicine, 346, 334 339. 3. Wistrom J, Norrby SR, Myhre EB, et al. (2001) Frequency of antibiotic-associated diarrhoea in 2462 antibiotic-treated hospitalized patients: a prospective study. Journal of Antimicrobial Chemotherapy, 47, 43 50. 4. Kelly CP, Pothoulakis C, LaMont JT (1994) Clostridium difficile colitis. New England Journal of Medicine, 330, 257 262. 5. Gagan MJ (2003) Review: probiotics are effective in preventing antibiotic associated diarrhoea. Evidence Based Nursing, 6, 16. 6. Cremonini F, Di Caro S, Nista EC, et al. (2002) Metaanalysis: the effect of probiotic administration on antibiotic-associated diarrhoea. Alimentary Pharmacology and Therapeutics, 16, 1461 1467. 7. Kotowska M, Albrecht P, Szajewska H (2005) Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea in children: a randomized double-blind placebo-controlled trial. Alimentary Pharmacology and Therapeutics, 21, 583 590. 8. McConaghy JR (2003) Do probiotics decrease antibiotic-associated diarrhea? Journal Family Practice, 52, 273. 9. Shaughnessy A (2003) Probiotics use decreases antibiotic-associated diarrhea. American Family Physician, 67, 1782. 10. Szajewska H, Mrukowicz JZ (2003) Probiotics in prevention of antibiotic-associated diarrhea: metaanalysis. Journal of Pediatrics, 142, 85. 11. Thomas MR, Litin SC, Osmon DR, et al. (2001) Lack of effect of Lactobacillus GG on antibiotic-associated diarrhea: a randomized, placebo-controlled trial. Mayo Clinic Proceedings, 76, 883 889. 12. Tankanow RM, Ross MB, Ertel IJ, et al. (1990) A double-blind, placebo-controlled study of the efficacy of Lactinex in the prophylaxis of amoxicillininduced diarrhea. Dicp, 24, 382 384. 13. Lewis SJ, Potts LF, Barry RE (1998) The lack of therapeutic effect of Saccharomyces boulardii in the prevention of antibiotic-related diarrhoea in elderly patients. Journal of Infections, 36, 171 174.
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