Azithromycin to Prevent Post-discharge Morbidity and Mortality in Kenyan Children

Summary

Children hospitalized with severe illness in sub-Saharan Africa are at high risk of morbidity and mortality following discharge from hospital. These children represent an accessible high-risk population in which targeted interventions to prevent morbidity and mortality could have dramatic impact. A large cluster randomized trial of azithromycin delivered in a mass drug administration program within trachoma endemic areas in sub-Saharan Africa demonstrated an almost 50% mortality benefit in children 1-9 years of age in treated communities. However, mass drug administration of azithromycin leads to the rapid emergence of macrolide resistance within treated communities and is expensive. The targeted delivery of azithromycin to children at hospital discharge may be a novel and practical intervention to maximize benefit while minimizing risk of antibiotic resistance. This is a randomized, double-blind, placebo-controlled trial to determine the efficacy of azithromycin provided at discharge, compared to placebo, in reducing mortality and re-hospitalization rates in children age 1-59 months in Kenya. The study will also investigate potential mechanisms by which azithromycin may reduce morbidity and mortality in this population and will assess the emergence of antibiotic resistance among treated individuals and their primary caregivers. A cost-effectiveness analysis of the intervention will also be conducted.

Timeline

Start

2016-06-28

Primary completion

2020-05-04

Completion

2025-12-28

Publications

• Background Porco TC, Gebre T, Ayele B, House J, Keenan J, Zhou Z, Hong KC, Stoller N, Ray KJ, Emerson P, Gaynor BD, Lietman TM. Effect of mass distribution of azithromycin for trachoma control on overall mortality in Ethiopian children: a randomized trial. JAMA. 2009 Sep 2;302(9):962-8. doi: 10.1001/jama.2009.1266.
• Background Moisi JC, Gatakaa H, Berkley JA, Maitland K, Mturi N, Newton CR, Njuguna P, Nokes J, Ojal J, Bauni E, Tsofa B, Peshu N, Marsh K, Williams TN, Scott JA. Excess child mortality after discharge from hospital in Kilifi, Kenya: a retrospective cohort analysis. Bull World Health Organ. 2011 Oct 1;89(10):725-32, 732A. doi: 10.2471/BLT.11.089235. Epub 2011 Jul 13.
• Background Lozano R, Wang H, Foreman KJ, Rajaratnam JK, Naghavi M, Marcus JR, Dwyer-Lindgren L, Lofgren KT, Phillips D, Atkinson C, Lopez AD, Murray CJ. Progress towards Millennium Development Goals 4 and 5 on maternal and child mortality: an updated systematic analysis. Lancet. 2011 Sep 24;378(9797):1139-65. doi: 10.1016/S0140-6736(11)61337-8. Epub 2011 Sep 19.
• Background Veirum JE, Sodeman M, Biai S, Hedegard K, Aaby P. Increased mortality in the year following discharge from a paediatric ward in Bissau, Guinea-Bissau. Acta Paediatr. 2007 Dec;96(12):1832-8. doi: 10.1111/j.1651-2227.2007.00562.x.
• Background Snow RW, Howard SC, Mung'Ala-Odera V, English M, Molyneux CS, Waruiru C, Mwangi I, Roberts DJ, Donnelly CA, Marsh K. Paediatric survival and re-admission risks following hospitalization on the Kenyan coast. Trop Med Int Health. 2000 May;5(5):377-83. doi: 10.1046/j.1365-3156.2000.00568.x.
• Background Keenan JD, Ayele B, Gebre T, Zerihun M, Zhou Z, House JI, Gaynor BD, Porco TC, Emerson PM, Lietman TM. Childhood mortality in a cohort treated with mass azithromycin for trachoma. Clin Infect Dis. 2011 Apr 1;52(7):883-8. doi: 10.1093/cid/cir069.
• Background Trehan I, Goldbach HS, LaGrone LN, Meuli GJ, Wang RJ, Maleta KM, Manary MJ. Antibiotics as part of the management of severe acute malnutrition. N Engl J Med. 2013 Jan 31;368(5):425-35. doi: 10.1056/NEJMoa1202851.
• Background Walker AS, Mulenga V, Ford D, Kabamba D, Sinyinza F, Kankasa C, Chintu C, Gibb DM; CHAP Team. The impact of daily cotrimoxazole prophylaxis and antiretroviral therapy on mortality and hospital admissions in HIV-infected Zambian children. Clin Infect Dis. 2007 May 15;44(10):1361-7. doi: 10.1086/515396. Epub 2007 Apr 12.
• Background Roy SK, Chowdhury AK, Rahaman MM. Excess mortality among children discharged from hospital after treatment for diarrhoea in rural Bangladesh. Br Med J (Clin Res Ed). 1983 Oct 15;287(6399):1097-9. doi: 10.1136/bmj.287.6399.1097.
• Background Wiens MO, Pawluk S, Kissoon N, Kumbakumba E, Ansermino JM, Singer J, Ndamira A, Larson C. Pediatric post-discharge mortality in resource poor countries: a systematic review. PLoS One. 2013 Jun 25;8(6):e66698. doi: 10.1371/journal.pone.0066698. Print 2013.
• Background Berkley JA, Bejon P, Mwangi T, Gwer S, Maitland K, Williams TN, Mohammed S, Osier F, Kinyanjui S, Fegan G, Lowe BS, English M, Peshu N, Marsh K, Newton CR. HIV infection, malnutrition, and invasive bacterial infection among children with severe malaria. Clin Infect Dis. 2009 Aug 1;49(3):336-43. doi: 10.1086/600299.
• Background Bernstein DS. Medical student indebtedness and choice of specialty. JAMA. 1992 Apr 8;267(14):1921. No abstract available.
• Background Pavlinac PB, Singa BO, John-Stewart GC, Richardson BA, Brander RL, McGrath CJ, Tickell KD, Amondi M, Rwigi D, Babigumira JB, Kariuki S, Nduati R, Walson JL. Azithromycin to prevent post-discharge morbidity and mortality in Kenyan children: a protocol for a randomised, double-blind, placebo-controlled trial (the Toto Bora trial). BMJ Open. 2017 Dec 29;7(12):e019170. doi: 10.1136/bmjopen-2017-019170.
• Libby TE, Karani A, Tickell KD, Akech D, Singa B, Rwigi D, Kariuki K, Onamu N, Ounga D, Berkley JA, Walson JL, Scott JAG, Pavlinac PB. The Effect of a 5-Day Course of Azithromycin on Streptococcus Pneumoniae Carriage and Antimicrobial Resistance Among Kenyan Children Discharged From Hospital. J Infect Dis. 2026 May 15;233(5):957-965. doi: 10.1093/infdis/jiag028.
• Atlas HE, Mogeni P, Shawon RA, Tickell KD, Bunyige L, Monchari I, Oongo S, Diakhate MM, Brander RL, Liru M, Bogonko G, Nduati R, Richardson BA, John-Stewart G, Walson JL, Singa BO, Pavlinac PB, McGrath CJ. Effect of azithromycin on post-discharge growth in Kenyan children. BMJ Glob Health. 2025 Nov 23;10(11):e020294. doi: 10.1136/bmjgh-2025-020294.
• Mogeni P, Ochieng JB, Atlas HE, Tickell KD, Rwigi D, Kariuki K, Aluoch LR, Sonye C, Apondi E, Ambila L, Diakhate MM, Singa BO, Liu J, Platts-Mills JA, Fang FC, Walson JL, Houpt ER, Pavlinac PB. Impact of Macrolide Resistance on Azithromycin for Prevention of Rehospitalization or Death Among Children Discharged From Hospitals in Western Kenya. J Infect Dis. 2025 Aug 14;232(2):e301-e308. doi: 10.1093/infdis/jiaf208.
• Pavlinac PB, Singa B, Huang ML, Shrestha L, Li V, Atlas HE, Diakhate MM, Brander R, Meshak L, Bogonko G, Tickell KD, McGrath CJ, Machuara IM, Ounga DO, Berkley JA, Richardson BA, John-Stewart G, Walson JL, Slyker J. Cytomegalovirus Viremia Predicts Postdischarge Mortality in Kenyan HIV-Exposed Uninfected Children. J Infect Dis. 2022 Nov 1;226(9):1519-1527. doi: 10.1093/infdis/jiac047.
• Pavlinac PB, Singa BO, Tickell KD, Brander RL, McGrath CJ, Amondi M, Otieno J, Akinyi E, Rwigi D, Carreon JD, Tornberg-Belanger SN, Nduati R, Babigumira JB, Meshak L, Bogonko G, Kariuki S, Richardson BA, John-Stewart GC, Walson JL. Azithromycin for the prevention of rehospitalisation and death among Kenyan children being discharged from hospital: a double-blind, placebo-controlled, randomised controlled trial. Lancet Glob Health. 2021 Nov;9(11):e1569-e1578. doi: 10.1016/S2214-109X(21)00347-8. Epub 2021 Sep 21.

Drugs

Indications