Dr Girish Deshpande, FRACP Senior Neonatologist, Department of NeonatologyNepean Hospital Sydney Senior Lecturer, University of Sydney

Brief background Introducing probiotics in AustraliaRegulatory approach towards unregistered drugs (probiotics)

Process followed by Nepean Hospital Sydney, to introduce probiotics in tertiary institute

Necrotising enterocolitis (NEC) Commonest GI emergency of unknown cause

Incidence 5-6% in <32 weeks & VLBW 9-10% in <28 weeks

Mortality  (20-40%), higher in <1000grams

Morbidity – cerebral palsy Expensive

$100,000 to $250,000/NEC case

USA – $1 billion/yearBisquera JA, Pediatrics 2002Neu NEJM 2011

Girish Deshpande, Shripada Rao, Sanjay PatoleLancet 2007, Pediatrics 2010, AJCN 2014

7 trials, n=1393

Outcome RR 95% CI p‐values NNT

Definite NEC 0.36 0.20-0.65 p<0.00001 25Mortality 0.47 0.30-0.73 p<0.00001 20Sepsis 0.94 0.74-1.20 p=0.80

DOI: 10.1542/peds.2009-1301 published online Apr 19, 2010; Pediatrics

Girish Deshpande, Shripada Rao, Sanjay Patole and Max Bulsara Preterm Neonates

Updated Meta-analysis of Probiotics for Preventing Necrotizing Enterocolitis in

Conclusive meta‐analysis

Results (11 trials n=2176)Outcome RR 95% CI p‐values

Definite NEC 0.35 0.23-0.55 p<0.00001Mortality 0.42 0.29-0.62 p<0.00001Sepsis 0.98 0.81-1.10 p=0.80

Trial sequential analysis

Conclusion (Pediatrics 2010) It is unlikely that ongoing RCTs will change the results of meta‐analysis

“Probiotics should be offered routinely provided safe and effective product is available”

A RCT of 2000 neonates and a baseline incidence of 8% would have to show a doubling of the incidence of NECto overturn the benefits shown in the trials completed to date. Such a reversal of effects has never been demonstrated in clinical medicine.

Barrington KJ, Arch Dis Child Educ Pract Ed 2011

Which Probiotic? 

Probiotic sepsis in neonates

Broughton et al. Neonatal meningitis due to lactobacillus. Pediatr Infect Dis. 1983

Perapoch et al. Fungemia with Saccharomyces cerevisiae in two newborns. Eur J Clin Microbiol Infect Dis. 2000

Thompson et al. Lactobacillus acidophilus sepsis in a neonate. J Perinatol. 2001

Kunz et al. Two cases of lactobacillus bacteremia during probiotic treatment of short gut syndrome. JPGN 2004

Land et al. Lactobacillus sepsis associated with probiotic therapy. Pediatrics 2005

Probiotics regulation in Australia Food supplement   vs. drug

FSANZ                    vs.        TGA (equivalent to FDA)

Status of probiotic as food or drugs is not clear in Australia

Intent to use: Pharmaceutical or food supplement Prevention of NEC – classified as drug Currently there are no registered drug quality probiotics in Australia and many other countries

Access to unregistered drugsSpecial Access Scheme (SAS Category A or Category B)Clinical trials (CTN or CTX)Authorised prescriber pathway

Stepwise approach at Nepean1. Develop evidence based guidelines to use routine 

probiotics2. Identifying a suitable probiotic product 3. Approval of selected probiotic product (overseas)  from 

local area drug and therapeutics committee. 4. Endorsement from local Ethics Committee and prepare 

parent information sheet 5. Authorised Prescriber application to TGA, Australia6. Approval from authorities regarding importing probiotic 

product from overseas 7. Independent quality assessment of the product 8. Develop the practical protocol for routine use 9. Perform prospective audit after introducing routine 

probiotics for prevention of NEC and monitor safety

Evidence based guidelines

Deshpande et al, BMC Medicine 2011:92

Independent quality assessmentMicrobiology and University laboratory FAO/WHO 2001, (G Reid, Sanders ME), GMP guidelines of Australia and Italy

Taxonomy confirmation of strains (Infloran: lactobacillus acidophilus and bifidobacterium bifidum)

Colony count, rule out contaminants (fungus, gram negatives)

Sterility certificate from manufacturer Antibiotic sensitivity (Penicillin MIC:2 ugram/mL)

QA for every new batch of probiotic supplement 

Ongoing progress Probiotics n=146(Jan 2012-Jan 2014)

Controls n=142 (Jan 2010-Dec 2011)

p-value

NEC (≥Stage II) 1 (0.06%) 8 (5.5%) 0.01

NEC (≥Stage II)BW<1000g

0/61 6/65 (9.2%) 0.02

LOS - Proven 16 (10.8%) 34 (23.6%) 0.004

Death (>7days) 4 5 0.49

TFF 150ml/kg* 13.7(6.3) (n=129) 16.43(8.62) (n=124) -2.73 days p=0.02

Deshpande et al, Psanz 2013, submitted for publication

• In Australia and New Zealand : probiotics in preterm neonates standard practice

• Scope: Asia –pacific, Europe Nepean model and protocol 

First baby in Australia to receive routine probiotics Born at 26 weeks and birth weight 620 grams