Analysis of serious adverse events in a pediatric community-acquired pneumonia randomized clinical trial in Malawi

Amy Sarah Ginsburg, Susanne May, Amy Sarah Ginsburg, Susanne May

Abstract

Amoxicillin is recommended as first-line antibiotic treatment for community-acquired pneumonia, the leading infectious cause of mortality in children aged less than 5 years. We conducted a double-blind, randomized controlled non-inferiority trial comparing 3- to 5-day amoxicillin treatment for non-severe chest-indrawing pneumonia in HIV-negative children aged 2 to 59 months in Malawi. In a secondary analysis, we assessed the frequency of serious adverse events (SAEs) during the trial to evaluate the safety of treatment with amoxicillin. Enrolled children with non-severe chest-indrawing pneumonia were randomized to either 3- or 5-day amoxicillin and followed for 14 days to track clinical outcomes. In addition to evaluation for treatment failure (primary endpoint, day 6), relapse, and study drug adherence, children were assessed for adverse events, including SAEs, which were managed per local standard clinical practice until resolution or stabilization. Between March 2016 and April 2019, 3000 children were enrolled, with male and younger children (aged less than 24 months) demonstrating more SAEs (10.3% for males vs 8.1% for females, p = 0.04; 10.0% for 2-6 months, 10.8% for 7-11 months, 9.7% for 12-23 months and 5.6% for 24-59 months, p = 0.01). The most common SAEs were progression of or recurrent pneumonia (220 SAEs in 217 children), acute gastroenteritis (14 SAEs in 14 children), and fever (8 SAEs in 8 children); however, there were no significant or substantive differences in the percentage of children with pneumonia-related, acute gastroenteritis, or fever SAEs noted between the 3- versus 5-day amoxicillin treatment groups. In our pediatric community-acquired pneumonia trial evaluating amoxicillin treatment, there were relatively few SAEs overall and very few attributed to amoxicillin. Duration of amoxicillin treatment did not impact the frequency of SAEs. We found male and younger children appear to be more vulnerable to SAEs in our trial; however, our data support previous data demonstrating the safety of amoxicillin use in children with pneumonia.Clinical trial registration: ClinicalTrials.gov (NCT02678195).

Conflict of interest statement

The authors declare no competing interests.

© 2022. The Author(s).

References

    1. Rogawski ET, Platts-Mills JA, Seidman JC, John S, Mahfuz M, Ulak M, et al. Use of antibiotics in children younger than two years in eight countries: A prospective cohort study. Bull: World Health Organ. 2017;95(1):49–61.
    1. Klein EY, Van Boeckel TP, Martinez EM, Pant S, Gandra S, Levin SA, et al. Global increase and geographic convergence in antibiotic consumption between 2000 and 2015. Proc. Natl. Acad. Sci. U. S. A. 2018;115(15):E3463–E3470. doi: 10.1073/pnas.1717295115.
    1. Smyth RM, Gargon E, Kirkham J, Cresswell L, Golder S, Smyth R, et al. Adverse drug reactions in children—A systematic review. PLoS ONE. 2012;7(3):e24061. doi: 10.1371/journal.pone.0024061.
    1. Lovegrove MC, Geller AI, Fleming-Dutra KE, Shehab N, Sapiano MRP, Budnitz DS. US emergency department visits for adverse drug events from antibiotics in children, 2011–2015. J. Pediatr. Infect. Dis. Soc. 2019;8(5):384–391. doi: 10.1093/jpids/piy066.
    1. World Health Organization (WHO). Revised WHO classification and treatment of pneumonia in children at health facilities: evidence summaries. (World Health Organization, 2014).
    1. FDA. Amoxil. Available:
    1. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury (2012).
    1. Gillies M, Ranakusuma A, Hoffmann T, Thorning S, McGuire T, Glasziou P, et al. Common harms from amoxicillin: A systematic review and meta-analysis of randomized placebo-controlled trials for any indication. CMAJ. 2015;187(1):E21–E31. doi: 10.1503/cmaj.140848.
    1. Nkwopara E, Schmicker R, Mvalo T, Phiri M, Phiri A, Couasnon M, et al. Analysis of serious adverse events in a paediatric fast breathing pneumonia clinical trial in Malawi. BMJ Open Respir. Res. 2019;6(1):e000415. doi: 10.1136/bmjresp-2019-000415.
    1. Ginsburg AS, Mvalo T, Nkwopara E, McCollum ED, Phiri M, Schmicker R, et al. Amoxicillin for 3 or 5 days for chest-indrawing pneumonia in Malawian children. N. Engl. J. Med. 2020;383(1):13–23. doi: 10.1056/NEJMoa1912400.
    1. Ginsburg AS, May S. Adherence to oral amoxicillin dispersible tablets in children with community-acquired pneumonia enrolled in clinical trials in Malawi. Pneumonia (Nathan) 2021;13(1):10. doi: 10.1186/s41479-021-00089-4.
    1. U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1. [July 2017]. Available from:
    1. Ginsburg AS, May S. Fast-breathing vs chest-indrawing childhood pneumonia: Baseline characteristics. Int. J. Infect. Dis. 2021;104:361–362. doi: 10.1016/j.ijid.2020.12.082.
    1. le Roux DM, Nicol MP, Myer L, Vanker A, Stadler JAM, von Delft E, et al. Lower respiratory tract infections in children in a well-vaccinated South African birth cohort: Spectrum of disease and risk factors. Clin Infect Dis. 2019;69(9):1588–1596. doi: 10.1093/cid/ciz017.
    1. Marrs T, Fox AT, Lack G, du Toit G. The diagnosis and management of antibiotic allergy in children: Systematic review to inform a contemporary approach. Arch. Dis. Child. 2015;100(6):583–588. doi: 10.1136/archdischild-2014-306280.
    1. Addo-Yobo E, Anh DD, El-Sayed HF, Fox LM, Fox MP, MacLeod W, et al. Outpatient treatment of children with severe pneumonia with oral amoxicillin in four countries: The MASS study. Trop. Med. Int. Health. 2011;16(8):995–1006. doi: 10.1111/j.1365-3156.2011.02787.x.
    1. Sadruddin S, Khan IUH, Fox MP, Bari A, Khan A, Thea DM, et al. Comparison of 3 days amoxicillin versus 5 days co-trimoxazole for treatment of fast-breathing pneumonia by community health workers in children aged 2–59 months in Pakistan: A cluster-randomized trial. Clin. Infect. Dis. 2019;69(3):397–404. doi: 10.1093/cid/ciy918.
    1. Shahrin L, Chisti MJ, Sarmin M, Rahman ASMM, Shahid ASMS, Islam MZ, et al. Intravenous amoxicillin plus intravenous gentamicin for children with severe pneumonia in Bangladesh: An open-label, randomized, non-inferiority controlled trial. Life (Basel) 2021;11(12):1299.

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