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

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

Brief background Introducing probiotics in Australia Regulatory 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 <1000 grams Morbidity cerebral palsy Expensive $100,000 to $250,000/NEC case USA $1 billion/year Bisquera JA, Pediatrics 2002 Neu NEJM 2011

Girish Deshpande, Shripada Rao, Sanjay Patole Lancet 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 25 Mortality 0.47 0.30-0.73 p<0.00001 20 Sepsis 0.94 0.74-1.20 p=0.80

Conclusive meta analysis Updated Meta-analysis of Probiotics for Preventing Necrotizing Enterocolitis in Preterm Neonates Girish Deshpande, Shripada Rao, Sanjay Patole and Max Bulsara Pediatrics published online Apr 19, 2010; DOI: 10.1542/peds.2009-1301

Results (11 trials n=2176) Outcome RR 95% CI p values Definite NEC 0.35 0.23-0.55 p<0.00001 Mortality 0.42 0.29-0.62 p<0.00001 Sepsis 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 NEC to 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 drugs Special Access Scheme (SAS Category A or Category B) Clinical trials (CTN or CTX) Authorised prescriber pathway

Stepwise approach at Nepean 1. Develop evidence based guidelines to use routine probiotics 2. 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, Australia 6. 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 assessment Microbiology 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) 0/61 6/65 (9.2%) 0.02 BW<1000g 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 In Australia and New Zealand : probiotics in preterm neonates standard practice Scope: Asia pacific, Europe Nepean model and protocol Deshpande et al, Psanz 2013, submitted for publication

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