Azithromycin for the prevention of rehospitalisation and death among Kenyan children being discharged from hospital: a double-blind, placebo-controlled, randomised controlled trial
Summary: Background: Mass drug administration of azithromycin to children in sub-Saharan Africa has been shown to improve survival in high-mortality settings. The period after hospital discharge is a time of elevated risk unaddressed by current interventions and might provide an opportunity for tar...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-11-01
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| Series: | The Lancet Global Health |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214109X21003478 |
| _version_ | 1819026373733253120 |
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| author | Patricia B Pavlinac, PhD Benson O Singa, MBChB Kirkby D Tickell, MBBS Rebecca L Brander, PhD Christine J McGrath, PhD Mary Amondi, BA Joyce Otieno, DIP Elizabeth Akinyi, BSc Doreen Rwigi, BSc Joseph D Carreon, MS Stephanie N Tornberg-Belanger, MPH Ruth Nduati, MMed Joseph B Babigumira, PhD Liru Meshak, MBChB George Bogonko, MMed Samuel Kariuki, PhD Barbra A Richardson, PhD Grace C John-Stewart, MD Judd L Walson, MD |
| author_facet | Patricia B Pavlinac, PhD Benson O Singa, MBChB Kirkby D Tickell, MBBS Rebecca L Brander, PhD Christine J McGrath, PhD Mary Amondi, BA Joyce Otieno, DIP Elizabeth Akinyi, BSc Doreen Rwigi, BSc Joseph D Carreon, MS Stephanie N Tornberg-Belanger, MPH Ruth Nduati, MMed Joseph B Babigumira, PhD Liru Meshak, MBChB George Bogonko, MMed Samuel Kariuki, PhD Barbra A Richardson, PhD Grace C John-Stewart, MD Judd L Walson, MD |
| author_sort | Patricia B Pavlinac, PhD |
| collection | DOAJ |
| description | Summary: Background: Mass drug administration of azithromycin to children in sub-Saharan Africa has been shown to improve survival in high-mortality settings. The period after hospital discharge is a time of elevated risk unaddressed by current interventions and might provide an opportunity for targeting empirical azithromycin administration. We aimed to assess the efficacy of azithromycin administered at hospital discharge on risk of death and rehospitalisation in Kenyan children younger than 5 years. Methods: In this double-blind, placebo-controlled randomised trial, children were randomly assigned (1:1) to receive a 5-day course of azithromycin (oral suspension 10 mg/kg on day 1, followed by 5mg/kg per day on days 2–5) or identically appearing and tasting placebo at discharge from four hospitals in western Kenya. Children were eligible if they were aged 1–59 months at hospital discharge, weighed at least 2 kg, and had been admitted to hospital for any medical reason other than trauma, poisoning, or congenital anomaly. The primary outcome was death or rehospitalisation in the subsequent 6-month period in a modified intention-to-treat population, compared by randomisation group with Cox proportional hazards regression and Kaplan-Meier. Azithromycin resistance in Escherichia coli isolates from a random subset of children was compared by randomisation group with generalised estimating equations. This trial is registered with ClinicalTrials.gov, NCT02414399. Findings: Between June 28, 2016, and Nov 4, 2019, 1400 children were enrolled in the trial at discharge from hospital, with 703 (50·2%) randomly assigned to azithromycin and 697 (49·8%) to placebo. Among the 1398 children included in the modified intention-to-treat analysis (702 in the azithromycin group and 696 in the placebo group), the incidence of death or rehospitalisation was 20·4 per 100 child-years in the azithromycin group and 22·5 per 100 child-years in the placebo group (adjusted hazard ratio 0·91, 95·5% CI 0·64–1·29, p=0·58). Azithromycin resistance was common in commensal E coli isolates from enrolled children before randomisation (37·7% of 406 isolates) despite only 3·7% of children having received a macrolide antibiotic during the hospitalisation. Azithromycin resistance was slightly higher at 3 months after randomisation in the azithromycin group (26·9%) than in the placebo group (19·1%; adjusted prevalence ratio 1·41, 95% CI 0·95–2·09, p=0·088), with no difference observed at 6 months (1·17, 0·78–1·76, p=0·44). Interpretation: We did not observe a significant benefit of a 5-day course of azithromycin delivered to children younger than 5 years at hospital discharge despite the overall high risk of mortality and rehospitalisation. These findings highlight the need for more research into mechanisms and interventions for prevention of morbidity and mortality in the post-discharge period. Funding: Eunice Kennedy Shriver National Institute of Child Health & Human Development. |
| first_indexed | 2024-12-21T05:25:33Z |
| format | Article |
| id | doaj.art-e59df23fed3b45fdab2c4f12a23fc9a2 |
| institution | Directory Open Access Journal |
| issn | 2214-109X |
| language | English |
| last_indexed | 2024-12-21T05:25:33Z |
| publishDate | 2021-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | The Lancet Global Health |
| spelling | doaj.art-e59df23fed3b45fdab2c4f12a23fc9a22022-12-21T19:14:42ZengElsevierThe Lancet Global Health2214-109X2021-11-01911e1569e1578Azithromycin for the prevention of rehospitalisation and death among Kenyan children being discharged from hospital: a double-blind, placebo-controlled, randomised controlled trialPatricia B Pavlinac, PhD0Benson O Singa, MBChB1Kirkby D Tickell, MBBS2Rebecca L Brander, PhD3Christine J McGrath, PhD4Mary Amondi, BA5Joyce Otieno, DIP6Elizabeth Akinyi, BSc7Doreen Rwigi, BSc8Joseph D Carreon, MS9Stephanie N Tornberg-Belanger, MPH10Ruth Nduati, MMed11Joseph B Babigumira, PhD12Liru Meshak, MBChB13George Bogonko, MMed14Samuel Kariuki, PhD15Barbra A Richardson, PhD16Grace C John-Stewart, MD17Judd L Walson, MD18Department of Global Health, University of Washington, Seattle, WA, USA; Correspondence to: Dr Patricia B Pavlinac, Department of Global Health, University of Washington, Seattle, WA 98105, USADepartment of Global Health, University of Washington, Seattle, WA, USA; Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya; Childhood Acute Illness and Nutrition Network, Nairobi, KenyaDepartment of Global Health, University of Washington, Seattle, WA, USA; Childhood Acute Illness and Nutrition Network, Nairobi, KenyaBill & Melinda Gates Foundation, Seattle, WA, USADepartment of Global Health, University of Washington, Seattle, WA, USA; Childhood Acute Illness and Nutrition Network, Nairobi, KenyaInternational AIDS Vaccine Initiative, Nairobi, KenyaCentre for Clinical Research, Kenya Medical Research Institute, Nairobi, KenyaCentre for Clinical Research, Kenya Medical Research Institute, Nairobi, KenyaCentre for Clinical Research, Kenya Medical Research Institute, Nairobi, KenyaThe Clovers' Leaves Limited Company, Tempe, AZ, USADepartment of Epidemiology, University of Washington, Seattle, WA, USADepartment of Pediatrics and Child Health, University of Nairobi, Kenyatta National Hospital, Nairobi, KenyaDepartment of Global Health, University of Washington, Seattle, WA, USAHoma Bay Teaching and Referral Hospital, Homa Bay, KenyaKisii Teaching and Referral Hospital, Kisii, KenyaCentre for Microbiology Research, Kenya Medical Research Institute, Nairobi, KenyaDepartment of Global Health, University of Washington, Seattle, WA, USA; Department of Biostatistics, University of Washington, Seattle, WA, USADepartment of Global Health, University of Washington, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA; Departments of Pediatrics and Medicine—Allergy and Infectious Diseases, University of Washington, Seattle, WA, USADepartment of Global Health, University of Washington, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA; Departments of Pediatrics and Medicine—Allergy and Infectious Diseases, University of Washington, Seattle, WA, USA; Childhood Acute Illness and Nutrition Network, Nairobi, KenyaSummary: Background: Mass drug administration of azithromycin to children in sub-Saharan Africa has been shown to improve survival in high-mortality settings. The period after hospital discharge is a time of elevated risk unaddressed by current interventions and might provide an opportunity for targeting empirical azithromycin administration. We aimed to assess the efficacy of azithromycin administered at hospital discharge on risk of death and rehospitalisation in Kenyan children younger than 5 years. Methods: In this double-blind, placebo-controlled randomised trial, children were randomly assigned (1:1) to receive a 5-day course of azithromycin (oral suspension 10 mg/kg on day 1, followed by 5mg/kg per day on days 2–5) or identically appearing and tasting placebo at discharge from four hospitals in western Kenya. Children were eligible if they were aged 1–59 months at hospital discharge, weighed at least 2 kg, and had been admitted to hospital for any medical reason other than trauma, poisoning, or congenital anomaly. The primary outcome was death or rehospitalisation in the subsequent 6-month period in a modified intention-to-treat population, compared by randomisation group with Cox proportional hazards regression and Kaplan-Meier. Azithromycin resistance in Escherichia coli isolates from a random subset of children was compared by randomisation group with generalised estimating equations. This trial is registered with ClinicalTrials.gov, NCT02414399. Findings: Between June 28, 2016, and Nov 4, 2019, 1400 children were enrolled in the trial at discharge from hospital, with 703 (50·2%) randomly assigned to azithromycin and 697 (49·8%) to placebo. Among the 1398 children included in the modified intention-to-treat analysis (702 in the azithromycin group and 696 in the placebo group), the incidence of death or rehospitalisation was 20·4 per 100 child-years in the azithromycin group and 22·5 per 100 child-years in the placebo group (adjusted hazard ratio 0·91, 95·5% CI 0·64–1·29, p=0·58). Azithromycin resistance was common in commensal E coli isolates from enrolled children before randomisation (37·7% of 406 isolates) despite only 3·7% of children having received a macrolide antibiotic during the hospitalisation. Azithromycin resistance was slightly higher at 3 months after randomisation in the azithromycin group (26·9%) than in the placebo group (19·1%; adjusted prevalence ratio 1·41, 95% CI 0·95–2·09, p=0·088), with no difference observed at 6 months (1·17, 0·78–1·76, p=0·44). Interpretation: We did not observe a significant benefit of a 5-day course of azithromycin delivered to children younger than 5 years at hospital discharge despite the overall high risk of mortality and rehospitalisation. These findings highlight the need for more research into mechanisms and interventions for prevention of morbidity and mortality in the post-discharge period. Funding: Eunice Kennedy Shriver National Institute of Child Health & Human Development.http://www.sciencedirect.com/science/article/pii/S2214109X21003478 |
| spellingShingle | Patricia B Pavlinac, PhD Benson O Singa, MBChB Kirkby D Tickell, MBBS Rebecca L Brander, PhD Christine J McGrath, PhD Mary Amondi, BA Joyce Otieno, DIP Elizabeth Akinyi, BSc Doreen Rwigi, BSc Joseph D Carreon, MS Stephanie N Tornberg-Belanger, MPH Ruth Nduati, MMed Joseph B Babigumira, PhD Liru Meshak, MBChB George Bogonko, MMed Samuel Kariuki, PhD Barbra A Richardson, PhD Grace C John-Stewart, MD Judd L Walson, MD Azithromycin for the prevention of rehospitalisation and death among Kenyan children being discharged from hospital: a double-blind, placebo-controlled, randomised controlled trial The Lancet Global Health |
| title | Azithromycin for the prevention of rehospitalisation and death among Kenyan children being discharged from hospital: a double-blind, placebo-controlled, randomised controlled trial |
| title_full | Azithromycin for the prevention of rehospitalisation and death among Kenyan children being discharged from hospital: a double-blind, placebo-controlled, randomised controlled trial |
| title_fullStr | Azithromycin for the prevention of rehospitalisation and death among Kenyan children being discharged from hospital: a double-blind, placebo-controlled, randomised controlled trial |
| title_full_unstemmed | Azithromycin for the prevention of rehospitalisation and death among Kenyan children being discharged from hospital: a double-blind, placebo-controlled, randomised controlled trial |
| title_short | Azithromycin for the prevention of rehospitalisation and death among Kenyan children being discharged from hospital: a double-blind, placebo-controlled, randomised controlled trial |
| title_sort | azithromycin for the prevention of rehospitalisation and death among kenyan children being discharged from hospital a double blind placebo controlled randomised controlled trial |
| url | http://www.sciencedirect.com/science/article/pii/S2214109X21003478 |
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