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Figure.
Risk of Transfer to Inpatient Care and Weight Gain During and After Program Discharge
Risk of Transfer to Inpatient Care and Weight Gain During and After Program Discharge

A, Weighted Kaplan-Meier estimates of survival (1 − risk) of transfer to inpatient care by intervention group during and after program discharge. Shaded areas are log-transformed 95% CIs. B, Weight gains during and after program discharge by intervention group, estimated using a hierarchical generalized linear model with a cubic spline, including a knot at the time of program discharge. Shaded areas are 95% CIs from 10 000 bootstraps.

Table.  
Clinical Outcomes and Anthropometric Gains From Admission to 12 Weeks by Intervention Group
Clinical Outcomes and Anthropometric Gains From Admission to 12 Weeks by Intervention Group
1.
Alcoba  G, Kerac  M, Breysse  S,  et al.  Do children with uncomplicated severe acute malnutrition need antibiotics? a systematic review and meta-analysis.  PLoS One. 2013;8(1):e53184. doi:10.1371/journal.pone.0053184PubMedGoogle Scholar
2.
Trehan  I, Goldbach  HS, LaGrone  LN,  et al.  Antibiotics as part of the management of severe acute malnutrition.  N Engl J Med. 2013;368(5):425-435. doi:10.1056/NEJMoa1202851PubMedGoogle ScholarCrossref
3.
Isanaka  S, Langendorf  C, Berthé  F,  et al.  Routine amoxicillin for uncomplicated severe acute malnutrition in children.  N Engl J Med. 2016;374(5):444-453. doi:10.1056/NEJMoa1507024PubMedGoogle ScholarCrossref
4.
Chevalier  P, Sevilla  R, Sejas  E, Zalles  L, Belmonte  G, Parent  G.  Immune recovery of malnourished children takes longer than nutritional recovery: implications for treatment and discharge.  J Trop Pediatr. 1998;44(5):304-307. doi:10.1093/tropej/44.5.304PubMedGoogle ScholarCrossref
5.
Robins  JM, Hernán  MA, Brumback  B.  Marginal structural models and causal inference in epidemiology.  Epidemiology. 2000;11(5):550-560. doi:10.1097/00001648-200009000-00011PubMedGoogle ScholarCrossref
6.
World Health Organization. Guideline: updates on the management of severe acute malnutrition in infants and children. https://apps.who.int/iris/handle/10665/95584. Published 2013. Accessed December 3, 2019.
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    Research Letter
    January 13, 2020

    Extended Follow-up From a Randomized Clinical Trial of Routine Amoxicillin in the Treatment of Uncomplicated Severe Acute Malnutrition in Niger

    Author Affiliations
    • 1Department of Research, Epicentre, Paris, France
    • 2Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
    • 3Department of Global Health and Population, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
    • 4Department of Biology and Emerging Pathogens Institute, University of Florida, Gainesville
    • 5Epicentre, Niamey, Niger
    • 6Médecins Sans Frontières Operational Center Paris, Paris, France
    • 7National Hospital, Niamey, Niger
    JAMA Pediatr. Published online January 13, 2020. doi:10.1001/jamapediatrics.2019.5189

    Evidence to support current guidelines recommending routine antibiotic use in the outpatient management of uncomplicated severe acute malnutrition (SAM) is limited and based largely on data from historical inpatient settings.1 The evidence from 2 clinical trials2,3 on the effect of routine antibiotic use on nutritional recovery differs. In Malawi, where HIV and kwashiorkor prevalence are high, routine antibiotics increased nutritional recovery and decreased mortality.2 In Niger, where HIV and kwashiorkor prevalence are low, we found no benefit of routine amoxicillin on nutritional recovery or mortality, although children receiving amoxicillin had a reduced risk of transfer to inpatient care.3

    Both reports only considered short-term risks and benefits during nutritional treatment (mean [SD] time to recovery, 29 [19] days in Malawi2 and 29 [13] days in Niger3), although immunodeficiencies and risk of relapse or morbidity associated with SAM may persist beyond nutritional recovery.4 To broaden the available evidence, we present the first analysis (to our knowledge) to assess the outcome of routine antibiotic use in outpatient SAM management, including follow-up during and after nutritional treatment.

    Methods

    A complete description of the trial design, procedures, and outcomes has been published previously.3 Briefly, children aged 6 to 59 months who presented with SAM in Madarounfa, Niger, between October 2012 and November 2013 were randomly assigned 1:1 to receive amoxicillin (80 mg/kg/d) or a placebo for 7 days. All children received standard care for uncomplicated SAM for a minimum of 3 weeks and a maximum of 8 weeks. Children were followed up weekly for anthropometric, clinical, and vital status during treatment and (as per trial protocol) at 4, 8, and 12 weeks after admission. The Comité Consultatif National d’Ethique, Niger, and the Comité de Protection des Personnes, Île-de-France, France, provided ethical approval. An independent data safety monitoring board reviewed study progress and safety events, and all participants provided written informed consent.

    We used the weighted Kaplan-Meier method and Cox proportional hazard models to assess the effect of routine amoxicillin vs placebo on sustained nutritional recovery, transfer to inpatient care, and death from admission to 12 weeks. Inverse probability weights5 were used to account for censoring at the time of death or transfer to inpatient care. The intervention outcomes on total anthropometric gains among children who had recovered from admission to 12 weeks were assessed using t tests (of weight) and linear regression adjusted for baseline measurements (of mid–upper arm circumference and height). Anthropometric gains over time were estimated by intervention group using hierarchical generalized linear models with a cubic spline.

    Data analysis took place from December 2017 to June 2018. Analyses were performed using R, version 3.3 (R Foundation for Statistical Computing). Two-sided P values were considered significant at less than .05.

    Results

    All 2399 children (mean [SD] age, 16.7 [8.6] months; 1196 female children [49.9%]) of the primary analysis were eligible for inclusion in this extended analysis. Analysis found no association of routine amoxicillin administration with the risk of nutritional recovery, transfer to inpatient care or death, total weight, mid–upper arm circumference, or height gain from admission to 12 weeks (Table). The nutritional and anthropometric benefits of amoxicillin reported previously,3 may have been limited to the first 2 to 4 weeks after admission to the nutritional program and not maintained thereafter, including a decreased risk of transfer to inpatient care (cumulative incidence 0-<2 weeks postadmission: amoxicillin group, 8%; placebo group, 9%; 2-12 weeks postadmission: amoxicillin group, 36%; placebo group, 27%) and improved mean (SD) weight gain (during treatment: amoxicillin group, 6.47 [2.65] g/kg/day; placebo group, 5.85 [2.85] g/kg/ day; after program discharge: amoxicillin group, 1.01 [1.12] g/kg/day; placebo group, 1.06 [1.14] g/kg/day) (Figure).

    Discussion

    Results from this clinical trial with extended follow-up from admission to 12 weeks suggest no longer-term benefit of routine antibiotic use in the treatment of uncomplicated SAM. Current guidelines rightly acknowledge that it would be inappropriate to withhold an intervention that may substantially reduce mortality in a high-risk population,6 and in settings where it can save lives, routine antibiotic use should remain part of clinical protocols for uncomplicated SAM. This use, however, should be weighed against the risk of the emergence of antibiotic resistance, implications for program costs and coverage, and likely short-lived individual benefits. Guidance that allows treatment protocols to be adapted and simplified in specific contexts while maintaining individual effectiveness, protecting public health safety, and assuring access to care should be prioritized.

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    Article Information

    Accepted for Publication: July 17, 2019.

    Published Online: January 13, 2020. doi:10.1001/jamapediatrics.2019.5189

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Isanaka S et al. JAMA Pediatrics.

    Corresponding Author: Sheila Isanaka, ScD, Epicentre, 8 Rue Saint Sabin, Paris 75011, France (sheila.isanaka@epicentre.msf.org).

    Author Contributions: Drs Isanaka and Grais had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: All authors.

    Acquisition, analysis, or interpretation of data: Isanaka, Grantz, Grais.

    Drafting of the manuscript: Isanaka, Grantz, Berthé.

    Critical revision of the manuscript for important intellectual content: Isanaka, Schaefer, Adehossi, Grais.

    Statistical analysis: Isanaka, Grantz.

    Obtained funding: Grais.

    Administrative, technical, or material support: Berthé, Schaefer, Adehossi, Grais.

    Supervision: Isanaka, Schaefer, Grais.

    Conflict of Interest Disclosures: Dr Grantz reported grants from US National Institutes of Health during the conduct of the study. No other disclosures were reported.

    Funding/Support: Epicentre receives core funding from Médecins Sans Frontières, and this study was supported by Médecins Sans Frontières–Operational Center Paris. Ms Grantz was supported by the US National Institutes of Health Models of Infectious Disease Agent Study program (grant U54 GM088491).

    Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, or analysis of data; or decision to submit the manuscript for publication. Authors from the funder participated in interpretation of the data and review and approval of the manuscript.

    Additional Contributions: We sincerely thank all the families and children who participated in this study. We would also like to thank the field, laboratory, administrative, logistics, and data management staff of Epicentre Niger who helped facilitate this study. We also wish to thank the Ministry of Health staff of the district of Madarounfa, Niger, for their support.

    Additional Information: Deidentified individual participant data will be made available on reasonable request to sheila.isanaka@epicenter.msf.org.

    References
    1.
    Alcoba  G, Kerac  M, Breysse  S,  et al.  Do children with uncomplicated severe acute malnutrition need antibiotics? a systematic review and meta-analysis.  PLoS One. 2013;8(1):e53184. doi:10.1371/journal.pone.0053184PubMedGoogle Scholar
    2.
    Trehan  I, Goldbach  HS, LaGrone  LN,  et al.  Antibiotics as part of the management of severe acute malnutrition.  N Engl J Med. 2013;368(5):425-435. doi:10.1056/NEJMoa1202851PubMedGoogle ScholarCrossref
    3.
    Isanaka  S, Langendorf  C, Berthé  F,  et al.  Routine amoxicillin for uncomplicated severe acute malnutrition in children.  N Engl J Med. 2016;374(5):444-453. doi:10.1056/NEJMoa1507024PubMedGoogle ScholarCrossref
    4.
    Chevalier  P, Sevilla  R, Sejas  E, Zalles  L, Belmonte  G, Parent  G.  Immune recovery of malnourished children takes longer than nutritional recovery: implications for treatment and discharge.  J Trop Pediatr. 1998;44(5):304-307. doi:10.1093/tropej/44.5.304PubMedGoogle ScholarCrossref
    5.
    Robins  JM, Hernán  MA, Brumback  B.  Marginal structural models and causal inference in epidemiology.  Epidemiology. 2000;11(5):550-560. doi:10.1097/00001648-200009000-00011PubMedGoogle ScholarCrossref
    6.
    World Health Organization. Guideline: updates on the management of severe acute malnutrition in infants and children. https://apps.who.int/iris/handle/10665/95584. Published 2013. Accessed December 3, 2019.
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