Acute malnutrition is defined as a condition characterized by a severe nutrient deficit due to inadequate intake of food or the inability of the body to properly absorb essential nutrients [1]. Worldwide, 45.4 million children aged <5 years have wasting [2]. In India, the National Family Health Survey (NFHS)-5 reported a 19.3% burden of wasting and a 7.7% burden of severe wasting [3]. Although the burden of wasting remains almost constant, there is an increase in severe wasting compared to NFHS-4 and NFHS-3 [3-5]. Severe wasting indicates severe acute malnutrition (SAM) and is defined as a weight-for-height z-score (WHZ) of <−3 SD, a mid-upper arm circumference (MUAC) of <115 mm, or bilateral pitting pedal edema [6].

From the management perspective, SAM is further classified into complicated and uncomplicated SAM. Children with complicated SAM exhibit no appetite or have medical complications, while those with uncomplicated SAM have a successful standard appetite test and no fever, clinical infections, or complications [7]. Children with both complicated and uncomplicated SAM have a higher risk for acute infections, such as pneumonia, diarrhea, and sepsis, which triples the mortality risk: a few reported reasons are a weakened immune system, altered gut microbiota, poverty, food insecurity, and inadequate access to health care [8,9]. The fatality rate among children with SAM receiving inpatient care ranges from 3.4% to 35%. These data show that 3.5 million deaths are estimated among children in India aged <5 years [10].

In 2013, the World Health Organization (WHO) recommended inpatient management at nutritional rehabilitation centers using medications in line with the complications exhibited for children with complicated SAM and ambulatory Community-based Management of Severe Acute Malnutrition (CSAM) using energy-dense food and empirical antibiotics for children with uncomplicated SAM [11]. The empirical administration of broad-spectrum antibiotics, such as amoxicillin, as part of Community-based Management of Acute Malnutrition (CMAM) for children with uncomplicated SAM was a strong recommendation but with low certainty of evidence as per the 2013 guidelines [11]. However, there is a lack of high-quality evidence on the efficacy of empirical antibiotic therapy for 5-7 days among children with uncomplicated SAM at the community level. In settings with low infection rates among children with uncomplicated SAM, empirical management might lead to antibiotic overuse. Even in children aged <5 years with infection, empirical antibiotics might be ineffective due to poor compliance with medications and alarming levels of antibiotic resistance [12,13]. Furthermore, the overuse of empirical antibiotics among children with uncomplicated SAM can contribute to emerging antimicrobial resistance (AMR) in the community, especially among children [13]. AMR impairs the child’s development and second-line antimicrobials can contribute to lifelong disability, and worldwide estimates for 2019 indicate that 254,000 deaths of children are attributable to AMR [14]. The irrational prescribing of antibiotics and the suboptimal use of antimicrobials are the major contributors for AMR emergence [15-17]. Thus, further evidence on the relevance and appropriateness of empirical antibiotics for CSAM among children with uncomplicated SAM is required in the wake of increasing AMR.

In 2023, the Government of India released the National Protocol for Management of Malnutrition in Children to strengthen the ongoing efforts and commitment to address the challenges of malnutrition [18]. Mission Saksham Anganwadi and Poshan 2.0 was launched to drive the efforts to reduce malnutrition by identifying and managing children aged <5 years with SAM in India [19]. Under this program, peripheral health workers and Anganwadi (rural child care center in India) teachers are trained to make initial decisions on the level of inpatient or community-based care, nutrition management, and follow-up care for the identified children aged <5 years with SAM. These children are enrolled for CSAM at Anganwadis and administered empirical amoxicillin for 5 days, twice a day, along with nutritional support for 4 months [20].

Although empirical antibiotics are currently in use, recent studies from the Africa region and one from India have not found them effective in improving nutritional recovery [21]. The potential reason was either a low rate of infection among children with uncomplicated SAM at the time of identification or AMR emergence, making empirical antibiotics ineffective [22-24]. Thus, the context-specific relevance of empirical antibiotics needed to be tested by assessing infection rates among children with uncomplicated SAM at the time of identification and by exploring antibiograms.

In India, a few observational studies in tertiary care hospitals among children with complicated SAM have reported a high prevalence of diarrhea (36%), fever (34%), and pneumonia (43%) [25-27]. However, this evidence does not warrant the use of empirical antibiotics among children with uncomplicated SAM managed at the community level without any clinical symptoms of infection. In addition, there is a lack of evidence on the burden of clinical/subclinical infection among children with uncomplicated SAM in India, and it is important to decide whether empirical antibiotics are necessary for this patient group.

A study [28] from India among children with sepsis in tertiary care centers reported that 48.2% and 90.3% of the children developed AMR to gentamicin and penicillin G, respectively. Another study [29] among pediatric patients in urban Delhi found high rates of AMR to commonly used antibiotics, such as amoxicillin and cotrimoxazole. Although the studies have reported high AMR prevalence among children, the literature on the burden of AMR among children aged <5 years with uncomplicated SAM in India is limited. Antibiograms and AMR profiles are necessary to decide whether the current choice of amoxicillin for empirical management of children with uncomplicated SAM is relevant.

Empirical antibiotics administered for 7 days can lead to poor medication compliance and suboptimal antibiotic use. In Niger, West Africa, empirical mass administration of a single dose of azithromycin was found feasible in a programmatic setting and was effective in reducing mortality due to meningitis, dysentery, malaria, and pneumonia among children aged <5 years [30,31]. A pilot randomized controlled trial (RCT) in Burkina Faso reported similar weight gain and fewer adverse events in the single-dose azithromycin group compared with the 7-day amoxicillin group [32]. However, azithromycin has not been tested in trial mode among children with uncomplicated SAM, and an RCT among children with uncomplicated SAM would generate evidence on the effectiveness of empirical antibiotics in nutritional recovery and aid in deciding whether a single dose of azithromycin is enough.

WHO recommends one course of amoxicillin for children with uncomplicated SAM; however, this is a conditional recommendation in both the 2013 and 2023 WHO guidelines on CSAM because of the low certainty of evidence [11,33]. The 2013 guideline was largely based on a single RCT [21] conducted in Malawi (2009-2011), which reported lower mortality in the amoxicillin group (4.63%) compared with the placebo group (7.48%). The trial included 924 children receiving amoxicillin, 923 receiving cefdinir, and 920 receiving a placebo. However, around 30% of the children had HIV, with no separate outcome analysis for HIV and non-HIV groups. Nearly 70% had kwashiorkor with edema, while only 20% had marasmus (WHZ<−3 SD). The study [21] was conducted in a high-infection setting, with 82% of children reporting fever, cough, or diarrhea prior to baseline, limiting the generalizability of its findings to settings with a lower infection burden.

However, a few other studies have reported different results. A double-blinded RCT [22] conducted by the Médecins Sans Frontières (MSF) in Niger (2012-2013) among children with uncomplicated SAM (n=1199 in the amoxicillin group and n=1200 in the placebo group) reported no difference in nutritional recovery between groups. Amoxicillin reduced early inpatient admissions within 2 weeks (14%), mainly by lowering diarrhea risk, slightly shortening the recovery time (28 vs 30 days, P<.001), and reducing mortality among children aged >2 years. However, by 8 weeks, there were no differences in death, default, or nonresponse between groups. Amoxicillin showed no benefit among children with confirmed bacterial infections, fever, or respiratory illness, and no differences were observed in inpatient admissions or recovery among hospitalized children. Hence, the authors concluded that amoxicillin does not play a significant role in nutritional recovery and that, as the study was conducted in a low-infection setting (10% bacterial gastroenteritis, 4% bacteremia, and 3% bacteriuria confirmed by blood, stool, and urine cultures), antibiotics can be recommended in context-specific settings with high rates of infection.

An RCT [34] conducted in Kanpur, India, among 100 children with uncomplicated SAM (amoxicillin vs placebo) reported no significant differences in clinical or anthropometric parameters between groups. A systematic review and meta-analysis [24] similarly reported that the evidence on empirical antibiotic usage among children with uncomplicated SAM is weak and may require urgent testing.

The Indian Council of Medical Research’s (ICMR) 2019 “Treatment Guidelines for Antimicrobial Use in Common Syndromes” recommend empirical antibiotic use in common illnesses, such as severe sepsis and septic shock, acute bacterial meningitis, community-acquired pneumonia, and necrotizing fasciitis, only when proven to be beneficial. The guidelines also suggest de-escalating or modifying therapy based on culture and drug susceptibility [35]. There is evidence of acute respiratory infection (ARI; 50%) [36] and diarrhea from the NFHS-5 (7.3%), ARI from the NFHS-5 (2.8%), and fever or ARI from the NFHS-5 (69%) [3]. However, there is no evidence in community-based studies of confirmed bacterial infection among children, and most infections among children aged <5 years are suspected to be of viral origin. A 2004 Lancet review [37] reported that the coverage offered by the aminopenicillins group of antibiotics is only 37% in the case of pediatric sepsis in Southeast Asia and the Pacific region [37].

Considering all this evidence, the rationale behind using empirical antibiotics requires urgent assessment, and there is a dire need for a control arm without antibiotics to assess the efficacy of empirical antibiotics in children with uncomplicated SAM. Therefore, this study aims to (1) estimate the clinical/subclinical infection and AMR patterns among children with uncomplicated SAM; (2) explore health-seeking behavior, antibiotic use, and care preferences among caregivers of pediatric patients and identify challenges and facilitators faced by health care providers in patient management; and (3) compare the effectiveness of single-dose azithromycin, 5-day amoxicillin, and no antibiotic therapy on nutritional recovery and clinical outcomes.

The primary objectives of this study are as follows:

The secondary objective of this study is to compare medication safety (clinical adverse events) and adherence in two intervention arms (amoxicillin and azithromycin).

Patients and the public were not involved in the trial design. However, children aged <5 years with uncomplicated SAM and their caregivers will participate in the study. Study findings will be shared with caregivers, community stakeholders, and program implementers through dissemination meetings and policy briefs.

This study protocol has been registered with Clinical Trial Registry – India (CTRI/2025/03/082358). The study will be conducted in three phases:

Phase 1 of the study will be conducted in Yadadri Bhuvangiri District, Telangana, India [38]. The district has a population of ~800,000, with 16% urban, 80% rural, and some tribal populations, with ~300 villages and 1 municipal corporation area. According to the 2011 Census, this district had 50,000 tribal people. Every month, ~50 new children with uncomplicated SAM and ~100 children with moderate acute malnutrition (MAM) are identified by Anganwadi teachers during routine monthly growth-monitoring drives, and the data are entered on the website of the Nutrition and Health Tracking System (NHTS) of the state government under the Supervised Supplementary Feeding Programme (SSFP) [20]. The identified children are provided with locally available nutrient- and energy-dense food, Balamruthuam Plus, an enhanced ready-to-use therapeutic food. Children with MAM receive this food for 2 months, while children with uncomplicated SAM receives it for 4 months. All children with uncomplicated SAM are administered a weight-adjusted dose of amoxicillin twice daily for 5 days.

Phase 2 of the study will be conducted both in the community and the hospital. In the community, caregivers of children with uncomplicated SAM will be contacted for participation in the FGDs. Caregivers who participate in the quantitative study on clinical/subclinical infections and AMR will be eligible for this phase. In the hospital setting—which includes primary health centers (PHCs), subcenters, and district and tertiary care centers—various health care providers, such as medical officers (MOs), auxiliary nurse midwives (ANMs), and pediatricians, will be contacted to participate in the study. IDIs will be conducted with them.

Phase 3 of the study will be carried out in the community via house-to-house visits, initially in Yadadri Bhuvangiri District and later in further districts as the sample gets saturated.

Figure 1 shows the CONSORT (Consolidated Standards of Reporting Trials)–based RCT flow diagram depicting the enrollment of participants for each phase of the study: randomization, follow-up, and endline assessment. Table 1 depicts the timeline of the trial activities.

In this phase, the investigator and co-investigators will form a technical advisory group, following which subject matter experts will be involved in RCT-related activities (including the final protocol and Standard Operating Procedures [SOPs] for implementing the intervention). The implementation plan will involve identifying blocks, the data collection process, quality monitoring, the safety reporting mechanism, management of adverse events, and ethical considerations. This period will also be used to recruit the project team and closely work with district stakeholders and the state government for approval of implementation.

Following eligibility testing, children will be enrolled in one of the three groups based on stratified randomization. Baseline data of various independent and dependent variables will be captured for each child with proper screening of anthropometric measures and medical assessment. Next, each child will receive either oral amoxicillin or azithromycin and standard nutritional care (Balamrutham Plus) based on the group. In addition, based on the hemoglobin level, children with anemia at baseline will be administered iron folic acid (IFA) syrup as per Anemia Mukt Bharat guidelines [41]. Any illness during the intervention period, physician (or pediatrician) visits, treatment details, and hospitalization details will be documented during the follow-up visits.

In the amoxicillin group, amoxicillin dispersible tablet (125 mg) will be administered, along with Balamrutham Plus. The first dose will be administered upon enrollment, following by medication at home (for 5 days, twice daily). The dosage will be determined based on weight of the child, as specified by the SSFP implemented by the Government of Telangana for managing children with SAM in all districts of Telangana (Table 2) [20].

In the azithromycin group, a single dose of azithromycin syrup (20 mg/kg) will be administered, along with Balamrutham Plus.

In the control group, no antibiotics will be prescribed; only standard nutritional treatment (Balamrutham Plus) will be provided.

Children with uncomplicated SAM are clinically well (ie, without signs of infection) and with a retained appetite (passed the appetite test), which is considered indicative of the absence of severe metabolic disturbance. SAM is defined as WHZ<–3 SD of the median WHO child growth standards and/or by the presence of bilateral pitting edema. Nonresponse to treatment is defined as children who do not meet discharge criteria (WHZ>–2 SD) after 4 months.

The primary outcomes of the RCT are as follows:

The secondary outcomes include the following:

Clinical outcomes and morbidity episodes will be assessed during scheduled follow-up visits through caregiver interviews and clinical examination by trained study personnel. Hemoglobin levels will be estimated using standard laboratory methods. Information related to inpatient referrals, adverse events, and mortality will be documented using study follow-up records.

The exploratory outcomes include the following:

Blood, urine, and stool samples will be collected and processed using standard microbiological and laboratory procedures to assess infection status and AMR patterns. Qualitative data will be collected through FGDs and IDIs using semistructured interview guides.

The following covariates will be assessed:

Information about day care absenteeism will be obtained from Integrated Child Development Services records. Socioeconomic status will be assessed using the BG Prasad socioeconomic scale. Dietary intake will be assessed using a 24-hour dietary recall method. Household food insecurity will be assessed using the Household Food Insecurity Access Scale and categorized into food-secure, mildly food-insecure, moderately food-insecure, and severely food-insecure households. Questions adapted from the NFHS-5 women’s questionnaire will be used to assess domestic violence.

This study protocol has been reviewed and approved by the Institutional Ethics Committee (IEC) and the Clinical Trial Review Committee (CTRC) of the All India Institute of Medical Sciences (AIIMS), Bibinagar, India (IEC approval #AIIMS/BBN/IEC/Feb/2025/611-R; CTRC approval #2024/12/08). Any important modifications to the study protocol, including changes to eligibility criteria, interventions, outcomes, or procedures, will be communicated promptly to the IEC, trial registries, and investigators. Participants and their guardians will be informed if the changes affect their participation.

Signed informed consent will be obtained from the parents or legal guardians of all participating children in the presence of a witness, along with the witness’s signature, prior to enrollment. Trained study staff will explain the study purpose, procedures, potential risks, and benefits in the local language and provide a patient information sheet in the local language. Parents/guardians will also be informed that participation is voluntary and that they have the right to withdraw from the study at any time without any consequences related to access to health care services.

Participant confidentiality will be strictly maintained. Personal identifiers will be stored separately from study data in secure, password-protected systems accessible only to authorized personnel. Any data shared for analysis or publication will be deidentified. Paper records, if any, will be kept in locked cabinets within the study site. An independent committee (Data & Safety Monitoring Board) will be established to ensure safety and review protocol amendments, data quality, completeness, compliance with the intervention, and other information relevant to the study.

During the study period, if any participants fall ill, they will be immediately referred to a nearby PHC, health center, or tertiary care center (AIIMS, Bibinagar) based on the care provider’s preference to provide care. Any medication use during the study period will be documented. No monetary compensation will be provided to participants for participation in the study.

This RCT is designed to estimate the prevalence of clinical and subclinical infections and AMR patterns among children with uncomplicated SAM in community-based settings. Further, the study aims to evaluate the necessity and effectiveness of empirical antibiotic therapy in this population.

The current recommendation outlined by WHO for routine empirical antibiotic use in children with uncomplicated SAM is conditional, based on low-certainty evidence, primarily derived from high-infection settings. Subsequent studies from sub-Saharan Africa and limited evidence from India have demonstrated inconsistent findings regarding the benefits of antibiotics in improving nutritional recovery. Notably, trials conducted in relatively low-infection settings have demonstrated no significant differences in recovery outcomes between antibiotic and placebo groups.

In the Indian context, evidence is scarce for community-based management settings in which children with uncomplicated SAM are less likely to present with overt infections. Simultaneously, increasing AMR to commonly used antibiotics raises concerns about the continued empirical use of such drugs without clear benefits. This study is, therefore, expected to generate context-specific evidence to inform more rational and targeted use of antibiotics in the CSAM in the Indian context. The RCT design with three arms—amoxicillin, azithromycin, and no antibiotics—will allow for a comprehensive evaluation of both the effectiveness and the necessity of empirical antibiotic therapy, which is one of the major strengths of this study. Moreover, the study is embedded within a community-based management framework, enhancing its relevance to current national programs and real-world implementation. In addition, the inclusion of laboratory investigations to assess infection status and AMR provides a stronger evidence base that is often lacking in similar studies.

However, the study will be conducted within specific programmatic and geographic settings, which may limit generalizability to regions with differing infection burdens or health care access. Moreover, subclinical infections may not be fully captured due to inherent limitations in diagnostic methods. Operational challenges, such as timely collection and transportation of samples, particularly urine and stool samples among pediatric participants, may be difficult. In addition, adherence to treatment and follow-up in community settings may also influence study outcomes.

The findings of this study have important implications for both policy and practice. If empirical antibiotics are found to provide limited benefits in children with uncomplicated SAM, this could support revisiting existing guidelines and promoting more judicious use of antibiotics, in line with antimicrobial stewardship principles. However, if benefits are observed in specific subgroups, the study may help refine criteria for targeted antibiotic use.

The evaluation of single-dose azithromycin as an alternative therapy regimen for SAM may offer operational advantages, particularly in improving medication adherence and reducing the treatment burden in large-scale programs implemented through community platforms, such as Anganwadis in India. Future research should focus on longitudinal studies to further explore the impact of antibiotic use on relapse rates, growth outcomes, and AMR patterns over time.