Is empirical antibiotics necessary for Community-based management of Severe Acute Malnutrition (CSAM) in children. Can single-dose Azithromycin replace one-week Amoxycillin for CSAM: Randomized-Control trial

Summary: Globally, an estimated 17 million children have Severe Acute Malnutrition (CSAM) with majority residing in South-Asia region. The WHO recommends empirical antibiotics for CSAM on community-based management to alleviate any subclinical or clinical infections and facilitate nutritional recovery. However, a few studies reported low prevalence of infection among CSAM and varied antibiogram. Thus, suggested targeted over empirical antibiotics to limit emerging antimicrobial resistance. Though national guidelines (2013) on community-based management of CSAM recommends empirical amoxicillin for seven-days, there is limited literature on the relevance of this recommendation. Despite single-dose of azithromycin being found effective over seven-days of amoxicillin elsewhere, effectiveness of it has not been tested in the programmatic settings of India. Thus, we aim to assess the relevance of empirical antibiotics practices and effectiveness of single-dose of azithromycin on the nutritional recovery among CSAM. This study will be embedded in the ongoing community-based CSAM management project implemented in the selected districts of Telangana with technical support from the State Centre of Excellence for Nutrition at AIIMS, Bibinagar. To assess relevance, the prevalence of subclinical/clinical infection and antibiogram including phenotypic resistance patterns among CSAM children at identification will be estimated along with qualitative exploration of current antibiotic prescription practices. In the second phase, a randomized control trial will be conducted to assess the effectiveness of single-dose azithromycin over seven-days of amoxicillin over no antibiotics on weight gain. This research would generate a primary evidence on rationale use of empirical antibiotic for CSAM in wake of concerns over antimicrobial resistance.

 Methodology:

Study Design:

Objective 1: Cross-sectional analytical study design

Objective 2: Qualitative study design using focus group discussions among caregivers of under-five children with uncomplicated SAM and in-depth interviews among the health care providers of under-five children.

Objective 3: An Open-label, randomized parallel group controlled trial will be done to achieve objective 3.

Study area:

Objective 1: Community with a laboratory component. The study will be done in Yadadri Bhuvangiri district of Telangana. The district has a population of 8 lakhs, consisting of 16% urban, 80% rural, and some tribal populations. According to the 2011 census, there were 50,000 tribal people in this district. There are around 300 villages and one municipal corporation area. Every month, around 50 new uncomplicated SAM children and 100 MAM are identified by Anganwadi teachers during routine monthly growth monitoring drives. The children identified with these two conditions are provided with nutrient and energy-dense food Balamruthuam Plus. The MAM children receive this food for two months, and uncomplicated SAM receives it for 4 months. All uncomplicated SAM received antibiotics - amoxicillin, weight-adjusted dose twice daily for a period of 7 days.

Objective 2: The study will be conducted both in the community and the hospital. In the community, the caregivers of under-five children with uncomplicated SAM will be contacted for participation in the focus group discussion. The caregivers who participated in quantitative study on clinical/ sub-clinical infections and AMR will be eligible for this objective. At the hospital settings, which include primary health centres, sub-center, district, and tertiary care centers, various health care providers such as medical officers, ANM, and pediatricians will be contacted for participation in the study. In-depth interviews will be conducted among them.

Objective 3: Objective 3 of the study will be done in the community by house-to-house visits. The study will be done in Yadadri Bhuvangiri district of Telangana.

 Sample size:

Objective 1: Bhutta et al. (doi: 10.1371/journal.pone.0053184) reported that the clinical infections among children with complicated SAM vary from 15% to 68%. Considering 50% prevalence of LRTI among uncomplicated SAM children, 95%CI, 10% relative precision, 1.5% design effect 10% nonresponse rate, and 5% Type I error, we require 606 study participants with uncomplicated SAM of 6 months to 59 months.

Objective 2:

To attain this objective, a purposive sampling strategy will be followed for the selection of study participants. The primary caregivers of the under-five children with diagnosed will be identified based on their volunteerism and participation. For each focus group discussion we will be including 8-10 participants. Around 10-12 such FGDs will be conducted. Two in-depth interviews will be conducted in each of the healthcare worker groups - ASHA, Anganwadi teacher (Anganwadi center), ANM (Sub-centre), MO (PHC), pediatrician (district hospital and tertiary care center). The number of FGDs and IDI will be based on the level of information saturation.

Objective 3:

A study conducted by Rao at el in 2023 reported mean (SD) WHZ in amoxicillin group as -1.29 (0.84) and no antibiotic group was -1.45 (0.93) at the end of 2 weeks of intervention. Considering these values, with 95% CI and 80% power we require 480 study participants in each groups. Considering logistic issues, feasibility and long follow-up period we will be recruiting 250 uncomplicated SAM children of 7-59 months age in each of the three groups.

Inclusion and exclusion criteria:

Objective 1:

Inclusion criteria: a) Age: 7-59 months aged children b) Both gender c) Resident of the place d) Weight for height -2SD to -3SD (moderate acute malnutrition) e) Weight for height -3SD without any signs of complications (uncomplicated SAM)

Exclusion criteria: a) Weight for height -3SD with any signs of complications (complicated SAM) b) Bilateral pitting edema c) Children with congenital anomalies, inborn errors of metabolism, developmental delay d) Malabsorption syndromes Sampling strategy: The list of SAM children will be identified from the National Health Tracking Portal through the district health administration. During the study period, all eligible children will be contacted to participate in the study.

Objective 2:

The primary caregivers of the under-five children with diagnosed SAM will be identified based on their volunteerism and participation. For each focus group discussion we will be including 8-10 participants. Around 10-12 such FGDs will be conducted. Two in-depth interviews will be conducted in each of the healthcare worker groups - ASHA, Anganwadi teacher (Anganwadi center), ANM (Sub-centre), MO (PHC), pediatrician (district hospital and tertiary care center). The number of FGDs and IDI will be based on the level of information saturation.

Objective 3:

Inclusion criteria: 7-59 months children enrolled in SSFP/ CMAM programme WHZ -3D or MUAC 115mm, passed appetite test using balamrutham plus (RUTF), both gender, available for full 8-week study, no oedema, no antibiotic use in past one month, no clinical complication requiring antibiotic treatment, no clinical complication requiring inpatient care, primary resident of the catchment area. The children who participated in phase 1 will also be eligible to be part of phase II RCT provided no significant growth in blood, urine, or stool culture.

Exclusion criteria: Children identified as complicated case of SAM Children with antibiotic use in last one month.

 Study procedure:

Objective 1:

The list of children with uncomplicated SAM will be obtained from the Nutrition and Health Tracking portal. The children will be visited at their homes to confirm their diagnosis of malnutrition category and enrolled into the student after obtaining informed consent from the caregivers. The children’s sociodemographic, nutritional, and health-related information will be obtained through questionnaires and interviews. Under a sterile environment, 4ml of blood sample will be taken from the children. Two sterile containers will be given to the children to collect their urine and stool samples, and those samples will be collected from the caregivers the next day. The blood samples will be analyzed in the biochemistry (hs-CRP, pro-calcitonin) laboratory and pathology (RBC and WBC) laboratory. The blood, stool, and urine samples will be analyzed in the microbiology laboratory for culture and sensitivity.

 Objective 2:

A focus group discussion guide and an in-depth interview guide will be prepared based on the literature review and the knowledge gap requiring further data. The potential participants for qualitative interviews will be identified prior, and an appointment will be obtained for their participation. A moderator who is trained in qualitative research will be conducting the FDGs and IDIs. The date and time of the FGDs and IDIs will be fixed at the convenience of the participants. On the day of the FGD and IDI, informed consent will be obtained, and the entire process will be audio recorded. An assistant will be taking field notes, and a sociogram will be used to map the pattern of participation. Participatory rural appraisal techniques will be used to encourage active participation and to generate more discussion among the participants in the FGD. The duration of the FGD/ IDI will last for 30-45 minutes.

 Objective 3:

A randomization sequence of unequal block size will be generated. The list of children enrollled under NHTS as uncomplicated SAM will be identified. A house visit will be made and the nutritional category of the children will be confirmed. At enrolment, Children will be assigned a unique identification number using a number assigned to the list. After completion of the baseline assessment children will be randomized to receive either a Group A vs Group B vs Group C. The randomization sequence will be generated using an online software. Children will be randomized in a 1:1:1 ratio without stratification. The allocation will be concealed centrally in the institute. Based on the intervention plan, study participants and administrators will not be masked in the study. The outcome assessors will be masked on the treatment assignment.