Reestablishing exclusive breastfeeding is the cornerstone of the 2013 World Health Organization (WHO) treatment guidelines for acute malnutrition in infants less than 6 months. However, no studies have investigated guideline implementation and subsequent outcomes in a public hospital setting in Africa. To facilitate implementation of the WHO 2013 guidelines in Kilifi County Hospital, Kenya, we developed standard operating procedure, recruited, and trained three breastfeeding peer supporters (BFPS). Between September 2016 and January 2018, the BFPS provided individual breastfeeding support to mothers of infants aged 4 weeks to 4 months admitted to Kilifi County Hospital with an illness and acute malnutrition (midupper-arm circumference < 11.0 cm OR weight-for-age z score < −2 OR weightfor-length z score < -2). Infants were followed daily while in hospital then every 2 weeks for 6 weeks after discharge with data collected on breastfeeding, infant growth, morbidity, and mortality. Of 106 infants with acute malnutrition at admission, 51 met the inclusion criteria for the study. Most enrolled mothers had multiple breastfeeding challenges, which were predominantly technique based. Exclusive breastfeeding was 55% at admission and 81% at discharge; at discharge 67% of infants had attained a weight velocity of >5 g/kg/day for three consecutive days on breastmilk alone. Gains in weight-for-length z score and weight-for-age z score were generally not sustained beyond 2 weeks after discharge. BFPS operated effectively in an inpatient setting, applying the 2013 updated WHO guidelines and increasing rates of exclusive breastfeeding at discharge. However, lack of continued increase in anthropometric Z scores after discharge suggests the need for more sustained interventions.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Background Fosfomycin has the potential to be re-purposed as part of a combination therapy to treat neonatal sepsis where resistance to current standard of care (SOC) is common. Limited data exist on neonatal fosfomycin pharmacokinetics and estimates of bioavailability and CSF/plasma ratio in this vulnerable population are lacking. Objectives To generate data informing the appropriate dosing of IV and oral fosfomycin in neonates using a population pharmacokinetic analysis of plasma and CSF data. Methods The NeoFosfo study (NCT03453177) was a randomized trial that examined the safety and pharmacokinetics of fosfomycin comparing SOC versus SOC plus fosfomycin. Sixty-one neonates received fosfomycin (100 mg/kg IV q12h for 48 h) and then they converted to oral therapy at the same dose. Two plasma pharmacokinetic samples were taken following the first IV and oral doses, sample times were randomized to cover the whole pharmacokinetic profile and opportunistic CSF pharmacokinetic samples were collected. A population pharmacokinetic model was developed in NONMEM and simulations were performed. Results In total, 238 plasma and 15 CSF concentrations were collected. A two-compartment disposition model, with an additional CSF compartment and first-order absorption, best described the data. Bioavailability was estimated as 0.48 (95% CI = 0.347–0.775) and the CSF/plasma ratio as 0.32 (95% CI = 0.272–0.409). Allometric weight and postmenstrual age (PMA) scaling was applied; additional covariates included postnatal age (PNA) on clearance and CSF protein on CSF/plasma ratio. Conclusions Through this analysis a population pharmacokinetic model has been developed that can be used alongside currently available pharmacodynamic targets to select a neonatal fosfomycin dose based on an infant’s PMA, PNA and weight.
ObjectiveTo assess pharmacokinetics and changes to sodium levels in addition to adverse events (AEs) associated with fosfomycin among neonates with clinical sepsis.DesignA single-centre open-label randomised controlled trial.SettingKilifi County Hospital, Kenya.Patients120 neonates aged ≤28 days admitted being treated with standard-of-care (SOC) antibiotics for sepsis: ampicillin and gentamicin between March 2018 and February 2019.InterventionWe randomly assigned half the participants to receive additional intravenous then oral fosfomycin at 100 mg/kg two times per day for up to 7 days (SOC-F) and followed up for 28 days.Main outcome(s) and measure(s)Serum sodium, AEs and fosfomycin pharmacokinetics.Results61 and 59 infants aged 0–23 days were assigned to SOC-F and SOC, respectively. There was no evidence of impact of fosfomycin on serum sodium or gastrointestinal side effects. We observed 35 AEs among 25 SOC-F participants and 50 AEs among 34 SOC participants during 1560 and 1565 infant-days observation, respectively (2.2 vs 3.2 events/100 infant-days; incidence rate difference −0.95 events/100 infant-days (95% CI −2.1 to 0.20)). Four SOC-F and 3 SOC participants died. From 238 pharmacokinetic samples, modelling suggests an intravenous dose of 150 mg/kg two times per day is required for pharmacodynamic target attainment in most children, reduced to 100 mg/kg two times per day in neonates aged <7 days or weighing <1500 g.Conclusion and relevanceFosfomycin offers potential as an affordable regimen with a simple dosing schedule for neonatal sepsis. Further research on its safety is needed in larger cohorts of hospitalised neonates, including very preterm neonates or those critically ill. Resistance suppression would only be achieved for the most sensitive of organisms so fosfomycin is recommended to be used in combination with another antimicrobial.Trial registration numberNCT03453177.
Infants and young children with severe acute malnutrition (SAM) are treated with empiric broad‐spectrum antimicrobials. Parenteral ceftriaxone is currently a second‐line agent for invasive infection. Oral metronidazole principally targets small intestinal bacterial overgrowth. Children with SAM may have altered drug absorption, distribution, metabolism, and elimination. Population pharmacokinetics of ceftriaxone and metronidazole were studied, with the aim of recommending optimal dosing. Eighty‐one patients with SAM (aged 2–45 months) provided 234 postdose pharmacokinetic samples for total ceftriaxone, metronidazole, and hydroxymetronidazole. Ceftriaxone protein binding was also measured in 190 of these samples. A three‐compartment model adequately described free ceftriaxone, with a Michaelis–Menten model for concentration and albumin‐dependent protein binding. A one‐compartment model was used for both metronidazole and hydroxymetronidazole, with only 1% of hydroxymetronidazole predicted to be formed during first‐pass. Simulations showed 80 mg/kg once daily of ceftriaxone and 12.5 mg/kg twice daily of metronidazole were sufficient to reach therapeutic targets.
Background: Far less is known about the reasons for hospitalization or mortality during and after hospitalization among school-aged children than among under-fives in low- and middle-income countries. This study aimed to describe common types of illness causing hospitalisation; inpatient mortality and post-discharge mortality among school-age children at Kilifi County Hospital (KCH), Kenya. Methods: A retrospective cohort study of children 5−12 years old admitted at KCH, 2007 to 2016, and resident within the Kilifi Health Demographic Surveillance System (KHDSS). Children discharged alive were followed up for one year by quarterly census. Outcomes were inpatient and one-year post-discharge mortality. Results: We included 3,907 admissions among 3,196 children with a median age of 7 years 8 months (IQR 74−116 months). Severe anaemia (792, 20%), malaria (749, 19%), sickle cell disease (408, 10%), trauma (408, 10%), and severe pneumonia (340, 8.7%) were the commonest reasons for admission. Comorbidities included 623 (16%) with severe wasting, 386 (10%) with severe stunting, 90 (2.3%) with oedematous malnutrition and 194 (5.0%) with HIV infection. 132 (3.4%) children died during hospitalisation. Inpatient death was associated with signs of disease severity, age, bacteraemia, HIV infection and severe stunting. After discharge, 89/2,997 (3.0%) children died within one year during 2,853 child-years observed (31.2 deaths [95%CI, 25.3−38.4] per 1,000 child-years). 63/89 (71%) of post-discharge deaths occurred within three months and 45% of deaths occurred outside hospital. Post-discharge mortality was positively associated with weak pulse, tachypnoea, severe anaemia, HIV infection and severe wasting and negatively associated with malaria. Conclusions: Reasons for admissions are markedly different from those reported in under-fives. There was significant post-discharge mortality, suggesting hospitalisation is a marker of risk in this population. Our findings inform guideline development to include risk stratification, targeted post-discharge care and facilitate access to healthcare to improve survival in the early months post-discharge in school-aged children.
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