Extended effect of short-course azithromycin for the treatment of diarrhoea in children on antimicrobial resistance in nasopharyngeal and intestinal bacteria: Study Protocol for the antimicrobial resistance sub-study of the multicountry AntiBiotics for Children with Diarrhea (ABCD) trial.

IntroductionAntimicrobial resistance (AMR) is a major public health challenge worldwide, threatening the important gains that have been made in reducing mortality due to infectious diseases. Despite current World Health Organization guidelines restricting antibiotics to a small subset of children with dysentery or suspected cholera, many children with diarrhea continue to be treated with antibiotics. We aim to determine the impact of a 3-day course of azithromycin on the risk of AMR at 90 and 180 days after treatment, among a subset of children and their household contacts enrolled into a multi-country, randomized, double-blind, placebo-controlled clinical trial of azithromycin children under 2 years with diarrhea in low income settings, Methods and analysisThe AntiBiotics for Children with Diarrhea (ABCD) trial is testing the efficacy of a 3-day course of azithromycin, compared to placebo, in reducing mortality and linear growth faltering in the subsequent 6 months among 11,500 children aged 2-23 months of age across multiple sites in Bangladesh, India, Kenya Malawi, Mali, Pakistan and Tanzania with diarrhea and one or more of the following; dehydration, severe stunting, or moderate wasting (https://clinicaltrials.gov/ct2/show/NCT03130114). A sub-set of enrolled children are randomly selected to participate in a sub-study of AMR. A fecal sample (stool or rectal swab) will be collected at baseline from all enrolled children. A fecal sample and a nasopharyngeal (NP) swab will be collected at day 90 and 180 after enrolment from participating children and a close household child contact. Escherichia coli and Streptococcus pneumoniae will be isolated and Minimum Inhibitory Concentration for azithromycin and other commonly used antibiotics will be determined and compared between trial arms. Ethics and disseminationThis study was reviewed by an independent ethical review committee. Dissemination of results is planned to local and international policy makers and the public. Registration details (Parent ABCD trial)https://clinicaltrials.gov/ct2/show/NCT03130114 Strengths and limitations of this study (3-5 points) This study will provide evidence from a randomized controlled trial regarding the risk of short term azithromycin use on resistance to azithromycin and selected commonly used antibiotics, 90 and 180 days after administration in treated children and their household contacts. Few RCTs of antibiotics for diarrhoea have provided such long-term follow-up and close contact data, both of which are key to understanding the potential risk of short-term antibiotic use in the context of diarrhoea. This study will also provide data on antibiotic resistance from multiple countries in sub-Saharan Africa and Asia where availability of such data is limited. Escherichia coli and Streptococcus pneumoniae will be used as indicator organisms to monitor the impact of empiric antibiotic azithromycin administration on the development of resistance in bacteria colonising the gut and nasopharynx respectively - both are suitable for this purpose as they have pathogenic potential and are also commensal organisms which may act as reservoirs of transmissible genetic resistance elements. With only two follow-up visits at 90 and 180 days, lack of culturing of other bacterial pathogens, and minimal collection of information on other antibiotic use during follow-up, this study will not evaluate impact of azithromycin beyond 180 days, the impact on other pathogenic bacteria, nor the added impact of the use of other antibiotics on resistance profiles