A life inside: probiotics in practice Probiotics in acute ... · ESPEN Congress Leipzig 2013 A life inside: probiotics in practice Probiotics in acute diarrhoea: friends or foe? S.

ESPEN Congress Leipzig 2013

A life inside: probiotics in practice

Probiotics in acute diarrhoea: friends or foe?

S. Kolacek (HR)

Sanja Kolaček

FRIENDS or FOE ??

IN ACUTE DIARRHOEA

PROBIOTICS

Children’s Hospital Zagreb

aims To discuss

Role in treatment of acute diarrhoea

GUT flora & Probiotics Basic facts

Role in prevention of acute diarrhoea: - Nosocomial / health related

- Antibiotic associated / Clostridium difficile - Traveller’s diarrhoea

Probiotics Safety issues

GUT flora: basic facts

Surface of 250 - 400 m2

One line of epithelial cells separates inside from outside

> 1000 different species

MacDonald TT et al. Regulation of homeostasis and inflammation in the Intestine. Gastroenterology 2011

Bacteria in GUT >eukaryotic cells

70% of immune cells located in GUT to: - tolerate commensal & harmless antigens (food)

- destroy pathogen without excesive inflammation - to maintain physiologic inflammation without autoimmune or malignant alteration

>150 x quantitity of genes

Firmicutes Bacteroides

Kelly et al. Immunological Review, 2012

Immunomodulatory

role of GUT flora

Anti-infectious

Trophic and metabolic

Vael C, et al. Importance of development of intestinal microflora. Curr Opin Pediatr 2009; Thomas FW, et al. Probiotics and prebiotics in pediatrics. Pediatrics 2010;126

of gastrointestinal microflora

Live microorganisms which, when administred in adequate amounts, confer a health benefit on the host

SYNBIOTIC

Therapeutic methods for modification

PROBIOTIC

Thomas DW et al. Clinical report of Committee on Nutrition – Probiotics and Prebiotics

In pediatrics. Pediatrics 2010;126

POSTBIOTIC

PREBIOTIC Nondigestible food ingredient that benefits host by stimulating growth of indigenous probiotic bacteria

Product that contains both, probiotics and prebiotics

Metabolic byproduct generated by probiotic microorganism that influences host’s biological functions

a successfull probiotic How to become

Human origin

Confers clinically proven health benefit

Viable & active through entire shell life, adequate dose preserved 109-1010 CFU

Geneticaly stable strain, identified after FAO/WHO/SCF

FAP/WHO 2002; SCF-EC2004; Agostoni C et al. ESPGHAN Position Paper JPGN 2004 Zuccotti GV, et al. Probiotics in clinical practice. J Inter Med Research 2008;36(Suppl1):1-53

Resistant to low gastric pH, bile, enzymes & antibiotics

Survives GIT passage, colonizes colon mucosa

Reliable safety profile in respect to: - genetic stability - transfer of antibiotic resistance - invasiveness

ROLE OF PROBIOTICS IN THE TREATMENT OF ACUTE

DIARRHOEA

Developing countries

- highest incidence (> 6x/y in a child)

- accounts for 1.78 million deaths (3.7% of total deaths)

most in children ≤ 5y

Is diarrhoea still a burden ?

Developed countries - still cause of hospitalization

- costs of health care

- work absentism of diseased adults / parents

- increased incidence & severity of CDAD

Anti-infective role of probiotics

Hickson, et al. Ther Adv Gastroenterol 2011;4:185-197

Author Population Strain Effect

Szajewska (2001) Children Different 18.2 hours; 95% CI 9.5-26.9

Van Niel (2002) Children Lactobacilli 0.7 days; 95% CI 0.3-1.2

Szajewska (2007) Children LGG 1.1 days; 95% CI 0.3-1.9

Chmielewska (2008)

Children Lactobacillus reuteri

22 hours; 95% CI 6 -38

Szajewska (2009) Children S. boulardii 1.08 days ; 95% CI 0.53-1.64

Allen (2010) Children + adults

Different 24.8 hours; 95% CI 15.9-33.6

Dinleyici (2012) Children S. boulardii 0.99 days 95% CI 0.58-1.4

Probiotics in treatment of acute diarrhoea: disease duration

2001 - 2012: 7 meta-analysis

• Objective: to assess effects of probiotics in acute infectious diarrhoea • Data: 63 trials (56 in infants & children)

8014 participants 46 tested a single strain

RESULTS • Duration of diarrhoea: 24.76 h shorter ( 95%CI 15.9-33.6)

• Diarrhoea ≥ 4 days: RR 0.41 (0.32 – 0.53)

• Adverse effects reported in 43/63: NO adverse effects

AUTHOR’S CONCLUSION: EFFECTIVE & SAFE

PROBIOTICS: Dose-effect

Van Niel et al. Pediatrics 2002

Role of probiotics in treatment of acute diarrhoea: CONCLUSIONS

Dose related: better if >1010 CFU

Effective: shorten diarrhoea

diarrhoea less severe

Work better in watery (viral)

diarrhoea & if initiated early

Strain related: S. boulardii, LGG

however!!

Guarino et al. J Pediatr Gastroenterol Nutr. 2008;46:619-21.

Probiotics in PREVENTION of acute diarrhoea

Nosocomial diarrhoea

Traveller’s diarrhoea

Antibiotic associated

Clostridium difficile prevention & treat.

Nosocomial infection – incidence

Acute care hospitals – 5 to 10% of hospitalized patients

– 90,000 deaths/year (5th leading cause of mort.)

– 25% in ICU

– add extra $5 billion/year to cost of patient care

– risk of acquiring infection 2–20x higher in developing countries

Chen et al. Infect Control Hosp Epidemiol. 2009;30:39–46.

Sydnor et al. Clin Microbiol Rev. 2011 Jan;24(1):141-73.

Nosocomial infections: how common in PICU and pediatric wards??

Rutledge-Taylor et al. Am J Infect Control. 2011

Probiotics in prevention of nosocomial diarrhoea

- 4 in acute care centres - 2 in hospitals for prolonged care

- 3 used LGG - 3 used other probiotics

6 RANDOMIZED CONTROLLED TRIALS -RCT

TYPE OF FACILITY

LGG studies: meta analysis

Szajewska et al. Aliment Pharmacol Ther 2011; 34: 1079–1087.

Role of probiotics in prevention of nosocomial diarrhoea: CONCLUSIONS

PROMISING in prevention of

nosocomial diarrhoea (LGG)

Work best in ACUTE hospital

setting but with PROLONGED

in-hospital stay

ROLE OF PROBIOTICS IN PREVENTION OF

ANTIBIOTIC ASSOCIATED DIARRHOEA (ADD) & CDAD

• Oral broad spectrum antibiotics:

- clindamycin - beta-lactams - amoxicillin - cephalosporines • Very young / very old

• ProIonged antibiotic use

• Hospitalization

• Previous AAD

Risk factors for AAD Clinical data & epidemiology • Incidence: 5% - 40% of

patients

• Mostly mild course

• In hospitalized old& young immunocomp. patients:

- toxic megacolon

- bowel preforation

- death

Antibiotic associated diarrhoea - AAD

Butler et al. BMJ. 2012;344:e682.

Prevention of AAD: META-ANALYSES

Author (year) Population Results

Cremonini (2002) Childern+adults RR 0.40; 95% CI 0.28-0.57

D'Souza (2002) Childern+adults OR 0.37; 95% CI 0.26-0.53

Szajewska (2006) Children RR 0.44; 95% CI 0.25-0.77

McFarland (2006) Childern+adults RR 0.43; 95% CI 0.31-0.58

Sazawal (2006) Childern+adults RR 0.48; 95% CI 0.35-0.65

Johnston (2006) Children RR 0.43; 95% CI 0.25-0.75

Johnston (2007) Children RR 0.43; 95% CI 0.25-0.75

Johnston (2011) Cildren RR 0.52; 95%CI 0.38-0.72

Videlock (2012) Childern+adults RR 0.53; 95% CI 0.44-0.63

Hempel (2012) Childern+adults RR 0.58; 95% CI 0.50-0.68

16 trials

RR = 0.55

95% CI 0.38-0.80

Children

16 trials

RR = 0.54

95% CI 0.34-0.85

Antibiotic associated diarrhoea - AAD

3 trials

RR = 0.81

95% CI 0.40-1.63

Adults Elderly

Hempel et al. JAMA 2012;307:1959-69.

Prevention of AAD – single strain meta-analysis

Author (year) Population Strain Results

Kale-Pradhan (2010)

Childern+ adults

Lactobacillus RR 0.35; 95% CI 0.19-0.67

McFarland (2010) Adults Saccharomyces boulardii

RR 0.47; 95% CI 0.35-0.63

Szajewska (2005) Childern+ adults

Saccharomyces boulardii

RR 0.43; 95% CI 0.23-0.78

Hempel (2012) Children + adults

Saccharomyces boulardii

RR 0.48; 95% CI 0.35-0.65

Hempel (2012) Children + adults

Lactobacillus

RR 0.64; 95% CI 0.47-0.86

J Clin Gastroenterol 2011;45:S168–S171

AAD is mostly mild, self-limited

condition!! WHEN TO PREVENT??

Risk factors for severe disease: - very young / elderly

- hospitalized & chronically ill

- caused by Clostridium difficile

Probiotic in prevention of AAD

Serious problem: more virulent strains

resistant, 10% mortality

recurrence 10%-30%

Increased costs: 3.6 d longer in hospital

3.669 USD / day

Clostridium diff associated diarrhoea - CDAD

Common: 10%-30% of AAD

> 300 000 hospitalized/y in USA

Risk factors: old, hospitalized,

on antibiotics, immunocompromised

Cartman ST. Intern Med Microb 2010; Friedman G. Gastroenterol Clin N Am 2012

Probiotics in prevention of Clostridium difficile associated diarrhoea – meta-analyses

Author (year) Population Strain Results

Avadhani A (2010)

Hospitalized adults

different RR 0.29; 95% CI 0.18-0.46

Johnson BC (2012)

Children & adults

Lactobacillus Saccharomyces boulardii

RR 0.34; 95% CI 0.24-0.49

Hempel S (2012)

Children & adults

different RR 0.29; 95% CI 0.17-0.48

Probiotics in prevention of Clostridium difficile Adverse effects, meta-analysis in Johnson 2012

Probiotics in prevention of AAD & CDAD CONCLUSIONS

Effective !!!

Saccharomyces, Lactobacillus

most commonly studied

To be used in patients when severe course is anticipated: - Hospitalized , sick, very young/very old, recurrent ADD

- In Clostridium difficile associated diarrhoea

- However, patients often immunocompromised

→ SAFETY ISSUES

ROLE OF PROBIOTICS IN PREVENTION OF

TRAVELER’S DIARRHOEA

> 100 million travelers / year

10%-15% travel into high risk areas tropical/subtropical Latin America

the Caribbean, South Asia, Africa

TRAVELER’S DIARRHOEA - A PROBLEM ??

Up to 40 million cases / year

de la Cabada Bauche et al. Gastroenterol Hepatol (N Y) 2011;7:88-95

McFarland LV. Meta-analysis of probiotics for prevention of traveler’s diarrhoea. Travel Med Infec Dis 2007

Du Pont HL et al. Review of evidence base for prevention of traveler’s diarrhoea. J Travel Med 2009

PROBIOTICS

SAFETY ISSUES

Probiotics as a foe??

Potential mechanisms ??

Infective dissemination

Transfer of antibiotic resistance

Transfer of genetic material

Long term saftey issues

Bacterial translocation

Probiotics as a cause of adverse effects Hempel S et al. Agency for Healthcare & Quality Report on Safety of Probiotics to

Reduce Risk and Prevent or Treat Disease . AHRQ 2011

11,981 publications identified 622 included in the review: - 235 with broad non-specific satefy statements - 387 reported on specific adverse events - 24,615 participants used probiotic product

- Lactobacillus - Bifidobacterium - Saccharomyces - Streptococcus - Enterococcus - Bacillus

AIM TO ASSES SAFETY OF 6 PROBIOTIC GENERA

METHODOLOGY & SEARCH RESULTS

Probiotics as a cause of adverse effects Hempel S et al. Agency for Healthcare & Quality Report on Safety of

Probiotics to Reduce Risk and Prevent or Treat Disease . AHRQ 2011

- Not increased in short-term studies (RR 0.98) - Common GIT complaints NOT more prevalent (RR 0.03) - No effect of dose, timing, mode of administration & age, gender and immunological status of participants - No increase in hospitalization & duration of hospit. - NO increase in patients on steroids, immunosupressants,

antibiotics...

Probiotics as a cause of adverse effects Hempel S et al. Agency for Healthcare & Quality Report on Safety of Probiotics to Reduce Risk and Prevent or Treat Disease . AHRQ 2011

Probiotics as a cause of adverse effects Hempel S et al. Agency for Healthcare & Quality Report on Safety of Probiotics to Reduce Risk and Prevent or Treat Disease . AHRQ 2011

Probiotics as a cause of adverse effects Hempel S et al. Agency for Healthcare & Quality Report on Safety of Probiotics to Reduce Risk and Prevent or Treat Disease . AHRQ 2011

- Lack of assessment & systematic reporting - Very few studies with adverse effects as

primary outcome

- Current evidence not equipped to answer specific questions on safety

HOWEVER

Safety of probiotics in severly ill Whelan K et al. Safety of probiotics in patients receiving nutritional support: a systematic review of case reports, RCTs & nonRCTs. Am J Clin Nutr 2010

3/40 studies: increased complication rate in probiotic group none was infection with probiotics 1. Children after liver transplantation (fistule, biliary stenosis)

2. Propatria study: increased mortality (bowel ishaemia)

3. Preterms in NICU: increased rate of sepsis (any cause!)

1. Preterms in NICU 2. Children in ICU 3. Adults in ICU → NO increase in adverse effects

SAFETY TRIALS: 3 STUDIES

NON-SAFETY RANDOMIZED TRIALS: N=40

Safety of probiotics in severly ill Whelan K et al. Safety of probiotics in patients receiving nutritional support: a systematic review of case reports, RCTs & nonRCTs. Am J Clin Nutr 2010

CASE REPORTS: 32 1. Infection with Saccharomyces boulardii 27/32

2. Infection with Lactobacillus genera 5/32

SAFETY OF PROBIOTICS Hojsak I, Shamir R. In Guarino A... Probiotic bacteria... Basel, Karger 2013, Vol 107

- All together 45 episodes - S. Boulardii & cerevisiae 27 - Lactobacillus 13 (Lactobacillus GG, acidophilus, casei)

- Bacillus cereus 3 - Bifidobacterium 2

- All episodes were in severelly ill patients

PUBLISHED CASE REPORTS ON PROBIOTIC

STRAIN CAUSED SEPSIS

Probiotics as a foe??

Potential mechanisms ??

Infective dissemination: proven but

only in severly ill patients

Transfer of antibiotic resistance: possible, not documented in humans

Transfer of genetic material possible, particularly to designed „turbo”

probiotics, but never in vivo proven

Long term saftey issues important for use in infant formula - unknown

Current evidence does not indicate increased risk in not severly sick

PROBIOTICS AS A FOE: CONCLUSIONS

FDA grants GRAS status to Bidifobacteria & Lactobacillus

Probiotics could be very usefull in sick patients (prevention of CD infection) but special caution is required

When introducing probiotic strain: premarketing assessment & postmark. surveillance

RCT with adverse effects as primary outcome

THANK YOU

FOR YOUR

KIND

ATTENTION