Every day. In times of crisis. For our future.

Stephen Wall, MD, SM, MSW, FAAPSaving Newborn Lives/Save the Children

BNF, Dhaka, November 28, 2015

Simplified antibiotics for newborn infection when hospitalization is

not possible

Causes of Newborn Deaths

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Possible Severe Bacterial Infections* (PSBI): Estimates

• Incidence ~ 6.7% of newborns• Overall CFR – 9.8%• Estimated annual deaths due to PSBI > 600,000

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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

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

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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

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Hospitalization is frequently not possible • In low resource settings, hospitalization may not

be possible for 80-90% of newborns with PSBI

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• Hospital not available/accessible

• Family cannot accept hospitalization

• Plus, outpatient IMCI treatment not available or acceptable

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)

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

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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.

Treatment regimensControl 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

Inclusion and Exclusion Criteria

Clinical Severe Infection

• Fever (temp ≥380 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

Primary Outcome: Treatment Failure

DeathHospitalizationDeteriorationNo improvement after 4 days of antibioticsRe-emergence of clinical signsSevere adverse reaction

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

Main Findings: Isolated Rapid Breathing

• AFRINEST – Arm E (7 days of oral amoxillin) was

equivalent to the reference regimen

New WHO Recommendations

Simplified antibiotics for outpatient treatment of newborn sepsis when hopsitalization is not possible or accepted by the family

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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

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 oC or <35.5oC

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

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

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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

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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

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)

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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 1st level facility may help rationalize

use of gent (instead of 3rd 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)

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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

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.

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Thanks!Photo by Jason Tanner/Save the Children