A Gastroenterologist's Guide to Probiotics
2012; Elsevier BV; Volume: 10; Issue: 9 Linguagem: Inglês
10.1016/j.cgh.2012.03.024
ISSN1542-7714
Autores Tópico(s)Helicobacter pylori-related gastroenterology studies
ResumoThe enteric microbiota contribute to gastrointestinal health, and their disruption has been associated with many disease states. Some patients consume probiotic products in attempts to manipulate the intestinal microbiota for health benefit. It is important for gastroenterologists to improve their understanding of the mechanisms of probiotics and the evidence that support their use in practice. Clinical trials have assessed the therapeutic effects of probiotic agents for several disorders, including antibiotic- or Clostridium difficile–associated diarrhea, irritable bowel syndrome, and the inflammatory bowel diseases. Although probiotic research is a rapidly evolving field, there are sufficient data to justify a trial of probiotics for treatment or prevention of some of these conditions. However, the capacity of probiotics to modify disease symptoms is likely to be modest and varies among probiotic strains—not all probiotics are right for all diseases. The current review provides condition-specific rationale for using probiotic therapy and literature-based recommendations. The enteric microbiota contribute to gastrointestinal health, and their disruption has been associated with many disease states. Some patients consume probiotic products in attempts to manipulate the intestinal microbiota for health benefit. It is important for gastroenterologists to improve their understanding of the mechanisms of probiotics and the evidence that support their use in practice. Clinical trials have assessed the therapeutic effects of probiotic agents for several disorders, including antibiotic- or Clostridium difficile–associated diarrhea, irritable bowel syndrome, and the inflammatory bowel diseases. Although probiotic research is a rapidly evolving field, there are sufficient data to justify a trial of probiotics for treatment or prevention of some of these conditions. However, the capacity of probiotics to modify disease symptoms is likely to be modest and varies among probiotic strains—not all probiotics are right for all diseases. The current review provides condition-specific rationale for using probiotic therapy and literature-based recommendations. Podcast interview: www.gastro.org/cghpodcast. Also available on iTunes. Podcast interview: www.gastro.org/cghpodcast. Also available on iTunes. For more than a hundred years it has been recognized that certain microorganisms may impart health benefits to the host when administered in adequate amounts. These microorganisms, termed probiotics, have recently become a topic of significant focus in basic and clinical investigation. Relevant to the practice of gastroenterology, probiotics are commonly used by patients with gastrointestinal (GI) complaints or diseases. Increasingly, probiotics are also being recommended by the clinicians who treat these conditions.1Williams M.D. Ha C.Y. Ciorba M.A. Probiotics as therapy in gastroenterology: a study of physician opinions and recommendations.J Clin Gastroenterol. 2010; 44: 631-636PubMed Google Scholar The goal of this review is to provide clinicians with an overview of the rationale and data which support or refute the role of probiotics for treating commonly encountered GI disorders. The information provided is based on review of primary literature from randomized controlled trials (RCTs), meta-analyses, expert consensus panel recommendations, and society-based practice recommendations. References are provided for more in-depth reading and tables or figures summarize key information. To understand the role that probiotics may have in influencing health, it is important to have an appreciation of the roles of the normal intestinal microbiome (commensal microbiota). The human GI tract is host to over 500 bacterial species as well as a less well-described virome. These microbiota form a virtual bioreactor facilitating digestion, nutrient provision, and the shaping of our immune system.2Kau A.L. Ahern P.P. Griffin N.W. et al.Human nutrition, the gut microbiome and the immune system.Nature. 2011; 474: 327-336Crossref PubMed Scopus (1712) Google Scholar Our intestinal bacteria weigh up to 1 kg and bacterial cells outnumber human cells by 10:1. The bacterial genome may outnumber the human genome by 100:1. Nutritional factors including several B vitamins, vitamin K, folate, and short-chain fatty acids are produced by these bacteria. Up to 10% of an individual's daily energy needs can be derived from the by-products of bacterial fermentation. Gastrointestinal microbiota are also critical for normal immune system development.3Macpherson A.J. Harris N.L. Interactions between commensal intestinal bacteria and the immune system.Nat Rev Immunol. 2004; 4: 478-485Crossref PubMed Scopus (1130) Google Scholar The physiologic impact mediated by our resident microbes is substantial enough to have earned the label of “other organ” from some.4Sekirov I. Russell S.L. Antunes L.C. et al.Gut microbiota in health and disease.Physiol Rev. 2010; 90: 859-904Crossref PubMed Scopus (2449) Google Scholar Beyond contributing to or modifying the metabolic and nutritional functions of the commensal microbiota, probiotic bacteria have several putative mechanisms by which they may confer specific beneficial effects. General categories include modulation of immune or sensory-motor function, enhancement of mucosal barrier function, and antipathogen effects (Figure 1).5Ng S.C. Hart A.L. Kamm M.A. et al.Mechanisms of action of probiotics: recent advances.Inflamm Bowel Dis. 2009; 15: 300-310Crossref PubMed Scopus (402) Google Scholar, 6Madsen K.L. Interactions between microbes and the gut epithelium.J Clin Gastroenterol. 2011; 45: S111-S114Crossref PubMed Scopus (11) Google Scholar, 7Rousseaux C. Thuru X. Gelot A. et al.Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors.Nat Med. 2007; 13: 35-37Crossref PubMed Scopus (579) Google Scholar Some of these mechanisms have been worked out in animal models and/or in vitro systems only. Soluble products secreted or shed by probiotics also mediate important physiologic benefits; thus, viable bacteria are not necessarily required for all benefits.8Ciorba M.A. Riehl T.E. Rao M.S. et al.Lactobacillus probiotic protects intestinal epithelium from radiation injury in a TLR-2/cyclo-oxygenase-2-dependent manner.Gut. 2012; 61: 829-838Crossref PubMed Scopus (160) Google Scholar, 9Yan F. Cao H. Cover T.L. et al.Colon-specific delivery of a probiotic-derived soluble protein ameliorates intestinal inflammation in mice through an EGFR-dependent mechanism.J Clin Invest. 2011; 121: 2242-2253Crossref PubMed Scopus (237) Google Scholar The mechanisms by which probiotics exert benefit varies by specific probiotic strain and likely depends on the clinical indication.10Shanahan F. Probiotics in perspective.Gastroenterology. 2010; 139: 1808-1812Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 11Mileti E. Matteoli G. Iliev I.D. et al.Comparison of the immunomodulatory properties of three probiotic strains of lactobacilli using complex culture systems: prediction for in vivo efficacy.PLoS One. 2009; 4: e7056Crossref PubMed Scopus (203) Google Scholar Therefore, as with antibiotic prescribing, clinical use of probiotics should focus on matching the probiotic strain and dosage to the condition for which it has shown benefit in clinical trials. In the future, greater understanding of probiotic-specific mechanisms could allow for precise selection of a particular probiotic strain to target a patient's specific pathogenic defect and clinical problem. Definitions of the terms probiotic, prebiotic, and synbiotic are provided in Table 1. This review focuses on probiotics, though some probiotics have been tested as part of a synbiotic product. Lactobacillus and Bifidobacterium species are the most commonly used probiotics. However, 1 of the first probiotics, which is still in use, is the nonpathogenic Escherichia coli Nissle 1917 (ECN). Most probiotics were initially cultured from humans and resemble known commensal gut bacteria. However, the commensal population they resemble typically represents only a fraction of the total luminal bacteria. Saccharomyces boulardii is a probiotic yeast strain with the potential advantage of having resistance to most antibiotics.Table 1DefinitionsNOTE. Adapted from Guarner F, Khan AG, Garisch J, et al. Probiotics and prebiotics: world gastroenterology organisation global guidelines, 2011. Available at: http://www.worldgastroenterology.org/probiotics-prebiotics.html.48Guarner F. Khan A.G. Garisch J. et al.World Gastroenterology Organisation Practice Guideline—Probiotics and Prebiotics.http://www.worldgastroenterology.org/probiotics-prebiotics.htmlDate: October 2011Google ScholarProbioticsLive microorganisms that confer a health benefit on the host when administered in adequate amountsPrebioticDietary substances that nurture specific changes in the composition and/or activity of the GI microbiota (favoring beneficial bacteria), thus conferring benefit(s) upon host healthSynbioticsProducts that contain both probiotics and prebiotics Open table in a new tab According to current definitions, probiotics should survive both gastric acid and bile to reach the small intestine and colon where they exert their effects. Clinical and basic investigations on probiotics have used a multitude of probiotic species, both as single strains and multispecies products. Many of these probiotics are available in a lyophilized (freeze-dried) pill form, though some are available in yogurt or as packets (sachets) which can be mixed into noncarbonated drinks. Whether synergism or antagonism exists between probiotic species when offered together has not been examined in clinical studies, though both scenarios are theoretically possible. Though not exhaustive, Table 2 lists several of the more commonly available probiotic preparations which have shown benefit in human trials. Probiotics are considered dietary supplements; thus, they are not covered by medical insurance and their production is not regulated by the Food and Drug Administration. As such, product quality, purity, and viability have been reported to be variable.12Berman S. Spicer D. Safety and reliability of lactobacillus supplements in Seattle, Washington.Internet J Altern Med. 2003; 1Google Scholar However, several clinically tested probiotic products with quality-controlled production are now marketed by reputable companies.Table 2Available Probiotic Products Specifically Tested for Gastrointestinal DisordersBrand name (Company)Bacterial speciesClinical conditionEffectiveness32Floch M.H. Walker W.A. Madsen K. et al.Recommendations for probiotic use-2011 update.J Clin Gastroenterol. 2011; 45: S168-S171Crossref PubMed Scopus (171) Google Scholar, 42Ringel Y. Ringel-Kulka T. The rationale and clinical effectiveness of probiotics in irritable bowel syndrome.J Clin Gastroenterol. 2011; 45: S145-S148Crossref PubMed Scopus (33) Google Scholar,aEffectiveness based on expert panel recommendations where: A = strong, positive, well-conducted, controlled studies in the primary literature; B = some positive, controlled studies but presence of some negative studies or inadequate amount of work to establish the certainty; C = some positive studies but clearly inadequate amount of work to establish the certainty.Practice guidelines15Thomas D.W. Greer F.R. et al.American Academy of Pediatrics Committee on NutritionProbiotics and prebiotics in pediatrics.Pediatrics. 2010; 126: 1217-1231Crossref PubMed Scopus (313) Google Scholar, 48Guarner F. Khan A.G. Garisch J. et al.World Gastroenterology Organisation Practice Guideline—Probiotics and Prebiotics.http://www.worldgastroenterology.org/probiotics-prebiotics.htmlDate: October 2011Google Scholar, 84Mowat C. Cole A. Windsor A. et al.Guidelines for the management of inflammatory bowel disease in adults.Gut. 2011; 60: 571-607Crossref PubMed Scopus (967) Google Scholar,bPractice guidelines include those of (1) World Gastroenterology Organisation's global guidelines evidence level assignment48 where 1a = systematic review with homogeneity of RCTs; 1b = individual RCT with narrow confidence interval; and 2b = individual cohort study (including low quality RCT)85; (2) American Academy of Pediatrics recommended (AAP)15; (3) British Society of Gastroenterology guidelines Grade of Evidence (BSG)84: grade A indicates consistent results among RCTs, grade B indicates consistent cohort studies or smaller RCTs.Bacteria count/dosingCost/quantityActivia (Dannon, White Plains, NY)B lactis DN-173010 (plus yogurt starters L bulgaricus, L lactis, and Streptococcus thermophilus)IBSC1bcAdult.4 oz/cup, 1–4 qd$10–$18/24 countAlign (Proctor and Gamble, Cincinnati, OH)B infantis 35624IBSB1bcAdult.1 Billion/1 qd$29.99/28 countBioGaia (Everidis Health Sciences, St Louis, MO)L reuteri Protectis SD2112 (ATCC 55730)Infectious diarrhea treatmentIBSAC1adPediatric.1bdPediatric.100 Million qd$22–$30/5 mL (29 servings)Bio-K+ (Bio-K Plus International, Inc, Laval, QC, Canada)L acidophilus CL1285 and L casei LBC80RAAD preventionCDAD prevention1bcAdult.1bcAdult.50 Billion/capsule bid$29.99/15 countCulturelle (Valio, Helsinki, Finland/i-Health, Inc, Cromwell, CT)LGG (LGG also included in Danimals yogurt; Dannon)AAD preventionInfectious diarrhea treatmentInfectious diarrhea preventionCDAD preventionCDAD prevention of recurrenceCrohn's diseaseIBSAABB/CB/CCB/C (children)AAP, 1bcAdult., 1bdPediatric.AAP, 1adPediatric., 2bcAdult.1bcAdult., 1bdPediatric.1adPediatric.,1bcAdult.,eAs part of a multispecies probiotic product.10 Billion/1 qd$18–$25/30 countDanactive (Dannon)L casei DN-114001AAD preventionInfectious diarrhea preventionCDAD preventionA1bcAdult.1bdPediatric.1bcAdult.3.1 oz/cup; 10 billion/cup$5.00/8 countFlorastor (Biocodex, Inc, Creswell, OR)Saccharomyces boulardii (yeast)AAD preventionInfectious diarrhea treatmentInfectious diarrhea preventionCDAD preventionCDAD prevention of recurrenceCrohn's diseaseAABB/CB/CCAAP, 1adPediatric., 1bcAdult.1adPediatric., 1bcAdult.1bcAdult.250 mg/1 bid$19.99/20 countMutaflor (Ardeypharm, Herdecke, Germany)ECNUC inductionUC maintenanceBA1bcAdult., BSG “A”100 mg/capsule bid$62–$81/60CanadafECN is currently removed from the US market respecting the FDA's decision on the classification of the product as a “biologic” instead of its former status as a “medical food.”VSL*3 (Sigma-Tau Pharmaceuticals, Inc, Towson, MA)Combination probiotic product (Streptococcus thermophilus, B breve, B longum, B infantis, L acidophilus, L plantarum, L paracasei, L delbreuckii/bulgaricus)IBSUC inductionUC maintenancePouchitis: prevention and maintaining remissionB/CBAA1bcAdult.1bcAdult., BSG “B”122.5 Billion/capsule; 450 billion/sachet; IBS: ½–1 sachet/d; Pouchitis: 2–4 sachets/d; UC: 1–8 sachets/d$86/30 sachets$52/60 counta Effectiveness based on expert panel recommendations where: A = strong, positive, well-conducted, controlled studies in the primary literature; B = some positive, controlled studies but presence of some negative studies or inadequate amount of work to establish the certainty; C = some positive studies but clearly inadequate amount of work to establish the certainty.b Practice guidelines include those of (1) World Gastroenterology Organisation's global guidelines evidence level assignment48Guarner F. Khan A.G. Garisch J. et al.World Gastroenterology Organisation Practice Guideline—Probiotics and Prebiotics.http://www.worldgastroenterology.org/probiotics-prebiotics.htmlDate: October 2011Google Scholar where 1a = systematic review with homogeneity of RCTs; 1b = individual RCT with narrow confidence interval; and 2b = individual cohort study (including low quality RCT)85Centre for Evidence Based MedicineLevels of Evidence.http://www.cebm.net/index.aspx?o=1025Date: 2009Google Scholar; (2) American Academy of Pediatrics recommended (AAP)15Thomas D.W. Greer F.R. et al.American Academy of Pediatrics Committee on NutritionProbiotics and prebiotics in pediatrics.Pediatrics. 2010; 126: 1217-1231Crossref PubMed Scopus (313) Google Scholar; (3) British Society of Gastroenterology guidelines Grade of Evidence (BSG)84Mowat C. Cole A. Windsor A. et al.Guidelines for the management of inflammatory bowel disease in adults.Gut. 2011; 60: 571-607Crossref PubMed Scopus (967) Google Scholar: grade A indicates consistent results among RCTs, grade B indicates consistent cohort studies or smaller RCTs.c Adult.d Pediatric.e As part of a multispecies probiotic product.f ECN is currently removed from the US market respecting the FDA's decision on the classification of the product as a “biologic” instead of its former status as a “medical food.” Open table in a new tab Lactic acid–producing bacteria have been used for centuries in food fermentation. Many yogurts contain live-active lactobacillus cultures and are considered functional food products; however, most are not considered probiotics per se. This term is reserved for products with an adequate number of microorganisms at time of consumption specifically shown to confer health benefits in controlled human trials. Yogurts fortified with an adequate number of viable bacteria shown to exert benefit in controlled trials are classified as probiotics. Given this information, and the knowledge that probiotic benefits appear species-specific, expected clinical end points may not be achieved by generically recommending yogurt to patients in whom a purported probiotic benefit is desired. It should be noted, however, that yogurt consumption has other benefits including improved lactose tolerance and the provision of protein, vitamin D, and calcium. As viable microorganisms, probiotics can survive in the human gut and impact microbes which colonize the gut. Probiotics are often detectable in the stool by culture or gene-based assays during periods of consumption. However, many probiotic strains do not colonize the gut and are no longer recoverable in stool 1 to 4 weeks after stopping consumption.13Sanders M.E. Impact of probiotics on colonizing microbiota of the gut.J Clin Gastroenterol. 2011; 45: S115-S119Crossref PubMed Scopus (89) Google Scholar For example, McNulty and colleagues recently evaluated a fermented milk product with probiotic strains matching the commercially available Activia (Dannon, White Plains, New York). The investigators showed that the probiotic product did not change the gut's overall bacterial composition, but instead altered gene expression patterns relevant to carbohydrate metabolism in the host's resident gut microbes.14McNulty N.P. Yatsunenko T. Hsiao A. et al.The impact of a consortium of fermented milk strains on the gut microbiome of gnotobiotic mice and monozygotic twins.Sci Transl Med. 2011; 3 (106ra106)Crossref PubMed Scopus (401) Google Scholar These changes in the human fecal “metatranscriptome” were transient, confined only to the time of the probiotic consumption. Thus, if sustained benefit from a probiotic is desired, continued consumption is likely required. Data for probiotic use in several GI disorders are reviewed in the following section. For AAD and viral gastroenteritis, supporting data are strong and probiotics are among the only treatment modalities available. However, the duration of symptoms in these conditions is typically short regardless of probiotic use. In ulcerative colitis (UC), pouchitis, and irritable bowel syndrome (IBS), adequate data exist for clinicians to consider recommending a therapeutic trial of specific probiotic strains or preparations in selected patients. In these conditions probiotics are usually administered as adjunctive therapy, rather than primary or first-line therapy. The decision to recommend probiotic therapy ultimately depends on the clinical scenario, patient interest, and clinician preference. In hepatic encephalopathy, Crohn's disease (CD), and Clostridium difficile–associated diarrhea (CDAD), conventional medical therapies remain the gold standard. Practice relevant probiotic concepts are summarized in Table 3.Table 3Practical Considerations Relevant to Probiotics in PracticeCommon side effects of probiotics are typically transient but include gas and bloatingDifferent probiotic strains possess unique properties for benefiting host physiologyOne probiotic does not fit all GI illnesses; probiotic selection should be based on the clinical indication and take into consideration the strain and dosage used in clinical trialsSymptomatic benefits offered by probiotics are likely to be modest; thus, probiotic therapies may best be used to supplement rather than replace conventional therapiesContinuous consumption throughout the period of desired effect appears required for probioticsAvoid probiotics in the critically ill and those with severe immune compromise Open table in a new tab Several RCTs have evaluated the use of probiotics in acute infectious diarrhea. The data are largely from pediatric studies where both prevention and treatment were examined. Trials were conducted across the world with durations of up to 1 year. In the pediatric population, rotavirus has been the most common cause of infectious diarrhea. Data suggest that the benefit of probiotics in preventing acute infectious diarrhea is modest.15Thomas D.W. Greer F.R. et al.American Academy of Pediatrics Committee on NutritionProbiotics and prebiotics in pediatrics.Pediatrics. 2010; 126: 1217-1231Crossref PubMed Scopus (313) Google Scholar, 16Guandalini S. Probiotics for prevention and treatment of diarrhea.J Clin Gastroenterol. 2011; 45: S149-S153Crossref PubMed Scopus (196) Google Scholar Lactobacillus rhamnosus GG (LGG), Lactobacillus reuteri and Lactobacillus casei all have shown benefit, with an approximate number needed-to-treat (NNT) of 7 children to prevent 1 case of rotavirus in the child care center setting.17Weizman Z. Asli G. Alsheikh A. Effect of a probiotic infant formula on infections in child care centers: comparison of two probiotic agents.Pediatrics. 2005; 115: 5-9Crossref PubMed Scopus (428) Google Scholar, 18Pedone C.A. Arnaud C.C. Postaire E.R. et al.Multicentric study of the effect of milk fermented by Lactobacillus casei on the incidence of diarrhoea.Int J Clin Pract. 2000; 54: 568-571PubMed Google Scholar, 19Szajewska H. Kotowska M. Mrukowicz J.Z. et al.Efficacy of Lactobacillus GG in prevention of nosocomial diarrhea in infants.J Pediatr. 2001; 138: 361-365Abstract Full Text Full Text PDF PubMed Scopus (362) Google Scholar With the currently available rotavirus vaccine in consideration, the American Academy of Pediatrics states that probiotics for preventing acute infectious diarrhea are not universally endorsed, but acknowledges that they may have a role in special circumstances.15Thomas D.W. Greer F.R. et al.American Academy of Pediatrics Committee on NutritionProbiotics and prebiotics in pediatrics.Pediatrics. 2010; 126: 1217-1231Crossref PubMed Scopus (313) Google Scholar According to the US Center for Disease Control, data are not sufficient to support the use of probiotics such as LGG to prevent traveler's diarrhea of bacterial origin. The data supporting treatment of acute infectious diarrhea with probiotics are stronger. LGG is the most effective probiotic reported to date, reducing both severity and duration of diarrhea by approximately 1 day.20Szymański H. Pejcz J. Jawień M. et al.Treatment of acute infectious diarrhoea in infants and children with a mixture of three Lactobacillus rhamnosus strains–a randomized, double-blind, placebo-controlled trial.Aliment Pharmacol Ther. 2006; 23: 247-253Crossref PubMed Scopus (137) Google Scholar, 21Allen S.J. Martinez E.G. Gregorio G.V. et al.Probiotics for treating acute infectious diarrhoea.Cochrane Database Syst Rev. 2010; (CD003048)Crossref PubMed Scopus (409) Google Scholar The American Academy of Pediatrics supports the recommendation of LGG early in the course of acute infectious diarrhea to reduce symptom duration.15Thomas D.W. Greer F.R. et al.American Academy of Pediatrics Committee on NutritionProbiotics and prebiotics in pediatrics.Pediatrics. 2010; 126: 1217-1231Crossref PubMed Scopus (313) Google Scholar Antibiotic use is common in children, and diarrhea develops in approximately 20% of those taking antibiotics. Prevention of non–C difficile-related antibiotic-associated diarrhea (AAD) with probiotics has been assessed in RCTs. A 2011 Cochrane Review evaluating more than 3400 patients from 16 studies concluded that the overall evidence suggests a protective effect of probiotics in preventing AAD.22Johnston B.C. Goldenberg J.Z. Vandvik P.O. et al.Probiotics for the prevention of pediatric antibiotic-associated diarrhea.Cochrane Database Syst Rev. 2011; (CD004827)Crossref Google Scholar Studies using LGG and S boulardii produced the most convincing results.23Szajewska H. Ruszczyński M. Radzikowski A. Probiotics in the prevention of antibiotic-associated diarrhea in children: a meta-analysis of randomized controlled trials.J Pediatr. 2006; 149: 367-372Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar The NNT to prevent 1 case of AAD was approximately 7 in the Cochrane Review. The American Academy of Pediatrics supports the recommendation of probiotics for prevention of, but not treatment of, AAD.15Thomas D.W. Greer F.R. et al.American Academy of Pediatrics Committee on NutritionProbiotics and prebiotics in pediatrics.Pediatrics. 2010; 126: 1217-1231Crossref PubMed Scopus (313) Google Scholar In the adult population probiotics also appear effective in limiting AAD. A meta-analysis evaluating studies on various probiotics and antibiotic regimens published between 1977 and 2005 found that both LGG and S boulardii offered a reduction in risk of AAD development (combined RR 0.31 and 0.37, respectively).24McFarland L.V. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease.Am J Gastroenterol. 2006; 101: 812-822Crossref PubMed Scopus (651) Google Scholar Two recent placebo-controlled RCTs evaluated combination probiotic products for the prevention of AAD as their primary end point. Hickson et al used the probiotic mixture currently marketed as DanActive (Dannon) in the United States and found that it significantly reduced AAD (12% vs 34%) in an older cohort of hospitalized patients.25Hickson M. D'Souza A.L. Muthu N. et al.Use of probiotic lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial.BMJ. 2007; 335: 80Crossref PubMed Scopus (487) Google Scholar A second study evaluated a combination probiotic containing both L casei and Lactobacillus acidophilus (Bio-K+; Bio-K Plus International, Laval, Quebec, Canada) in 255 patients. Patients given the higher dose of probiotic concurrent with antibiotics (and for 5 days afterward) had fewer occurrences of AAD (15.5% vs 44.1%).26Gao X.W. Mubasher M. Fang C.Y. et al.Dose-response efficacy of a proprietary probiotic formula of Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R for antibiotic-associated diarrhea and Clostridium difficile-associated diarrhea prophylaxis in adult patients.Am J Gastroenterol. 2010; 105: 1636-1641Crossref PubMed Scopus (238) Google Scholar As a secondary end point, both of these studies also showed a reduction in development of CDAD (discussed below). C difficile–associated diarrhea is a common nosocomial and community-based medical condition. Typically linked to antibiotic-induced disturbance of the intestinal microbiota, CDAD is now increasingly identified in patients without recent antibiotic exposure.27Kelly C.P. LaMont J.T. Clostridium difficile–more difficult than ever.N Engl J Med. 2008; 359: 1932-1940Crossref PubMed Scopus (1077) Google Scholar Antibiotic therapy with metronidazole, oral vancomycin, and now fidaxomicin make up the current treatment paradigm.28Lo Vecchio A. Zacur G.M. Clostridium difficile infection: an update on epidemiology, risk factors, and therapeutic options.Curr Opin Gastroenterol. 2012; 28: 1-9Crossref PubMed Scopus (147) Google Scholar Recurrence of CDAD remains a clinical problem. In 1994, a trial reported that S boulardii (500 mg twice a day) offered for 4 weeks after antibiotic therapy reduced overall CDAD recurrence rates.29McFarland L.V. Surawicz C.M. Greenberg R.N. et al.A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease.JAMA. 1994; 271: 1913-1918Crossref PubMed Scopus (750) Google Scholar However, the finding was only significant for those with a history of recurrent CDAD. A follow-up study, designed to be confirmatory, did not find S boulardii to significantly reduce CDAD recurrence after standard therapy.30Surawicz C.M. McFarland L.V. Greenberg R.N. et al.The search for a better treatment for recurrent Clostridium difficile disease: use of high-dose vancomycin combined with Saccharomyces boulardii.Clin Infect Dis. 2000; 31: 1012-1017Crossref PubMed Scopus (473) Google Scholar Though a favorable trend was found in patients treated with high-dose vancomycin (2 g/d) in the latter study, the clinical significance of this is less clear. Lactobacillus probiotics have been tested as single species and as combination probiotic products for preventing CDAD recurrence. While some results have been promising, most studies are underpowered, have methodological flaws, or have not been reproduced.31Na X. Kelly C. Probiotics in Clostridium difficile infection.J Clin Gastroenterol. 2011; 45: S154-S158Crossref PubMed Scopus (61) Google Scholar Probiotic-based primary prevention still may be an approach to the current scourge of C difficile. The 2 recent
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