Pharmacy and Poisons Board: Applications

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Protocol No:

ECCT/15/10/04

Date of Protocol:

27-08-2015

Study Title:	Azithromycin (AZM) to prevent post-discharge morbidity and mortality in Kenyan children
Study Objectives:	OBJECTIVES Overall objective: To establish the burden, risk factors, and potential sharing of antibiotic resistance determinants in bacterial isolates from children recently discharged from hospital. Specifically, we aim to: Objective 1: Establish the burden of clinically and epidemiologically important molecular markers of ESBL (bla_CTX-M,bla_TEM, bla_SHV, bla_OXA,ampC) and macrolide (mef(A), erm(B), erm(C), mph(A)) resistance in commensal E. coli from children at hospital discharge and in a subset of their caregivers. Hypothesis: At hospital discharge, children and their caregivers will have a high prevalence of ESBL as determined by presence of any one of the molecular markers mentioned. Macrolide resistance, as determined by presence of mef(A), erm(B), erm(C), or mph(A) will be less common. Caregivers of children with ESBL and macrolide resistance genes in commensal E. coli will be more likely to have similar resistance gene patterns in their own commensal E. coli. Objective 2: Determine host, clinical, and environmental correlates of molecular markers of ESBL and macrolide resistance in commensal E. coli from children at hospital discharge. Hypothesis: Shared correlates of ESBL and macrolide resistance in commensal E. coli of discharged children will include age less than 1-year, malnutrition, and 4-day or longer hospital stay. β-lactam and macrolide use during the hospital stay will be associated with ESBL and macrolide resistance, respectively, in E. coli. Objective 3: Determine the concordance of molecular markers of ESBL and macrolide resistance in commensal E. coli to those in Salmonella or Shigella isolated from the same child. Hypothesis: Among children and caregivers with E. coli and either Salmonella or Shigella isolated from stool samples, resistance patterns in E. coli will be at least 80% concordant to resistance patterns in either Salmonella or Shigella.
Laymans Summary:	Deaths in children have been decreasing worldwide, due in part to the use of antibiotics for illnesses caused by common bacteria. However, bacteria are increasingly becoming resistant to antibiotics, which heightens the risk of treatment failure and death. In order to inform antibiotic prescribing policy it is necessary to know the types of antibiotic resistance in bacteria present in individuals. Due to the spread of resistance between close contacts it is also important to understand the genetic mechanisms of resistance in order to better interpret how bacteria are acquiring resistance. Information on the presence of antibacterial resistance is lacking in Sub-Saharan Africa and is non-existent in children who have previously been hospitalized, a group with a high risk of death in the months following hospitalization. We plan to examine bacteria previously isolated from the stool of recently hospitalized children for genes that suggest resistance to antibiotics used to treat common illnesses in Africa. We will compare the likelihood of resistance in groups of children defined by age, nutritional status, and length of hospital stay to better understand which children are at highest risk and should be targeted for interventions to prevent antibiotic resistance. We will also compare resistance genes between caregivers and children and between bacteria within the same stool sample. This information will help to understand how antibiotic resistance is transmitted between and within individuals
Abstract of Study:	An estimated 3.5 million deaths occur annually in children less than 5 years of age in sub-Saharan Africa, approximately 70% of which are due to infectious causes. One-year mortality rates as high as 15% have been documented following hospital discharge in sub-Saharan Africa, a rate that is 8-fold higher than non-hospitalized children. Children being discharged from hospital in Africa may represent an accessible high-risk population in which to target interventions to reduce mortality. A recent trial of mass drug administration of azithromycin reduced childhood mortality by half among children in Ethiopia in communities receiving the intervention. However, concerns about the potential for the emergence of antimicrobial resistance, possible toxicity, and the feasibility of delivery are all barriers to community-wide distribution of antibiotics. We propose a randomized, double-blind, placebo-controlled trial of a 5-day course of azithromycin in children age 1 to 59 months discharged from Kisii Teaching and Homabay county Referral hospitals in Western Kenya to reduce post-discharge re-hospitalizations and mortality, to explore possible mechanisms by which azithromycin has benefit and risk, and to identify correlates and intermediate markers of re-hospitalization and death in the post-discharge period. The proposed study will examine a pragmatic post-discharge intervention that could be used in low resource settings to lower mortality and re-hospitalization rates in high-risk children. In addition the trial will also explore a number of scientific questions including the effect of antibiotics on enteric and nasopharyngeal infections, inflammation, and the causes of post-discharge mortality. Kisii and Homabay counties are the ideal areas in Western Kenya to test this intervention because the child mortality rate is high in Nyanza province yet the health facilities in which this study will be conducted have established pediatric research infrastructure.