1. Every day. In times of crisis. For our future. Stephen Wall, MD, SM, MSW, FAAP Saving Newborn Lives/Save the Children BNF, Dhaka, November 28, 2015 Simplified antibiotics for newborn infection when hospitalization is not possible

2. Causes of Newborn Deaths 2

3. Possible Severe Bacterial Infections * (PSBI): Estimates Incidence ~ 6.7% of newborns Overall CFR – 9.8% Estimated annual deaths due to PSBI > 600,000 3 PSBI defined as presence of any one of the following: history of difficulty feeding, history of convulsions, movement only when stimulated, respiratory rate > 60, severe chest in-drawing, and a temperature >37.5 or < 35.5 Source: Seale et al. Lancet Inf Dis 2014: 14: 731-41

4. WHO Guidelines For newborns and young infants (0-59 days) with signs of serious bacterial infection, WHO recommends 7-10 days of gentamicin + penicillin or ampicillin in hospital 4

5. IMCI Chart Booklet – first level facility For newborns and young infants 0-59 days with signs of PSBI, give pre-referral dose of gentamicin and ampicillin, then refer to hospital. If referral not possible, treat for 5 days with gentamicin and ampicillin 5

6. Hospitalization is frequently not possible In low resource settings, hospitalization may not be possible for 80-90% of newborns with PSBI 6 Hospital not available/accessible Family cannot accept hospitalization Plus, outpatient IMCI treatment not available or acceptable

7. Home-based treatment Evidence from research studies - community-based packages included home-based treatment of sepsis – Bang (India): 62% NMR reduction – Baqui (Bangladesh): 34% NMR reduction MINI (Nepal): feasibility and acceptability of community-based management of newborn infections 2007 Global Newborn Sepsis Consultation – Expert recommendations – Insufficient evidence for program scale up of home-based treatment – Research to identify effective alternative simplified regimens (combinations of injectable and oral)

8. SATT & AFRINEST Three separate trials (Bangladesh; Pakistan; combined study in DRC, Kenya, and Nigeria) - common protocol with same/similar – inclusion/exclusion criteria – intervention and controls – same outcomes Purpose of common protocol - to provide clear and robust evidence to enable rapid WHO policy change based on this new evidence Supported by BMGF and USAID 8

9. SATT & AFRINEST Objectives To evaluate if simpler antibiotic regimens are equivalent to a ‘standard course’ of parenteral antibiotics for treatment of possible serious bacterial infections in young infants whose families do not accept hospitalization.

10. Treatment regimens Control arm (reference treatment) – A : IM Gent and Procaine Pen once daily for 7 days 14 injections Experimental arms for clinical severe infections – B: IM Gent once daily and oral Amox twice daily for 7 days 7 injections – C: IM Gent and Procaine Pen once daily for 2 days, thereafter oral Amox twice daily for 5 days 4 injections – D: IM Gent once daily and oral Amox twice daily for 2 days, thereafter oral Amox twice daily for 5 days (AFRINEST only) 2 injections Experimental arms for isolated rapid breathing – E: Oral amoxicillin twice daily for 7 days (AFRINEST only) 0 injections

11. Inclusion and Exclusion Criteria Clinical Severe Infection Fever (temp ≥38 0 C) Hypothermia (temp≤35.5 0 C) Lethargy (movement only with stimulation) Severe chest indrawing Poor feeding Isolated Rapid Breathing RR > 60 bpm Hospitalization not accepted Exclusion Criteria: Signs of critical illness Vomiting or unable to take oral medication Weight <1500 grams

12. Primary Outcome: Treatment Failure Death Hospitalization Deterioration No improvement after 4 days of antibiotics Re-emergence of clinical signs Severe adverse reaction

13. Main Findings: Clinical Severe Infection SATT-Bangladesh, SATT-Pakistan and AFRINEST – Arms B (7 injections) and Arm C (4 injections) were equivalent to the reference regimen AFRINEST – Arm D (2 injections) was equivalent to the reference regimen

14. Main Findings: Isolated Rapid Breathing AFRINEST – Arm E (7 days of oral amoxillin) was equivalent to the reference regimen

15. New WHO Recommendations Simplified antibiotics for outpatient treatment of newborn sepsis when hopsitalization is not possible or accepted by the family 15

16. Fast breathing* Recommendation Strength of recommendation Quality of Evidence Young infants 7-59 days old with fast breathing as the only sign of illness should be treated with oral amoxicillin, 50 mg/kg per dose twice daily for 7 days, by an appropriately trained health worker. Strong Moderate Infants 0-6 days with fast breathing as the only sign of illness should be referred to hospital. If referral is not accepted, they should also be treated with oral amoxicillin, 50 mg/kg per dose twice daily for 7 days, by an appropriately trained health worker. Strong Moderate *Fast breathing 60 or more breaths per minutes

17. Clinical Severe Infection* Recommendation Strength of recommendation Quality of Evidence Young infants 0-59 days old with clinical severe infection whose families do not accept or cannot access hospital care should be managed in outpatient settings by an appropriately trained health worker with one of the following regimens: Option 1: IM gentamicin 5-7.5 mg/kg once daily for 7 days and twice daily oral amoxicillin, 50 mg/kg per dose for 7 days. Close follow up is essential. Option 2: IM gentamicin 5-7.5 mg/kg once daily for 2 days and twice daily oral amoxicillin, 50 mg/kg per dose for 7 days. Close follow up is essential. A careful assessment on day 4 is mandatory. Strong Strong Moderate Low *Stopped feeding well, movement only when stimulated, severe chest in-drawing, Temperature ≥ 38.0 o C or <35.5 o C

18. Critical Illness* Recommendation Strength of recommendation Quality of Evidence Young infants 0-59 days old who have any sign of critical illness (at presentation or developed during treatment of clinical severe infection) should be hospitalized after pre- referral treatment. Strong (Current standard) * unconscious, convulsions, inability to feed, inability to cry, apnoea, cyanosis, bulging fontanel, persistent vomiting, suspicion of meningitis

19. Implementation – pilot and learning before scale up Priority learning agenda: – Coverage ‘Demand’ Utilization of services – Feasibility within existing health systems – Acceptability to families and health workers – How to provide health systems requirements and quality of care Health worker performance Supervision & monitoring Supply & logistics management Adherence by families to recommended treatment and follow up 19

20. Country implementation research - 1 Bangladesh – Comprehensive Newborn Care Package in existing GoB health systems – New policy: 2-injection gentamicin regimen at union level where hospitalization not feasible Oral amoxicillin for isolated rapid breathing given by trained health worker – Implementation support by SNL (Kushtia district) and Mamomi Health Systems Strengthening project – Evaluation and learning partners: icddr,b and Johns Hopkins University 20

21. Country implementation research - 2 Ethiopia: 7-injection regimen by Health Extension Workers being scaled up Implementation research in two districts re: 2-injection regimen (WHO TSU) Nigeria: Implementation research in two states re: 2-injection regimen (WHO TSU) India: Implementation research in Bihar (7-injection regimen by ANM and PHCs) by IFHI project WHO TSU sites (TBD) Other implementation research (2-injection regimen) sites: DRC, Malawi, Nepal, Pakistan, and possibly Uganda 21

22. Global Actions Global ‘core PSBI group’ - WHO, UNICEF, BMGF, USAID, MCSP, SNL – Implementation guidelines and FAQs – Amox and gent PK review and new simplified dosing weight bands (eg, 3 simple weight bands: 1.5 kg – 6 kg) – Common implementation MLE framework – WHO/UNICEF Joint Statement (including partners and key professional societies) 22

23. Important considerations - AMR – Question: Will increased use of antibiotics ‘at community level’ increase AMR? – Positives: Increased use of appropriate and timely antibiotics will save many newborn lives Simplified regimen at 1 st level facility may help rationalize use of gent (instead of 3 rd generation cephalosporin as first line agent, esp by private practitioners)? Use of Arm D (2 doses of gent) instead of Arm B (7 doses of gent) Increase use of appropriate antibiotics for newborn PSBI is minor contributor to AMR (eg, compared to widespread use of antibiotics in animal feeds) Global interest in setting up regional surveillance sites (including community) 23

24. Important considerations - 2 Ototoxicity of gentamicin – Arm D provides only 2 doses of gentamicin, compared to Arm B – Use of ‘extended-interval’ gentamicin – New pharmacokinetic data Follow up check – a health system requirement for Arm D – Need follow up check on Day 4 Check for deterioration, no improvement, new danger signs Emphasize and facilitate referral for signs of treatment failure Care of critically ill newborn and young infant – how to influence quality of care at hospitals? What about ‘back referrals’ from hospitals? 24

25. Conclusions New evidence and new WHO recommendations now provide options for effective treatment of newborn infections when hospitalization is not possible or acceptable to families. Implementation research is needed and underway in a number of ‘early adopter’ countries including Bangladesh. Based on country and global learning from implementation research, programs should be adjusted as needed and implemented at scale to reduce preventable newborn deaths. 25

26. Thanks! Photo by Jason Tanner/Save the Children