A multi-country implementation research initiative to jump-start scale-up of outpatient management of possible serious bacterial infections (PSBI) when a referral is not feasible: Summary findings and implications for programs.

INTRODUCTION: Research on simplified antibiotic regimens for outpatient treatment of 'Possible Serious Bacterial Infection' (PSBI) and the subsequent World Health Organization (WHO) guidelines provide an opportunity to increase treatment coverage. This multi-country implementation research initiative aimed to learn how to implement the WHO guideline in diverse contexts. These experiences have been individually published; this overview paper provides a summary of results and lessons learned across sites. METHODS SUMMARY: A common mixed qualitative and quantitative methods protocol for implementation research was used in eleven sites in the Democratic Republic of Congo (Equateur province), Ethiopia (Tigray and Oromia regions), India (Haryana, Himachal Pradesh, Maharashtra, and Uttar Pradesh states), Malawi (Central Region), Nigeria (Kaduna and Oyo states), and Pakistan (Sindh province). Key steps in implementation research were: i) policy dialogue with the national government and key stakeholders, ii) the establishment of a 'Technical Support Unit' with the research team and district level managers, and iii) development of an implementation strategy and its refinement using an iterative process of implementation, programme learning and evaluation. RESULTS SUMMARY: All sites successfully developed and evaluated an implementation strategy to increase coverage of PSBI treatment. During the study period, a total of 6677 young infants from the study catchment area were identified and treated at health facilities in the study area as inpatients or outpatients among 88179 live births identified. The estimated coverage of PSBI treatment was 75.7% (95% CI 74.8% to 78.6%), assuming a 10% incidence of PSBI among all live births. The treatment coverage was variable, ranging from 53.3% in Lucknow, India to 97.3% in Ibadan, Nigeria. The coverage of inpatient treatment ranged from 1.9% in Zaria, Nigeria, to 33.9% in Tigray, Ethiopia. The outpatient treatment coverage ranged from 30.6% in Pune, India, to 93.6% in Zaria, Nigeria. Overall, the case fatality rate (CFR) was 14.6% (95% CI 11.5% to 18.2%) for 0-59-day old infants with critical illness, 1.9% (95% CI 1.5% to 2.4%) for 0-59-day old infants with clinical severe infection and 0.1% for fast breathing in 7-59 days old. Among infants treated as outpatients, CFR was 13.7% (95% CI 8.7% to 20.2%) for 0-59-day old infants with critical illness, 0.9% (95% CI 0.6% to 1.2%) for 0-59-day old infants with clinical severe infection, and 0.1% for infants 7-59 days old with fast breathing. CONCLUSION: Important lessons on how to conduct each step of implementation research, and the challenges and facilitators for implementation of PSBI management guideline in routine health systems are summarised and discussed. These lessons will be used to introduce and scale-up implementation in relevant Low- and middle-income countries.

High risk of early sub-therapeutic penicillin concentrations after intramuscular benzathine penicillin G injections in Ethiopian children and adults with rheumatic heart disease.

INTRODUCTION: Intramuscular benzathine penicillin G (BPG) injections are a cornerstone of secondary prophylaxis to prevent acute rheumatic fever (ARF) and rheumatic heart disease (RHD). Uncertainties regarding inter-ethnic and preparation variability, and target exposure profiles of BPG injection are key knowledge gaps for RHD control. METHODS: To evaluate BPG pharmacokinetics (PK) in patients receiving 4-weekly doses in Ethiopia, we conducted a prospective cohort study of ARF/RHD patients attending cardiology outpatient clinics. Serum samples were collected weekly for one month after injection and assayed with a liquid chromatography-mass spectroscopy assay. Concentration-time datasets for BPG were analyzed by nonlinear mixed effects modelling using NONMEM. RESULTS: A total of 190 penicillin concentration samples from 74 patients were included in the final PK model. The median age, weight, BMI was 21 years, 47 kg and 18 kg/m2, respectively. When compared with estimates derived from Indigenous Australian patients, the estimate for median (95% confidence interval) volume of distribution (V/F) was lower (54.8 [43.9-66.3] l.70kg-1) whilst the absorption half-life (t1/2-abs2) was longer (12.0 [8.75-17.7] days). The median (IQR) percentage of time where the concentrations remained above 20 ng/mL and 10 ng/mL within the 28-day treatment cycle was 42.5% (27.5-60) and 73% (58.5-99), respectively. CONCLUSIONS: The majority of Ethiopian patients receiving BPG as secondary prophylaxis to prevent RHD do not attain target concentrations for more than two weeks during each 4-weekly injection cycle, highlighting the limitations of current BPG strategies. Between-population variation, together with PK differences between different preparations may be important considerations for ARF/RHD control programs.

Innovative approach for potential scale-up to jump-start simplified management of sick young infants with possible serious bacterial infection when a referral is not feasible: Findings from implementation research.

BACKGROUND: Neonatal bacterial infections are a common cause of death, which can be managed well with inpatient treatment. Unfortunately, many families in low resource settings do not accept referral to a hospital. The World Health Organization (WHO) developed a guideline for management of young infants up to 2 months of age with possible serious bacterial infection (PSBI) when referral is not feasible. Government of Ethiopia with WHO evaluated the feasibility of implementing this guideline to increase coverage of treatment. OBJECTIVE: The objective of this study was to implement a simplified antibiotic regimen (2 days gentamicin injection and 7 days oral amoxicillin) for management of sick young infants with PSBI in a programme setting when referral was not feasible to identify at least 80% of PSBI cases, achieve an overall adequate treatment coverage of at least 80% and document the challenges and opportunities for implementation at the community level in two districts in Tigray, Ethiopia. METHODS: Using implementation research, we applied the PSBI guideline in a programme setting from January 2016 to August 2017 in Raya Alamata and Raya Azebo Woredas (districts) in Southern Tigray, Ethiopia with a population of 260884. Policy dialogue was held with decision-makers, programme implementers and stakeholders at federal, regional and district levels, and a Technical Support Unit (TSU) was established. Health Extension Workers (HEWs) working at the health posts and supervisors working at the health centres were trained in WHO guideline to manage sick young infants when referral was not feasible. Communities were sensitized towards appropriate home care. RESULTS: We identified 854 young infants with any sign of PSBI in the study population of 7857 live births. The expected live births during the study period were 9821. Assuming 10% of neonates will have any sign of PSBI within the first 2 months of life (n = 982), the coverage of appropriate treatment of PSBI cases in our study area was 87% (854/982). Of the 854 sick young infants, 333 (39%) were taken directly to a hospital and 521 (61%) were identified by HEW at health posts. Of the 521 young infants, 27 (5.2%) had signs of critical illness, 181 (34.7%) had signs of clinical severe infection, whereas 313 (60.1%) young infants 7-59 days of age had only fast breathing pneumonia. All young infants with critical illness accepted referral to a hospital, while 117/181 (64.6%) infants with clinical severe infection accepted referral. Families of 64 (35.3%) infants with clinical severe infection refused referral and were treated at the health post with injectable gentamicin for 2 days plus oral amoxicillin for 7 days. All 64 completed recommended gentamicin doses and 63/64 (98%) completed recommended amoxicillin doses. Of 313 young infants, 7-59 days with pneumonia who were treated by the HEWs without referral with oral amoxicillin for 7 days, 310 (99%) received all 14 doses. No deaths were reported among those treated on an outpatient basis at health posts. But 35/477 (7%) deaths occurred among young infants treated at hospital. CONCLUSIONS: When referral is not feasible, young infants with PSBI can be managed appropriately at health posts by HEWs in the existing health system in Ethiopia with high coverage, low treatment failure and a low case fatality rate. Moreover, fast breathing pneumonia in infants 7-59 days of age can be successfully treated at the health post without referral. Relatively higher mortality in sick young infants at the referral level health facilities warrants further investigation.