PROBIOTICS Are we ON or OFF the bandwagon?

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1 Disclosure PROBIOTICS Are we ON or OFF the bandwagon? We have no conflicts of interest to disclose for this presentation Presented by: Ivy Chow BSc(Pharm), ACPR, PharmD Gloria Su BSc(Pharm), ACPR CSHP AGM Nov 2013 Learning Objectives To explain when probiotics are used To review the benefits and risks of using probiotics in the setting of AAD/CDI/VAP Outline Background Evidence AAD/CDI/Critical Care Risk of Probiotics Summary/Application to Practice Conclusions What are Probiotics? Live microbial supplements that beneficially affect the host by improving microbial flora balance Multiple mechanisms of action Restore intestinal microbial flora balance Enhance immune responses (immunomodulation) Antimicrobial activity inhibiting bacterial growth [ ph] Intestinal barrier protection interfering with binding of toxins/pathogen adhesion Types of Probiotics Bacterial Lactobacillus (acidophilus, casei, rhamnosus) Bifidus regularis Bifidobacterium Streptococcus salivaris/thermophilus Yeast Saccharomyces boulardii # of probiotics evaluated in the literature Katz JA. J Clin Gastroenterol 2006; 40: McFarland. Am J Gastroenterol 2006; 101; Parkes GC et al. Lancet Infect Dis 2009; 9:

2 Why take Probiotics? Application of Probiotics Benefits to human health Added to various foods (i.e., Yogurt) Potential application in prevention & treatment of various health conditions & diseases Acute infectious diarrhea in children Prevention of necrotizing entercolitis in very low birth weight children Prevention of atopic dermatitis in children Prevention of relapse for ulcerative colitis Prevention of ventilator associated pneumonia (VAP) Prevents antibiotic associated diarrhea (AAD) Prevents recurrent C. difficile infections (CDI) Other Applications Focus of this Presentation Treatment of the common cold Reducing cholesterol levels Treating obesity/weight loss Treatment/prevention of yeast infections Prevention of urinary tract infections Use of Probiotics in: Prevention of Antibiotic Associated Diarrhea (AAD) Prevention, Treatment and Recurrence of CDI Prevention of Ventilator Associated Pneumonia (VAP) Something to Consider? Use of probiotics with antibiotics/antifungals seems counterintuitive Inactivate the preventative agent? Is this the case for bacterial probiotics while on antibiotics? Is this the case for yeast probiotics while on antifungals? Probiotics for the Prevention of Antibiotic Associated Diarrhea Does this mean one probiotic strain is better depending on the clinical scenario? What does the Evidence Suggest? Would spacing make a difference? 2

3 Evidence AAD Objective Inclusion Results To evaluate the evidence for probiotic use in the prevention and treatment of AAD RCTs of probiotics for the prevention or treatment of AAD 82 RCTs included [63 trials in meta-analysis] - RR = 0.58 [95% CI ] Lactobacillus alone N=17 AAD RR 0.64 (95% CI ) Sacchromyces N=15 RR 0.48 (95% CI ) Hempel S et al. JAMA 2012; 307: Hempel S et al. JAMA 2012; 307: Evidence - AAD Prevention of AAD Conclusions Largest systematic review/meta-analysis 42% lower risk of developing AAD when given probiotics NNT=13 Limitations: Significant heterogeneity Lactobacillus Saccharomyces Unanswered Questions More studies are needed to determine: Which strain is associated with the greatest efficacy? Which patient population? Which specific concomitant antibiotic therapy? The exact duration of therapy? The exact dose of probiotics to be used? Hempel S et al. JAMA 2012; 307: Hempel S et al. JAMA 2012; 307: Which Probiotics in AAD? If I had to choose the probiotic to use to prevent AAD: Saccharomyces boulardii mg po BID for adults Duration Taken during and for up to 2 weeks after antibiotics Probiotics for the Prevention of Clostridium Difficile Infection What does the Evidence Suggest? Hempel S et al. JAMA 2012; 307:

4 CDI Why focus on CDI? In Canada, the # of cases and deaths associated with CDI has increased National Incidence Rate: 6.5 cases per 10,000 patient-days in 2009 BC Incidence Rate: 4.7 cases per 10,000 patient-days in 2007 Mortality Rate 1.5% in % in 2005 Public Health Agency of Canada 2013 Canadian Nosocomial Infection Surveillance Program CDI How would probiotics help? Pathogenesis of CDI Antibiotic Therapy Alteration of Colonic Microflora C. Difficile Exposure & Colonization Release of Toxins Colonic Mucosal Injury & Inflammation Probiotics Probiotics CDI Guidelines (IDSA 2010) Administration of currently available probiotics is NOT recommended to prevent primary Clostridium difficle infection, as there is limited data to support this approach and there is potential risk of bloodstream infection (C-III) Cohen SH et al. Infect Control Hospital Epidemiol 2010; 31: Johnston BC et al. Ann Intern Med 2012; 157: Evidence Prevention of CDI Results Objective Inclusion Efficacy/Safety of probiotics for the prevention of CDAD Studies comparing any dose/strain probiotic to placebo or no treatment in adults/children receiving antibiotic treatment Outcomes 1. CDAD with a positive CDT Results 2. Adverse events 20 RCTs [n=3818] -3 were pediatrics RCTs Johnston BC et al. Ann Intern Med 2012; 157: Johnston BC et al. Ann Intern Med 2012; 157:

5 Results Incidence of CDAD Adverse Events Probiotics Control RRR (95%CI) 2% 5.9% 66% (51 to 76) 10.6% 12.9% 18% (-5 to 35) NNT 26 NS Conclusion: In adults or children receiving antibiotic treatment, probiotics reduces CDAD without an increase in clinically significant ADEs Johnston BC et al. Ann Intern Med 2012; 157: Goldenberg JZ et al. Cochrane Database Syst Rev May 31;5:CD Evidence Prevention of CDI Results - Efficacy Objective Inclusion To assess efficacy & safety of probiotics for preventing CDAD in adults/pediatrics Studies comparing any dose/strain probiotic to placebo, alternative prophylaxis or no treatment in adults/children for prevention of CDAD Outcomes 1. Primary: Incidence of CDAD Results 2. Secondary: incidence of CDI, adverse events, AAD, length of hospital stay 31 RCTs [4492 patients] Goldenberg JZ et al. Cochrane Database Syst Rev May 31;5:CD Goldenberg JZ et al. Cochrane Database Syst Rev May 31;5:CD Results - Safety Conclusion: Moderate-quality evidence suggest that probiotics are both safe and effective for preventing Clostridium difficle-associated diarrhea. Goldenberg JZ et al. Cochrane Database Syst Rev May 31;5:CD Allen SJ et al. Lancet 2013 Epub Aug 8 5

6 Evidence Prevention of CDI Results Objective Design Inclusion Intervention Efficacy/Safety of probiotics for the prevention of CDAD MC, R, DB, PC 65 yo inpatients exposed to one or more oral or parenteral antibiotics Multi-strain preparation of lactobacilli & bifidobacteria 6 x organisms/day x 21 days vs placebo Outcomes 1. Occurrence of AAD within 8 weeks 2. Occurrence of CDAD within 12 weeks Results Conclusions 2941 patients 1470 pts [probiotic]; 1471 pts [placebo] AAD: 10.8% [probiotic] vs 10.4% [placebo] p=0.72 CDAD: 0.8% [probiotic] vs 1.2% [placebo] p=0.35 Multi-strain preparation of lactobacilli & bifidobacteria was ineffective in the prevention of AAD or CDAD Allen SJ et al. Lancet 2013 Epub Aug 8 Allen SJ et al. Lancet 2013 Epub Aug 8 Addition of Allen s study to MA Limitations of Meta-Analyses Does it make sense to pool various strains of probiotics? Heterogeneity Primary outcome of many of the trials included was not CDAD/CDI Secondary endpoint Methodological flaws with the studies Lack of power/small sample size Studies driving the results external validity? Daneman N. Lancet 2013 Epub Aug 8 Evidence Prevention of CDI LACTOBACILLUS SACCHAROMYCES Johnson S et al. Int J Infect Dis. 2012; 16:e Johnson S et al. Int J Infect Dis. 2012; 16:e

7 Prevention of CDI Bottom Line Which Probiotics in CDI Prevention? Moderate to weak quality evidence supporting the use of probiotics in the prevention of CDAD/CDI Unanswered Questions Which strain of probiotic to use? Single strain vs. Multiple strains Yeast vs. bacterial What is the appropriate dosing? What is the optimal duration of therapy? If I had to choose the probiotic to use to prevent CDI: Lactobacilli combination product Lactobacillus acidophilus & Lactobacillus casei Dose: 10 x CFU/day Duration Taken during and for up to 1 week after antibiotics Evidence Treatment of CDI No trials found investigating probiotics as the sole treatment of CDI Probiotics for the Treatment of Clostridium Difficile Infection Reviews/Meta-analyses looking at probiotics for treatment of CDI in conjunction with antibiotics What does the Evidence Suggest? Evidence Treatment of CDI Objective Inclusion Outcomes Results To assess efficacy of probiotics in the treatment C. difficle colitis Studies comparing probiotics as an adjunct to conventional antibiotics for treatment of recurrence or initial episode of CDI in adults Resolution of diarrhea/negative CDT 4 RCTs included One study showed benefit for treatment relapse but no benefit in the other studies Pillai A et al. Cochrane Database Syst Rev Jan 23;(1):CD Pillai A et al. Cochrane Database Syst Rev Jan 23;(1):CD

8 Treatment of CDI Bottom Line Insufficient evidence to recommend probiotics as adjunct therapy to antibiotics for CDI No evidence to support use of probiotics alone in the treatment of CDI Probiotics for the Prevention of Recurrent Clostridium Difficile Infection What does the Evidence Suggest? Evidence Recurrence of CDI Evidence CDI Recurrence Recurrence affects 20-30% of patients Despite successful appropriate initial treatment 8 studies have investigated probiotic use as secondary prevention against CDI recurrence Only 2 studies showed a benefit Probiotic: Saccharomyces boulardii The other 6 studies were limited by it s small sample size [underpowered] Study N Intervention Results McFarland et al. (1994) Recurrent or initial CDI Surawicz et al. (2000) Recurrent CDI 124 S. boulardii 500 mg BID vs. Placebo x 4 weeks [+ varied doses of vanco or metronidazole] 168 S. boulardii 500 mg BID vs. Placebo x 4 weeks [+ Vanco 2 g or 500 mg/day or Metro 1 g/day x 10 days] Recurrence: 26.3% (15/57) probiotic 44.8% (30/67) placebo p< 0.05 ARR: 18.5%; NNT: 5 Recurrence: Only high dose vancomycin dose saw a difference (p< 0.05) 16.7% (3/18) probiotic 50% (7/14) placebo ARR: 33.3%; NNT: 3 Recurrence of CDI Bottom Line Which Probiotics in Recurrent CDI? Moderate to Weak Quality Evidence For S. boulardii in treating recurrent CDI in conjunction with appropriate antibiotic treatment of CDI More studies required for other probiotics If I had to choose the probiotic to use to prevent recurrent CDI: Saccharomyces boulardii 500 mg po BID PLUS appropriate antibiotics for CDI treatment Duration 4 weeks Hempel S et al. JAMA 2012; 307:

9 Summary of Evidence VAP Prevention of AAD Strength of evidence: MODERATE for S. boulardii Prevention of CDI Strength of evidence: MODERATE to WEAK for Lactobacilli combination product [L. casei & L. acidophilus] Treatment of CDI No evidence to support efficacy of probiotics in treatment of CDI Recurrence of CDI Strength of evidence: MODERATE to WEAK for S. boulardii Pathogenesis: Healthcare devices, environment, transfer of microorganisms between patients/healthcare workers Aspiration of oropharyngeal pathogens, leakage of secretions around endotracheal tube Infected biofilm of endotracheal tube Reservoirs in stomach and sinuses Am J Respir Crit Care Med 2005;171: VAP Primary endogenous Pathogens carried in oral cavity, throat, stomach, intestines on admission to ICU Treated or prevented with short course systemic antibiotics Secondary endogenous Pathogens absent on admission to ICU, acquired during stay Theory: not possible if colonization prevented, loss of anaerobic intestinal flora hypothesized to increase colonization and infection with facultative aerobic bacteria Probiotics and VAP? Theoretical mechanism of action: Delays time to colonization of pathogenic bacteria Will not eliminate pathogenic organism from causing infection Administration along with prebiotics will promote survival of probiotics and stimulate endogenous flora Am J Respir Crit Care Med 2005;171: Crit Care 2011;15:R18-R27 Crit Care 2011;15:R18-R27 CHEST 2007;132(1): Probiotics and VAP? Theoretical benefits: Restore normal GI flora, prevent colonization of pathogenic bacteria Prevents VAP IDSA Guidelines - VAP Modulation of colonization: oral antiseptics and antibiotics Routine SDD with oral antibiotics +/- systemic antibiotics not recommended, especially in patients possibly colonized with highly resistant organisms Routine SOD with chlorhexidine not recommended until more data becomes available No mention of probiotics Update in progress Crit Care 2011;15:R18-R27 CHEST 2007;132(1): Am J Respir Crit Care Med 2005;171:

10 Probiotics and VAP? Numerous small RCTs looking at: Incidence of hospital acquired pneumonia Incidence of ventilator associated pneumonia Length of ICU/hospital stay Mortality rates in the ICU/hospital admission Varying results, different doses/durations of probiotics!!! Crit Care Med 2010;38(3): Siempos et al. Siempos et al. Inclusion RCTs in adult population Mechanical ventilation reporting on VAP Probiotics with or without prebiotics Exclusion Abstracts Outcomes other than VAP Pneumonia in critically ill patients with no mention of VAP Probiotics in both arms Assessed quality of RCTs utilizing JADAD scoring system (range 0-5) 3 trials with JADAD score > 3 No RCTs utilizing saccharomyces boulardii Crit Care Med 2010;38(3): Crit Care Med 2010;38(3): Evidence Prevention of VAP Evidence Prevention of VAP Crit Care Med 2010;38(3): Crit Care Med 2010;38(3):

11 Evidence Prevention of VAP Crit Care Med 2010;38(3): CHEST 2012;142(4): Gu et al. Gu et al. Inclusion Adult undergoing mechanical ventilation Probiotics compared with control VAP specifically defined Data on incidence of VAP available Exclusion Unclear definition of pneumonia/vap Median JADAD score = 4 No saccharomyces boulardii used in RCT Not used in search terms CHEST 2012;142(4): CHEST 2012;142(4): Evidence Prevention of VAP CHEST 2012;142(4): Crit Care Med 2012;40(12):

12 Petrof et al. Petrof et al. Inclusion RCT Probiotics compared to placebo Critically ill adult High baseline mortality rate 5% Exclusion Pseudo-randomization Multiple interventions, effect of probiotic cannot be clearly elicited Data in abstract form Probiotics administered IV or as oral swabs 23 trials included in systematic review 15 enrolled critically ill ICU patients 7 reporting on VAP Only 3 RCTs utilized saccharomyces boulardii Mean methodological score was 9.5 (range 6-13) Maximum possible was 14; good quality 10 Crit Care Med 2012;40(12): Crit Care Med 2012;40(12): Evidence Prevention of VAP Evidence Prevention of VAP Crit Care Med 2012;40(12): Crit Care Med 2013;41(3):e28-29 Evidence Prevention of VAP Probiotics and VAP Study Probiotic Dose Route Duration Knight 2009 Synbiotic 2000 FORTE CFU BID NG/OG 28 days after ICU admission/ ICU discharge Forestier 2008 Lactobacillus casei, rhamnosus 10 9 CFU BID NG/oral ICU discharge Klarin 2008 Lactobacillus plantarum CFU BID Oral mucosa ICU discharge Spindler-Vesel 2007 Synbiotic 2000 FORTE CFU OD NG/OG ICU discharge Kotzampassi 2006 Synbiotic 2000 FORTE CFU OD NG/OG 15 days/icu discharge Giamarellos- Bourboulis 2009 Synbiotic 2000 FORTE CFU OD NG/ Gastrotomy Barraud 2010 Ergyphilus 2 * CFU OD NG 28 days 15 days after admission Crit Care Med 2013;41(3):e28-29 Morrow 2010 Oudhuis 2011 Lactobacillus rhamnosus GG Lactobacillus plantarum 299/99 2 * 10 9 CFU BID NG and oropharynx Until extubation 5 * 10 9 CFU BID NG ICU discharge/removal of tube Besselink 2008 Ecologic CFU BID NJ/oral 28 days Tan 2011 Bifidobacterium, Total CFU OD NG 21 days lactobacillus, streptococcus Crit Care Med 2010;38(3): Crit Care Med 2012;40(12): CHEST 2012;142:

13 Probiotics and VAP Next Steps Study Probiotic Dose Route Duration Knight 2009 Synbiotic 2000 FORTE CFU BID NG/OG 28 days after ICU admission/ ICU discharge Forestier 2008 Lactobacillus casei, rhamnosus 10 9 CFU BID NG/oral ICU discharge Klarin 2008 Lactobacillus plantarum CFU BID Oral mucosa ICU discharge Spindler-Vesel 2007 Synbiotic 2000 FORTE CFU OD NG/OG ICU discharge Kotzampassi 2006 Synbiotic 2000 FORTE CFU OD NG/OG 15 days/icu discharge Giamarellos- Bourboulis 2009 Synbiotic 2000 FORTE CFU OD NG/ Gastrotomy Barraud 2010 Ergyphilus 2 * CFU OD NG 28 days Morrow 2010 Oudhuis 2011 Lactobacillus rhamnosus GG Lactobacillus plantarum 299/99 2 * 10 9 CFU BID NG and oropharynx 15 days after admission Until extubation 5 * 10 9 CFU BID NG ICU discharge/removal of tube Besselink 2008 Ecologic CFU BID NJ/oral 28 days Tan 2011 Bifidobacterium, Total CFU OD NG 21 days lactobacillus, streptococcus Crit Care Med 2010;38(3): Crit Care Med 2012;40(12): CHEST 2012;142: Many questions still unanswered One route better than the other? NG/OG vs. oral swabs Which strain or combination product? Quantity over quality? Duration of therapy While ventilated vs. duration of ICU stay Safety of probiotics in immunocompromised? Larger multi-centered trials powered to assess dose, length of treatment, and mortality Summary of Evidence Safety Concerns Prevention of VAP Strength of evidence: WEAK for Synbiotic 2000 FORTE or multiple strain product If I had to choose a probiotic to prevent VAP: Lactobacillus combination product CFU NG/OG once to twice per day Infection Reports of bacteremia/fungemia [Rare] Immunocompromised Severely ill Critical care [patients with indwelling catheters (CVCs)] % of infective endocarditis and bacteremia due to lactobacillus and bifidobacterium Have rates increased due to increased consumption? Clin Infect Dis 2003;36: Safety Concerns Safety Concerns Systematic review for patients receiving probiotics with nutritional support: 20 case reports (32 patients with bacteremia or fungemia) Lactobacillus rhamnosus GG or saccharomyces boulardii as causative organism Possible risk factors: on antibiotics, peripheral/central venous catheter, bacterial translocation, immune suppression 53 trials (4131 patients) 3 trials showed increase in complications (transplant and pancreatitis population) Am J Clin Nutr 2010;91: Multiple case reports of S. boulardii fungemia in ICU In both patients administered the probiotic and neighbouring patients Catheters removed, but never cultured Attributed to bedside preparation of the solution Given S. boulardii for previously indicated situation Contraindication for S. boulardii in patients with indwelling catheters (CVCs) Caution in the ICU setting Intensive Care Med 2002;28: J Clin Microbiol 2003;41:

14 Safety Concerns Safety Concerns Treatment of lactobacillus bacteremia Penicillin or clindamycin ± gentamicin Treatment of saccharomyces fungemia Fluconazole, voriconazole, micafungin, amphotericin B Majority treated successfully with fluconazole or amphotericin B in one review 37 cases in total of saccharomyces boulardii fungemia, unclear whether result of probiotic intake Which subset of immunocompromised patients? mortality seen when used in severe acute pancreatitis Lactobacillus/bifidobacterium combination product at organisms/day Safely used in post-liver transplant recipients Synbiotic BID OG/PO + prebiotics Sanfords Antimicrobial Therapy 2012 Clin Infect Dis 2005;41: Lancet 2008;371: Am J Transplant 2005;5: Safety Concerns Conclusions Intestinal bacterial translocation Altered intestinal permeability Antibiotic resistance of probiotic strains Product integrity Not regulated [dietary supplement] Lack of standardization Probiotics have been shown to decrease AAD Probiotics possibly can decrease the incidence of CDI and recurrent CDI but many limitations Need to weigh the risk versus benefits Choose the appropriate strain of probiotic & the appropriate dose of probiotic Need more quality studies to confirm the role of probiotics in the prevention of CDI (primary episode & recurrence) Conclusions Questions Use of probiotics for VAP is still unclear Trend towards benefit in reducing the incidence of VAP, but many limitations Strain, dose, how to administer Need larger studies focusing on VAP Risk versus benefit in immunocompromised patients unclear Caution in severely immunocompromised, critically ill patients, patients with acute pancreatitis & patients with CVCs 14

15 References References McFarland LV. Systematic review and meta-analysis of Saccharomyces boulardii in adult patients. World J Gastroenterol 2010; 16: Surawicz CM, McFarland LV, Greenberg RN 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: McFarland LV, Surawicz CM, Greenberg RN et al. A randomized placebocontrolled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA 1994; 271: Parkes GC, Sanderson JD, Whelan K. The mechanisms and efficacy of probiotics in the prevention of clostridium difficle-associated diarrhoea. Lancet Infect Dis 2009; 9: McFarland LV. Evidence-based review of probiotics for antibioticassociated diarrhea and Clostridium difficile infections. Anaerobe 2009; 15: D Souza AL, Rajkumar C, Cooke J, Bulpitt CJ. 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CMAJ 2004; 171:51-8. Gravel D, Miller M, Simor A et al. Health care-associated clostridium difficle infection in adults admitted to acute care hospitals in Canada: a Canadian Nosocomial Infection Surveillance Program Study. Clin Infect Dis 2009; 48: Sazawal S, Hiremath G, Dhingra U et al. Efficacy of probiotics in prevention of acute diarrhoea: a meta-analysis of masked, randomised, placebo-controlled trials. Lancet Infect Dis 2006; 6: Dendukuri N, Costa V, McGregor M, Brophy JM. Probiotic therapy for the prevention and treatment of Clostridium difficile-associated diarrhea: a systematic review. CMAJ 2005; 173: Scheike I, Connock M, Taylor R et al. Probiotics for the prevention of antibiotic associated diarrhea: a systematic review. DPHE 2006; 56. Pillai A, Nelson R. Probiotics for treatment of Clostridium difficleassociated colitis in adults. Cochran Database Syst Rev. 2008; CD Cohen SH, Gerding DN, Johnson S et al. Clinical practice guidelines for Clostridium difficle infection in adults: 201o update by the SHEA and IDSA. Infect Control Hosp Epidemiol 2010; 31: Johnson S, Maziade PJ, McFarland LV et al. Is primary prevention of Clostridium difficile infection possible with specific probiotics? Int J Infect Dis 2012; e786-e792 Goldenberg JZ, Ma SS, Saxton JD et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev May 31;5:CD Johnston BC, Ma SSY, Goldenberg JZ et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea. Ann Intern Med 2012; 157: Hempel S, Newberry SJ, Maher AR et al. Probiotics for the prevention fna treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. JAMA 2012; 307: References References Daneman N. A probiotic trial: tipping the balance of evidence? Lancet 2013; Epub Aug 8 Allen SJ, Wareham K, Wang D et al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarhoea and Clostridium difficle diarrheoa in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled multicentre trial. Lancet 2013 Epub Aug 8 Gao XW, Mubasher M, Fang CY 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: Schultz MJ, Haas LE. Antibiotics or probiotics as preventive measures against ventilator-associated pneumonia: a literature review. Crit Care 2011; 15:R Cassone M, Serra P, Mondello F et al. Outbreak of Saccharomyces cerevisiae subtype boulardii fungemia in patients neighbouring those treated with a probiotic preparation of the organism. J Clin Micobiol 2003;41: Isakow W, Morrow LE, Kollef MH. Probiotics for preventing and treating nosocomial infections. CHEST 2007;132: Siempos II, Ntaidou TK, Falagas ME. Impact of administration of probiotics on the incidence of ventilator-associated pneumonia: a meta-analysis of randomized controlled trials. Crit Care Med 2010;38: Gu WJ, Wei CY, Yin RX. Lack of efficacy of probiotics in preventing ventilator-associated pneumonia. CHEST 2012;142: Petrof EO, Dhaliwal R, Manzanares W et al. Probiotics in the critically ill: a systematic review of the randomized trial evidence. Crit Care Med 2012;40:

16 References Heyland DK, Dhaliwal R. Online letters to the editor. Crit Care Med 2013;41(3):e28-29 Borriello SP, Hammes WP, Holzapfel W et al. Safety of probiotics that contain lactobacilli or bifidobacteria. Clin Infect Dis 2003;36: Enache-Angoulvant A, Hennequin C. Invasive saccharomyces infection: a comprehensive review. Clin Infect Dis 2005;41: Whelan K, Myers CE. Safety of probiotics in patients receiving nutritional support: a systematic review of case reports, randomized controlled trials, and nonrandomized trials. Am J Clin Nutr 2010;91: Lherm T, Monet C, Nougiere B et al. Seven cases of fungemia with Saccharomyces boulardii in critically ill patients. Intensive Care Med 2002;28: