AbstractIntroductionAntimicrobial 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/NCT03130114Strengths 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

Twenty five infants who were small for gestational age received glucagon (0.5 mg/day by continuous infusion) in the treatment of hypoglycaemia. Twenty responded within three hours with a rise in blood glucose concentration to above 4 mmol/l. Five subjects subsequently required hydrocortisone to maintain glucose concentrations. Rebound hypoglycaemia occurred in nine infants after rapid discontinuation of glucagon or interruption of the intravenous infusions. Response was poor after maternal beta blockade.

Background Chlorhexidine, a broad-spectrum topical antiseptic with strong residual activity, has a potential to reduce infections during the neonatal period. However, the challenge remains what would be the best mode to deliver the intervention. As a part of formative research, we evaluated three possible modes of chlorhexidine delivery i.e. 100ml bottle with cotton swab, 10ml single use dropper bottle and 3g single application squeeze tube containing gel, as an umbilical cord care intervention using Trials for Improved Practices (TIPS) methodology in preparation for a large double-blind randomized controlled trial evaluating the impact of chlorhexidine. in Pemba, Tanzania. Methods 204 mother-newborn pairs were enrolled from hospital and community setting. Three different modes of application of intervention were tested (3 days for each preparation) in a cross over design. Mothers (on day 10), MCH, TBA and hospital staff was interviewed about their experience and feedback of their preference among the three delivery modes. Convenient and preference scores were calculated based on their feedback. Results 97% mothers applied intervention for all 9 days. 10ml dropper bottle (49.7%) was rated as most convenient by the mothers, gel tube (32.2%) and 100ml bottle (19.8%). Mothers opted 10ml dropper bottle (44.6%) as their first choice over the 100ml bottle (21.5%) or gel tube (33.9%). MCH/hospital staff’s choice was to use gel tube (84%) or 10ml dropper bottle (82%). Conclusions Overall acceptability was high, in terms of convenience and preference 10ml dropper bottle was a winner. Based on their choice the 10ml dropper bottle was selected for RCT.

Introduction Studies in Nepal, Pakistan, and Bangladesh have shown using 4% CHX solution for umbilical cord cleansing reduces neonatal mortality and omphalitis. Data evaluating the effect of 4% Chlorhexidine umbilical cord cleansing from the Sub-Saharan region is lacking. Considering this need we are undertaking a double blind, controlled study in Eastern Africa. Before starting the trial, in this pilot we tested the impact of 4% Chlorhexidine and control solution specially prepared for the trial on colonization and colony count. Methods Total 512 newborns in both the hospital and community were enrolled in the study. Newborns were randomly assigned the Chlorhexidine, placebo or dry cord care group. Umbilical swabs were collected at baseline (before the application of intervention), 2 hour and 48 hour after application of the assigned intervention. Presence of growth, identification to gram positive/negative groups and semi-quantitative colony count was estimated for all samples. Results The positivity was high baseline swabs 30% (154 of 512 samples). In 2 hour post intervention group Chlorhexidine significantly reduced the growth of pathogens compared to placebo (OR 0.15, p< 0.01) and dry cord [OR 0.07, p=0.00]. In 48-hour swabs reduction in growth and density of organisms was observed in Chlorhexidine group (OR 0.11, p<0.01). There was no difference between the control solution and dry cord group (OR 0.97, p=0.92). Conclusions Chlorhexidine preparation was effective in reducing the growth and density of pathogens over the umbilical cord. The control preparation did not increase colonization but was similar to dry cord care group.

Background Iron deficiency remains a major nutritional problem among infants and young children in India. The tablet/syrup-based programs do have logistic, supply and compliance challenges. Tablet/Syrup may have increased risk of free iron in blood, oxidative stress and risk of infections. Objective In a community based RCT we evaluated 3 approaches of iron delivery for impact on iron status, pro and anti-inflammatory interleukins and non-transferrin bound iron (NTBI) with 30 day intervention. Methods 300 children 22–34 months were enrolled and randomized to receive either iron fortified biscuit (n=74), iron tablet (n=77), iron+ zinc tablet (n=74) or placebo (n=75) for 30 days. Results Delivery of iron through biscuit showed better impact on hemoglobin (Mean Diff: 0.60; 95 % CI: 0.16–1.04) and other hematological markers like RDW, MCV and MCH at 30 day post supplementation. The NTBI estimation at day 1 and 30 post supplementation, 3 hours after ingestion of supplement dose; an indicator of oxidative stress caused by dose after iron status repletion, suggested the lowest burden with biscuit (2 %) and a higher burden with supplements (6–7 %). At day 30 there was no effect on interleukins in the biscuit group; increase in IL-6/IL10 in iron tablet, increase in IL-8/IL10 in iron+zinc tablet group. Conclusion Providing iron through fortified biscuits was as efficient and effective in improvement of iron status and hematological markers as iron tablets. Biscuit was marginally better for NTBI or immune response. The benefit of using biscuits needs to be evaluated in a larger community based effectiveness program.

Background Efficacy studies of application of chlorhexidine on umbilical cord have suggested significant improvement in neonatal outcomes. An important question for new trials and programs however is what should be the quantity used. There are concerns about the increased risk of hypothermia resulting from spillage or over use of any cleansing liquid solution in newborn. In context of a randomized controlled trial evaluating impact of cord cleansing in Africa, on recommendation of DSMB we undertook a pilot study, which aimed to determine the optimal quantity of the intervention solution required for application on umbilical cord of newborn. Methods Children were enrolled from both community and hospital in Pemba (n=62) and only from Hospitals in Delhi (n=50). Trained Hospital staff/MCH applied the intervention solution from a dropper bottle filled with 10 ml, on the umbilical cord of the baby generously such that it covered umbilical cord and periumbilical area. A study supervisor to maintain consistency supervised the process. After application the unused volume from each of the containers was measured to determine the actual usage. Results The mean volume of usage did not differ between Pemba and Delhi (4.58±0.8 ml and 4.79±1.88 ml respectively). The quantity of solution used ranged from 3ml to 7.5ml with a median of 4.5ml. Conclusions The optimal requirement for application was found to be 5 ml. However to be little conservative we recommend use 6 ml to adjust for any spillage and/or any abnormally long cord.

Background Infections in new-borns are the single most important cause for neonatal mortality in developing countries. Of topical antiseptics chlorhexidine has shown potential as an effective cord care agent. Results from randomized double-blind trials examining the effect of chlorhexidine in Asia have been encouraging. A 4% chlorhexidine solution is not comercially available we contracted Galantic Pharma to prepare supplies for two large clinical trials in Africa. This study aimed to evaluate the effect this 4% chlorhexidine solution on the colonization and colony counts in hospital born infants. Methods Newborns (n=247) from normal deliveries at a hospital in New Delhi were randomly assigned to one of three groups chlorhexidine, placebo or dry cord care. Swab samples were used to collect smear samples before, after 2hrs and 48hrs of application of chlorhexidine and at same times from the dry cord group. All swabs were analysed for growth and colony counts. Results The overall baseline positivity was 20% (50 of 247 swabs). Chlorhexidine reduced colonisation and bacterial counts in both (2hr and 48 hr) samples. As compared to placebo and dry cord, the reduction in positivity in chlorhexidine group in 2-hour samples was 80% [odds ratio of 0.20, p=0.001 and odds of 0.19, p=0.00 respectively]. In 48-hour post intervention, chlorhexidine significantly reduced colonisation in comparison to placebo [difference in mean of –1.01, p=0.006] and dry cord [difference in mean –1.16, p=0.004]. Conclusion Cord cleaning with 4% Chlorhexidine soon after birth reduces colonisation as well as density of pathogens significantly.

BACKGROUND:Anaemia caused by iron deficiency is common in children younger than age 5 years in eastern Africa. However, there is concern that universal supplementation of children with iron and folic acid in areas of high malaria transmission might be harmful. METHODS:We did a randomised, placebo-controlled trial, of children aged 1-35 months and living in Pemba, Zanzibar. We assigned children to daily oral supplementation with: iron (12.5 mg) and folic acid (50 mug; n=7950), iron, folic acid, and zinc (n=8120), or placebo (n=8006); children aged 1-11 months received half the dose. Our primary endpoints were all-cause mortality and admission to hospital. Analyses were by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59549825. FINDINGS:The iron and folic acid-containing groups of the trial were stopped early on Aug 19, 2003, on the recommendation of the data and safety monitoring board. To this date, 24 076 children contributed a follow-up of 25,524 child-years. Those who received iron and folic acid with or without zinc were 12% (95% CI 2-23, p=0.02) more likely to die or need treatment in hospital for an adverse event and 11% (1-23%, p=0.03) more likely to be admitted to hospital; there were also 15% (-7 to 41, p=0.19) more deaths in these groups. INTERPRETATION:Routine supplementation with iron and folic acid in preschool children in a population with high rates of malaria can result in an increased risk of severe illness and death. In the presence of an active programme to detect and treat malaria and other infections, iron-deficient and anaemic children can benefit from supplementation. However, supplementation of those who are not iron deficient might be harmful. As such, current guidelines for universal supplementation with iron and folic acid should be revised.

Recent studies have demonstrated the potential benefits of probiotic supplementation on morbidity and immune functions among children. Considering previous data on growth effects of morbidity and recent data suggesting early childhood morbidity may impact development of children, there is a strong potential for probiotics to play a role in improving the growth and development of children. We evaluated in a randomized trial the effect of milk containing pre- and probiotics on growth and development of children aged 1-3 years. The results showed a significantly higher weight gain among the supplemented children as compared to the control group but indicated no effect on height gains or the developmental scores of children. There was also a significant improvement in iron status and anemia in children.

Although there is increasing evidence demonstrating the beneficial effects of prebiotic and probiotic therapeutic effects on the gut, data from controlled clinical trials of adequate size evaluating preventive effects of probiotics on and beyond the gut are lacking. This double blind randomized controlled trial evaluated the efficacy of combined prebiotic and probiotic delivery via fortified milk in preventing diarrhea and other invasive bacterial and viral infections among preschool children. There was a significant reduction in incidence and prevalence of bloody diarrhea, febrile illness, days with severe illness, and a 10% reduction in diarrhea and days with ear discharge both of which were statistically non significant

Journal of Pediatric Gastroenterology and NutritionVolume 39, Issue S1 p. S417-S418 ABSTRACTS: Poster Session Abstracts P0946 EFFICACY OF ZINC AND IRON FORTIFICATION OF MILK IN PREVENTION OF ANEMIA, DIARRHEA, PNEUMONIA AND IRON DEFICIENCY–A COMMUNITY BASED DOUBLE MASKED RANDOMIZED TRIAL S. Sazawal, S. Sazawal Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, United StatesSearch for more papers by this authorD. Marwah, D. Marwah Center for Micronutrient Research, Annamalai University, New DelhiSearch for more papers by this authorS. Sazawal, S. Sazawal Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, United StatesSearch for more papers by this authorR. E. Black, R. E. Black Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, United StatesSearch for more papers by this authorS. Deb, S. Deb Center for Micronutrient Research, Annamalai University, New DelhiSearch for more papers by this authorU. Dhingra, U. Dhingra Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, United StatesSearch for more papers by this authorA. Sarkar, A. Sarkar Center for Micronutrient Research, Annamalai University, New DelhiSearch for more papers by this authorV. P. Menon, V. P. Menon Center for Micronutrient Research, Annamalai University, Chidambarm, IndiaSearch for more papers by this authorR. Sexena, R. Sexena Center for Micronutrient Research, Annamalai University, New DelhiSearch for more papers by this authorP. Dhingra, P. Dhingra Center for Micronutrient Research, Annamalai University, New DelhiSearch for more papers by this author S. Sazawal, S. Sazawal Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, United StatesSearch for more papers by this authorD. Marwah, D. Marwah Center for Micronutrient Research, Annamalai University, New DelhiSearch for more papers by this authorS. Sazawal, S. Sazawal Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, United StatesSearch for more papers by this authorR. E. Black, R. E. Black Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, United StatesSearch for more papers by this authorS. Deb, S. Deb Center for Micronutrient Research, Annamalai University, New DelhiSearch for more papers by this authorU. Dhingra, U. Dhingra Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, United StatesSearch for more papers by this authorA. Sarkar, A. Sarkar Center for Micronutrient Research, Annamalai University, New DelhiSearch for more papers by this authorV. P. Menon, V. P. Menon Center for Micronutrient Research, Annamalai University, Chidambarm, IndiaSearch for more papers by this authorR. Sexena, R. Sexena Center for Micronutrient Research, Annamalai University, New DelhiSearch for more papers by this authorP. Dhingra, P. Dhingra Center for Micronutrient Research, Annamalai University, New DelhiSearch for more papers by this author First published: 01 June 2004 https://doi.org/10.1002/j.1536-4801.2004.tb13376.x Submitted by: [email protected] Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume39, IssueS1June 2004Pages S417-S418 RelatedInformation

Iron and zinc deficiency have been associated with impairment of growth, motor and cognitive development. The data from randomized controlled trials however is sparse and inconclusive. To evaluate the effect of combined micronutrient fortification of milk on growth, iron status and development, 633 children were enrolled and randomly allocated to either receive a milk formulation containing zinc, iron, selenium, vitamins A, C and E, or the same milk formula without fortification. Supplementation was continued for one year. The fortified milk group had significant improvement in both height and weight velocity and Z-scores. There was also a marked improvement in hemoglobin and iron store status. Changes in developmental scores were not significant. Micronutrient fortification of milk is an effective strategy in ameliorating deficiency of zinc and iron and improvement of growth.

A randomized controlled, double-blind trial was undertaken in Delhi to determined the efficacy of consuming micronutrient fortified milk as compared to the same milk with natural levels of the micronutrients in the prevention of morbidity among children 1-3 years of age. Consumption of fortified milk as compared to unfortified milk resulted in a significant reduction in the occurrence of severe illness (non-diarrheoal), diarrhea and respiratory infections. There was a trend to a reduction in dysentery, and a substantial reduction in measles both of which were not statistically significant.

Background - Diarrhoea is still the major cause of childhood morbidity and mortality; estimated to cause more than 3 million deaths among children globally. Any non-invasive easily administrable intervention that may affect these morbidities would have very important implications for child health and survival. In recent years there has been increasing evidence for the role of probiotics in treatment of diarrhoea. There are very sparse data on prophylactic probiotic therapy and its effects. Objective - To evaluate the impact of milk fortified with pre- and probiotics in prevention of diarrhoea and on iron status and growth. Design - The study was conducted in Sangam Vihar, a peri-urban population in south Delhi. Healthy children aged 1- 3 years, permanent residents in the area and without any chronic illnesses or severe malnutrition were invited to participate. After informed consent 634 children were enrolled and randomly allocated to either receive a milk formulation containing Bifidobacterium lactis HN019 (DR-10 TM ) minimum of 10 7 -10 8 CFU/100 g and galacto- oligosaccharides 2.5 g/100 g (PP Milk), or the same milk without these two. The milk was provided in sachets of 32 g and children were advised to consume up to 3 sachets per day for 12 months. A blood sample was taken to measure the detailed haemogram, ZPP and retic count at baseline and end study. Twice weekly home visitations were done to collect data on morbidity and compliance. At baseline, six months and one year anthropometric measurements (weight, height) were made. Outcomes - Baseline characteristics of subjects in the two groups were comparable. Compliance was above 80%, with most children consuming at least two serves per day. Supplementation with PP milk resulted in a significant reduction in the incidence of dysentery OR 0.78 (95% CI 0.61, 1.00) as well as prevalence of dysentery OR 0.85 (95% CI 0.71, 1.01). Reduction in incidence of diarrhoea was 10%, but was not statistically significant. Consistent with improved immunity PP milk supplementation caused a significant reduction in the prevalence of severe illness days OR 0.84 (95%CI 0.74- 0.95, p<0.001), days with fever OR 0.68 (95%CI 0.54-0.84) and prevalence of ear infections OR 0.93 (95%CI 0.87- 1.00). Data on haematological parameters indicate a significant increase in the proportion of children with Hb levels above 10 g/L in the PP milk group. There was also a 35 % reduction in the proportion of iron deficient children and a significant reduction in stress of bone marrow as observed by a increase in the proportion of children with normal retic count, in the PP milk group. Children fed PP milk had significantly better growth at six month and one year assessments. After 1 year the children in the PP milk group had significantly better z scores for WAZ (mean diff 0.22, 95%CI 0.02- 0.41; p=0.03) and WHZ (mean diff 0.18, p=0.05), and higher weight gain (mean diff: 130g, 95%CI 30-230; p=0.02). Conclusions - Bifidobacterium lactis HN019 (DR-10 TM ) and galacto-oligosaccharide fortified milk resulted in better iron status even when both groups were receiving iso-caloric diets with the same iron content. This effect could be either due to better absorption due to effects on gut flora or more likely secondary to morbidity prevention effects. There was a significant reduction in bloody diarrhoea and a non significant 10% reduction in all diarrhoea. The magnitude of significant reduction in non diarrheal morbidity suggests effects are most likely on both viral and bacterial infections. This study was funded by New Zealand Milk Ltd, who also provided the milk products

BACKGROUND:Low birth weight infants have been noted to have low zinc concentrations in cord blood, and zinc deficiency in childhood is associated with reduced immunocompetence and increased infectious disease morbidity. This study investigates whether zinc supplementation of infants born full term and small for gestational age affects mortality.METHODS:A randomized, double-blind, controlled trial with 2-by-2 factorial design enrolled 1154 full-term small for gestational age infants to receive in syrup 1 of the following: riboflavin; riboflavin and zinc (5 mg as sulfate); riboflavin, calcium, phosphorus, folate, and iron; or riboflavin, zinc, calcium, phosphorus, folate, and iron. A fixed dosage of 5 mL per child was given daily from 30 to 284 days of age. Household visits were made 6 days per week to provide the syrup and conduct surveillance for illness and death. When a child's death was reported, parental reports and medical records were used to ascertain the cause. The effects of zinc and of the combination of iron, folate, calcium, and phosphorus were analyzed by intent to treat. The mortality analysis was performed using a survival analytic approach that models time until death as the dependent variable; all models had 2 terms as independent variables: 1 for the zinc effect and 1 for the vitamin and mineral (calcium and phosphorus, folate and iron) effect.RESULTS:Zinc supplementation was associated with significantly lower mortality, with a rate ratio of 0.32 (95% confidence interval: 0.12-0.89). Calcium, phosphorus, folate, and iron supplementation was not associated with a mortality reduction, although a statistically nonsignificant trend toward reduction was observed with a rate ratio of 0.88 (95% confidence interval: 0.36-2.15).CONCLUSIONS:Zinc supplementation in small for gestational age infants can result in a substantial reduction in infectious disease mortality.