1. Community Management of Possible Serious Newborn Infections: Simplified Antibiotic Regimens Bina Valsangkar, MD, MPH Saving Newborn Lives/Save the Children LAC Neonatal Alliance Annual Meeting September 23, 2014

2. Outline Background and rationale for simplified regimens Relevant pathogens Study design and methodology Preliminary results Programmatic implications

3. Background and Rationale Infection is a major contributor to neonatal mortality in developing countries Clinically-diagnosed sepsis rate is as high as 170/1000 in rural India (Bang, et. al.) Most deaths from neonatal sepsis occur at home, never coming to medical attention Current WHO recommendation for treating serious bacterial infection in infants <2 months: hospital admission and 10 days parenteral antibiotics

4. Background and Rationale Is there a safe way to provide neonatal sepsis management closer to home? Good evidence for community-based management of pneumonia already exists (Bang, Sazawal) Evidence for neonatal sepsis management, as part of greater home-based packages also exists SEARCH trial (India): 62% reduction in mortality w/ 7 days gent + cotrimoxazole Projahnmo trial (Bangladesh): 34% reduction in mortality w/ 7 days gent + procaine penicillin

5. Background and Rationale Global Consultation in 2007, convened by WHO, USAID, SNL Conclusions: Reasonable evidence of feasibility and impact of community-based sepsis management But, insufficient evidence of antibiotic regimens that would be feasible for weak health systems, acceptable to families, and effective in treating infections Recommendation: conduct robust research to evaluate simplified antibiotic regimens

6. Relevant Pathogens In Asia: Klebsiella (predominate) E. Coli Staph Aureus In Africa: Klebsiella E.Coli Staph Aureus GBS Strep pneumo Strep pyogenes

7. Study Design and Methodology Objective: To evaluate simpler antibiotic regimens for equivalence compared to the standard course of parenteral antibiotics for the empiric treatment of clinical severe infections in young infants whose families do not accept hospitalization.

8. Study Design and Methodology SATT= Simplified Antibiotic Therapy Trial AFRINEST= African Neonatal Sepsis Trial SATT – Bangladesh SATT – Pakistan AFRINEST DRC Kenya Nigeria Common study protocol

9. Study Design and Methodology Control arm (reference treatment) – A : IM Gent and Procaine Pen once daily for 7 days 14 injections Experimental arms – B: IM Gentamicin once daily and Oral Amoxicillin twice daily for 7 days 7 injections – C: IM Gentamicin and Procaine Penicillin once daily for 2 days, thereafter oral Amoxicillin twice daily for 5 days 4 injections – D: IM Gentamicin once daily and Oral Amoxicillin twice daily for 2 days, thereafter oral Amoxicillin twice daily for 5 days (AFRINEST only) 2 injections

10. Study Design and Methodology WHO IMNCI Case definitionSATT/AFRINEST inclusion criteria History of convulsions-- Respiratory rate > 60/min-- Severe chest indrawing Axillary temp >37.5Axillary temp > 38 Axillary temp <35.5 Movement only when stimulated, or none at all Movement only with stimulation Not feeding wellFeeding difficulty, confirmed by observation or poor suck

11. 11 Study Design and Methodology Randomization Infants were randomized to one of the antibiotic regimens using site and age- specific (<7 days or 7-59 days) computer- generated randomization sequences

12. Study Design and Methodology Treatment and Follow-up SATT: Study physicians provided injections at home Families were instructed to give evening doses of amox Enrolled infants visited for 7 days by study physician, assess for treatment failure AFRINEST Families brought infant to outpatient clinic for 7 days for treatment by study nurse Families gave evening dose of amox at home Outcome assessment by independent study nurse for “treatment failure” on days 4, 8, 11, and 15

13. Main Findings SATT-Bangladesh, SATT-Pakistan and AFRINEST Arms B (7 injections) and Arm C (4 injections) were equivalent to the reference regimen in each of the 3 trials Pooled analysis of all 3 studies found each of these simplified regimens to be equivalent to reference regimen AFRINEST only Arm D (2 injections) was equivalent to the reference regimen

14. Programmatic Implications Awaiting peer-reviewed publication and subsequent WHO guideline Some countries are proceeding with scale-up of community-based sepsis management prior to official guidance from WHO Ethiopia implementing Arm B Health extension workers to deliver treatment in the health post Families, with support from Health Development Army, self-refers for care