Twenty-four Month Outcomes of Extended- Versus Standard-course Antibiotic Therapy in Children Hospitalized With Pneumonia in High-risk Settings: A Randomized Controlled Trial

Hing C Kok^{1

2}, Gabrielle B McCallum¹, Stephanie T Yerkovich^{1

3}, Keith Grimwood^{4

5}, Siew M Fong², Anna M Nathan⁶, Catherine A Byrnes^{7

8}, Robert S Ware⁴, Nachal Nachiappan⁹, Noorazlina Saari⁹, Peter S Morris^{1

10}, Tsin W Yeo^{1

11}, Victor M Oguoma^{1

12}, I Brent Masters^{3

13}, Jessie A de Bruyne⁶, Kah P Eg⁶, Bilawara Lee^{1

14}, Mong H Ooi^{15

16}, John W Upham¹⁷, Paul J Torzillo^{18

19}, Anne B Chang^{1

3

13}

Affiliations

¹ From the Child and Maternal Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia.
² Department of Pediatrics, Sabah Women and Children's Hospital, Kota Kinabalu, Sabah, Malaysia.
³ Australian Centre for Health Services Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
⁴ School of Medicine and Dentistry, Griffith University, Gold Coast, Queensland, Australia.
⁵ Departments of Infectious Diseases and Pediatrics, Gold Coast Health, Gold Coast, Queensland,, Australia.
⁶ Department of Pediatrics, University of Malaya, Kuala Lumpur, Malaysia.
⁷ Department of Pediatrics, University of Auckland, Auckland, New Zealand.
⁸ Respiratory Department, Starship Children's Hospital, Auckland, New Zealand.
⁹ Department of Pediatrics, Tengku Ampuan Rahimah Hospital, Klang, Selangor, Malaysia.
¹⁰ Department of Pediatrics, Royal Darwin Hospital, Darwin, Northern Territory, Australia.
¹¹ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
¹² Poche Centre for Indigenous Health, The University of Queensland, Brisbane, Queensland, Australia.
¹³ Department of Respiratory and Sleep Medicine, Queensland Children's Hospital, Brisbane, Queensland, Australia.
¹⁴ First Nations Leadership & Engagement, Charles Darwin University, Darwin, Northern Territory, Australia.
¹⁵ Department of Pediatrics, Sarawak General Hospital, Sarawak, Malaysia.
¹⁶ Institute of Health and Community Medicine, Universiti Malaysia Sarawak, Sarawak, Malaysia.
¹⁷ Diamantina Institute, The University of Queensland, and Translational Research Institute, Brisbane, Queensland, Australia.
¹⁸ Central Clinical School, University of Sydney, Sydney, New South Wales, Australia.
¹⁹ Department of Respiratory Medicine, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.

PMID: 38830139
DOI: 10.1097/INF.0000000000004407

Randomized Controlled Trial

Twenty-four Month Outcomes of Extended- Versus Standard-course Antibiotic Therapy in Children Hospitalized With Pneumonia in High-risk Settings: A Randomized Controlled Trial

Hing C Kok et al. Pediatr Infect Dis J. 2024.

. 2024 Sep 1;43(9):872-879.

doi: 10.1097/INF.0000000000004407. Epub 2024 Jun 3.

Authors

Affiliations

¹ From the Child and Maternal Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia.
² Department of Pediatrics, Sabah Women and Children's Hospital, Kota Kinabalu, Sabah, Malaysia.
³ Australian Centre for Health Services Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
⁴ School of Medicine and Dentistry, Griffith University, Gold Coast, Queensland, Australia.
⁵ Departments of Infectious Diseases and Pediatrics, Gold Coast Health, Gold Coast, Queensland,, Australia.
⁶ Department of Pediatrics, University of Malaya, Kuala Lumpur, Malaysia.
⁷ Department of Pediatrics, University of Auckland, Auckland, New Zealand.
⁸ Respiratory Department, Starship Children's Hospital, Auckland, New Zealand.
⁹ Department of Pediatrics, Tengku Ampuan Rahimah Hospital, Klang, Selangor, Malaysia.
¹⁰ Department of Pediatrics, Royal Darwin Hospital, Darwin, Northern Territory, Australia.
¹¹ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
¹² Poche Centre for Indigenous Health, The University of Queensland, Brisbane, Queensland, Australia.
¹³ Department of Respiratory and Sleep Medicine, Queensland Children's Hospital, Brisbane, Queensland, Australia.
¹⁴ First Nations Leadership & Engagement, Charles Darwin University, Darwin, Northern Territory, Australia.
¹⁵ Department of Pediatrics, Sarawak General Hospital, Sarawak, Malaysia.
¹⁶ Institute of Health and Community Medicine, Universiti Malaysia Sarawak, Sarawak, Malaysia.
¹⁷ Diamantina Institute, The University of Queensland, and Translational Research Institute, Brisbane, Queensland, Australia.
¹⁸ Central Clinical School, University of Sydney, Sydney, New South Wales, Australia.
¹⁹ Department of Respiratory Medicine, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.

PMID: 38830139
DOI: 10.1097/INF.0000000000004407

Abstract

Background: Pediatric community-acquired pneumonia (CAP) can lead to long-term respiratory sequelae, including bronchiectasis. We determined if an extended (13-14 days) versus standard (5-6 days) antibiotic course improves long-term outcomes in children hospitalized with CAP from populations at high risk of chronic respiratory disease.

Methods: We undertook a multicenter, double-blind, superiority, randomized controlled trial involving 7 Australian, New Zealand, and Malaysian hospitals. Children aged 3 months to ≤5 years hospitalized with radiographic-confirmed CAP who received 1-3 days of intravenous antibiotics, then 3 days of oral amoxicillin-clavulanate, were randomized to either extended-course (8-day oral amoxicillin-clavulanate) or standard-course (8-day oral placebo) arms. Children were reviewed at 12 and 24 months. The primary outcome was children with the composite endpoint of chronic respiratory symptoms/signs (chronic cough at 12 and 24 months; ≥1 subsequent hospitalized acute lower respiratory infection by 24 months; or persistent and/or new chest radiographic signs at 12-months) at 24-months postdischarge, analyzed by intention-to-treat, where children with incomplete follow-up were assumed to have chronic respiratory symptoms/signs ("worst-case" scenario).

Results: A total of 324 children were randomized [extended-course (n = 163), standard-course (n = 161)]. For our primary outcome, chronic respiratory symptoms/signs occurred in 97/163 (60%) and 94/161 (58%) children in the extended-courses and standard-courses, respectively [relative risk (RR) = 1.02, 95% confidence interval (CI): 0.85-1.22]. Among children where all sub-composite outcomes were known, chronic respiratory symptoms/signs between groups, RR = 1.10, 95% CI: 0.69-1.76 [extended-course = 27/93 (29%) and standard-course = 24/91 (26%)]. Additional sensitivity analyses also revealed no between-group differences.

Conclusion: Among children from high-risk populations hospitalized with CAP, 13-14 days of antibiotics (versus 5-6 days), did not improve long-term respiratory outcomes.

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Conflict of interest statement

A.B.C., K.G., S.T.Y., R.S.W., G.B.M., P.S.M., J.W.U., and P.J.T. report grants from NHMRC and NHMRC-managed grants (Medical Research Futures Fund), during the conduct of the study. ABC is also an independent data management committee member for clinical trials for Moderna (COVID-19 and EBV vaccines) and of an unlicensed vaccine (GlaxoSmithKline) and monoclonal antibody (AstraZeneca), received fees from the institution for consulting on the study designs for Zambon and Boehringer Ingelheim, airfares for travel from the European Respiratory Society and Boehringer Ingelheim, and personal fees for being an author of two UpToDate chapters that are outside the submitted work. The other authors have no conflicts of interest to disclose.

References

1. McAllister DA, Liu L, Shi T, et al. Global, regional, and national estimates of pneumonia morbidity and mortality in children younger than 5 years between 2000 and 2015: a systematic analysis. Lancet Glob Health. 2019;7:e47–e57.
1. Madhi SA, De Wals P, Grijalva CG, et al. The burden of childhood pneumonia in the developed world: a review of the literature. Pediatr Infect Dis J. 2013;32:e119–e127.
1. Valery PC, Torzillo PJ, Mulholland K, et al. Hospital-based case-control study of bronchiectasis in indigenous children in Central Australia. Pediatr Infect Dis J. 2004;23:902–908.
1. Bui DS, Lodge CJ, Burgess JA, et al. Childhood predictors of lung function trajectories and future COPD risk: a prospective cohort study from the first to the sixth decade of life. Lancet Respir Med. 2018;6:535–544.
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Twenty-four Month Outcomes of Extended- Versus Standard-course Antibiotic Therapy in Children Hospitalized With Pneumonia in High-risk Settings: A Randomized Controlled Trial

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Twenty-four Month Outcomes of Extended- Versus Standard-course Antibiotic Therapy in Children Hospitalized With Pneumonia in High-risk Settings: A Randomized Controlled Trial

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