Probiotics for the Control of Clostridium difficile

Transcription

1 Probiotics for the Control of Clostridium difficile By: Charles Spielholz, Ph.D. Abstract: Clostridium difficile is a bacterium that can cause serious infections of the human intestine. Resistant to many commonly used antibiotics, C. difficile is transferred from patientto-patient by an oral-fecal route. Infection of susceptible people by C. difficile is on the rise in hospitals, nursing homes, and long-term care facilities. C. difficile gains a foothold in the intestine while patients are treated with antibiotics that kill both pathogenic bacteria and the natural population of harmless bacteria residing in the intestines. Preliminary clinical trials indicate probiotics may help prevent C. difficile infections in hospitals and similar settings. However, additional clinical trials are required in order to establish treatment protocols. Clostridium difficile is a gram positive, spore forming anaerobic bacillus that causes intestinal disease in humans. The bacteria attain a foothold in the human intestinal tract when populations of bacteria that are part of the normal flora and fauna of the digestive tract are compromised by factors such as antibiotic use. C. difficile infection is a significant cause of antibiotic-associated diarrhea (AAD). C. difficile infection can also cause a more serious condition, pseudomembranous colitis, a life threatening inflammation of the colon (large intestine). C. difficile is responsible for approximately 25% of the AAD cases in the United States. It is also responsible for at least half of all the cases of antibiotic-associated colitis and probably all of the cases of pseudomembranous colitis (1, 2). The incidence 1

2 of C. difficile infections has been increasing dramatically over the past decade (2, 3). Up to 20% of individuals with C. difficile infections die because of the infection (4). The bacteria are generally transferred by an oral-fecal route. In addition to antibiotic use, risk factors for intestinal infections by C. difficile include aging, hospitalizations, surgery, and stays in long-term care facilities. Diabetics and those taking medications to suppress the immune system are also at increased risk for C. difficile infections. Elderly people, who are at increased risk for surgery, diabetes, injury, infections and who are more likely to receive antibiotic treatment and to live in long-term care facilities, are particularly prone to C. difficile infection, AAD and pseudomembranous colitis. Standard treatment of C. difficile generally involves replacement of the antibiotics in use with antibiotics that have activity against C. difficile (the antibiotics in most common use for this purpose are metronidzole and 2 vancomycin). Such an approach greatly attenuates the population of C. difficile and stops the infection. However this approach does not replace the natural population of microbiota that populated the digestive tract before antibiotic treatment. Lack of natural populations of native microbiota appears to play a role in making an individual susceptible to recurrence of C. difficile infections (5). Therefore, proposals to add microbiota back to the digestive tract have been put forward and have been tested in preliminary clinical trials. In addition, there are reports of C. difficile resistance to metronidazole and vancomycin. Such reports strongly indicate a need to develop additional approaches to treating this infection. One approach to adding microbiota back to the digestive tract is to simply ingest probiotics. Probiotics are live microorganisms that, when fed to a host organism, confer a health benefit. Probiotics generally consist of yeast and/or bacteria and can be administered through a functional food. Probiotics can also be

3 administered in the form of supplements or suppositories. Foods like yogurt are well known sources of probiotics. It is always critical that the specific species and strain of probiotic be matched to the desired effect or condition. The best species and strains of probiotics for specific conditions can only be determined through well designed clinical trials. The literature contains a variety of reports regarding treatment of C. difficile infections with probiotics. Generally, the reports show that treatment of C. difficile infections with probiotics can be useful. However, a clear, well defined protocol for using probiotics to treat C. difficile has not yet been established. A brief review of some of the reports in the medical literature will provide a basic understanding of the current status of use of probiotics for C. difficile infection. Bacterial strains from the genus Lactobacillus and Bifidobacterium and a yeast strain from the genus Saccharomyces have been tested for their potential in the prevention and treatment of C. difficile infections (6, 7). For probiotics composed of bacterial species, a small number of reports indicate that probiotics are potentially useful in decreasing the potential for acquiring a C. difficile infection while confined in a hospital or similar institution. Patients admitted to a hospital free of C. difficile infection and receiving combinations of bacterial probiotics (Lactobacillus and Bifidobacterium) in a double-blind, placebo-controlled clinical trial were less likely to test positive for C. difficile toxins then control patients receiving placebo (8). This observation indicated that administration of bacterial based probiotics could be useful in preventing patients from developing C. difficile infections in settings like hospitals or long-term care facilities. Unfortunately, the results of this study were compromised by the low number of patients enrolled. An observational pilot study produced data that supported this conclusion (9); however that study was of limited value for generating strong 3

4 conclusions because it did not include a placebo control group. Another double-blind, placebocontrolled clinical trial using an additional bacterial strain from the genus Steptococcus showed that patients receiving the probiotic combination were less likely to develop diarrhea in a hospital setting and were less likely to express C. difficile toxins (10). This study provided further support for the idea that the administration of bacterial probiotics could play a role in the prevention of C. difficile infections in hospitals or, by extension, long term care facilities. However, not all clinical trials using bacterial based probiotics have been unequivocal (7, 11). Discrepancies in reports are probably due to the fact that different studies are performed under different conditions with different patient populations, different probiotics, and different end points (12). The results of these clinical trials should allow for the planning and development of well defined studies that could lead to well defined treatment protocols. 4 Use of Saccharomyces species and strains as a probiotic for the prevention of C. difficile infection has also been explored. In a randomized clinical trial, patients with an active C. difficile infection who were treated with Saccharomyces were less likely to experience a recurrence of the infection by nearly half relative to placebo (13). Further examination of the data showed that this difference was especially significant for those patients who had at least one prior C. difficile infection. In a separate doubleblind, placebo-controlled study, Saccharomyces was shown to prevent recurrence of C. difficile infections in patients on low dose antibiotic treatment, but not patients on high does antibiotic treatment (14). The medical literature does not appear to contain any controlled clinical trials using Saccharomyces for primary prevention of C. difficile infections. These results are very promising. Providing functional foods to patients in either a hospital or long term care facility may be a very easy and inexpensive method of preventing C.

5 difficile infections. Treatment with probiotics may also help to slow the rate of appearance of C. difficile strains that are resistant to antibiotics. Additional clinical trials are needed to precisely define the type of patient that would most likely benefit from the use of probiotics. Well designed clinical trials will also allow determination of the best species and strains of probiotics to use along with the best dose regime and will also identify any side effects or adverse reactions (6, 11, 15, 16). Probiotics may offer a way to prevent infections by C. difficile in hospitals, nursing homes, or long-term care facilities. The working hypothesis used to explain this benefit of probiotics is based on the idea that microbes comprising the probiotic preparation are able to repopulate the lost flora and fauna of the digestive tract and prevent opportunistic species like C. difficile from establishing a colony. If future clinical trials show that the promise of preliminary studies is real, then probiotics could provide a method to control C. difficile infection 5 with less dependence on antibiotics and decreased risk of causing the evolution of additional antibiotic resistant forms of this pathogen. References 1) Aslam S, Hamill RJ, Musher DM Treatment of Clostridium difficile-associated disease: old therapies and new strategies. Lancet Infect Dis. 5: ) Owens RC Clostridium difficile-associated disease: changing epidemiology and implications for management. Drugs.67: ) Surowiec D, Kuyumjian AG, Wynd MA, Cicogna CE Past, present, and future therapies for Clostridium difficile-associated disease. Ann Pharmacother. 40: ) Pepin J, Saheb N, Coulombe MA, Alary ME, Corriveau MP, Authier S, Leblanc M, Rivard G, Bettez M, Primeau V, Nguyen M, Jacob CE, Lanthier L Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis. 41: ) Pepin J, Alary ME, Valiquette L, Raiche E, Ruel J, Fulop K, Godin D, Bourassa C Increasing risk of relapse after treatment of Clostridium difficile colitis in Quebec, Canada. Clin Infect Dis. 40: ) Boyle RJ, Robins-Browne RM, Tang ML Probiotic use in clinical practice: what are the risks? Am J Clin Nutr. 83:

6 7) Katz JA Probiotics for the prevention of antibiotic-associated diarrhea and Clostridium difficile diarrhea. J Clin Gastroenterol. 40: ) Plummer S, Weaver MA, Harris JC, Dee P, Hunter J Clostridium difficile pilot study: effects of probiotic supplementation on the incidence of C. difficile diarrhoea. Int Microbiol. 7: ) Graul T, Cain AM, Karpa KD Lactobacillus and bifidobacteria combinations: a strategy to reduce hospitalacquired Clostridium difficile diarrhea incidence and mortality. Med Hypotheses. 73: ) Hickson M, D'Souza AL, Muthu N, Rogers TR, Want S, Rajkumar C, Bulpitt CJ Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ. 335: ) Surawicz CM, McFarland LV, Greenberg RN, Rubin M, Fekety R, Mulligan ME, Garcia RJ, Brandmarker S, Bowen K, Borjal D, Elmer GW The search for a better treatment for recurrent Clostridium difficile disease: use of high-dose vancomycin combined with Saccharomyces boulardii. Clin Infect Dis. 31: ) Borriello SP, Hammes WP, Holzapfel W, Marteau P, Schrezenmeir J, Vaara M, Valtonen V Safety of probiotics that contain lactobacilli or bifidobacteria. Clin Infect Dis. 36: ) Munoz P, Bouza E, Cuenca-Estrella M, Eiros JM, Perez MJ, Sanchez-Somolinos M, Rincon C, Hortal J, Pelaez T Saccharomyces cerevisiae fungemia: an emerging infectious disease. Clin Infect Dis. 40: ) Segarra-Newnham M Probiotics for Clostridium difficile-associated diarrhea: focus on Lactobacillus rhamnosus GG and Saccharomyces boulardii. Ann Pharmacother. 41: ) Lawrence SJ, Korzenik JR, Mundy LM Probiotics for recurrent Clostridium difficile disease. J Med Microbiol. 54: ) McFarland LV, Surawicz CM, Greenberg RN, Fekety R, Elmer GW, Moyer KA, Melcher SA, Bowen KE, Cox JL, Noorani Z, Harrington G, Rubin M, Greenwald D A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA. 271: