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Pharmacokinetics and pharmacodynamics of azithromycin in severe malaria bacterial co-infection in African children (TABS-PKPD): a protocol for a Phase II randomised controlled trial
Background: African children with severe malaria are susceptible to Gram-negative bacterial co-infection, largely non-typhoidal Salmonellae, leading to a substantially higher rates of in-hospital and post-discharge mortality than those without bacteraemia. Current evidence for treating co-infection...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
F1000 Research Limited
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10382785/ https://www.ncbi.nlm.nih.gov/pubmed/37519413 http://dx.doi.org/10.12688/wellcomeopenres.16968.2 |
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author | Olupot-Olupot, Peter Okiror, William Mnjalla, Hellen Muhindo, Rita Uyoga, Sophie Mpoya, Ayub Williams, Thomas N terHeine, Rob Burger, David M Urban, Britta Connon, Roisin George, Elizabeth C Gibb, Diana M Walker, A Sarah Maitland, Kathryn |
author_facet | Olupot-Olupot, Peter Okiror, William Mnjalla, Hellen Muhindo, Rita Uyoga, Sophie Mpoya, Ayub Williams, Thomas N terHeine, Rob Burger, David M Urban, Britta Connon, Roisin George, Elizabeth C Gibb, Diana M Walker, A Sarah Maitland, Kathryn |
author_sort | Olupot-Olupot, Peter |
collection | PubMed |
description | Background: African children with severe malaria are susceptible to Gram-negative bacterial co-infection, largely non-typhoidal Salmonellae, leading to a substantially higher rates of in-hospital and post-discharge mortality than those without bacteraemia. Current evidence for treating co-infection is lacking, and there is no consensus on the dosage or length of treatment required. We therefore aimed to establish the appropriate dose of oral dispersible azithromycin as an antimicrobial treatment for children with severe malaria and to investigate whether antibiotics can be targeted to those at greatest risk of bacterial co-infection using clinical criteria alone or in combination with rapid diagnostic biomarker tests. Methods: A Phase I/II open-label trial comparing three doses of azithromycin: 10, 15 and 20 mg/kg spanning the lowest to highest mg/kg doses previously demonstrated to be equally effective as parenteral treatment for other salmonellae infection. Children with the highest risk of bacterial infection will receive five days of azithromycin and followed for 90 days. We will generate relevant pharmacokinetic data by sparse sampling during dosing intervals. We will use population pharmacokinetic modelling to determine the optimal azithromycin dose in severe malaria and investigate azithromycin exposure to change in C-reactive protein, a putative marker of sepsis at 72 hours, and microbiological cure (seven-day), alone and as a composite with seven-day survival. We will also evaluate whether a combination of clinical, point-of-care diagnostic tests, and/or biomarkers can accurately identify the sub-group of severe malaria with culture-proven bacteraemia by comparison with a control cohort of children hospitalized with severe malaria at low risk of bacterial co-infection. Discussion: We plan to study azithromycin because of its favourable microbiological spectrum, its inherent antimalarial and immunomodulatory properties and dosing and safety profile. This study will generate new data to inform the design and sample size for definitive Phase III trial evaluation. Registration: ISRCTN49726849 (27 (th) October 2017). |
format | Online Article Text |
id | pubmed-10382785 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | F1000 Research Limited |
record_format | MEDLINE/PubMed |
spelling | pubmed-103827852023-07-30 Pharmacokinetics and pharmacodynamics of azithromycin in severe malaria bacterial co-infection in African children (TABS-PKPD): a protocol for a Phase II randomised controlled trial Olupot-Olupot, Peter Okiror, William Mnjalla, Hellen Muhindo, Rita Uyoga, Sophie Mpoya, Ayub Williams, Thomas N terHeine, Rob Burger, David M Urban, Britta Connon, Roisin George, Elizabeth C Gibb, Diana M Walker, A Sarah Maitland, Kathryn Wellcome Open Res Study Protocol Background: African children with severe malaria are susceptible to Gram-negative bacterial co-infection, largely non-typhoidal Salmonellae, leading to a substantially higher rates of in-hospital and post-discharge mortality than those without bacteraemia. Current evidence for treating co-infection is lacking, and there is no consensus on the dosage or length of treatment required. We therefore aimed to establish the appropriate dose of oral dispersible azithromycin as an antimicrobial treatment for children with severe malaria and to investigate whether antibiotics can be targeted to those at greatest risk of bacterial co-infection using clinical criteria alone or in combination with rapid diagnostic biomarker tests. Methods: A Phase I/II open-label trial comparing three doses of azithromycin: 10, 15 and 20 mg/kg spanning the lowest to highest mg/kg doses previously demonstrated to be equally effective as parenteral treatment for other salmonellae infection. Children with the highest risk of bacterial infection will receive five days of azithromycin and followed for 90 days. We will generate relevant pharmacokinetic data by sparse sampling during dosing intervals. We will use population pharmacokinetic modelling to determine the optimal azithromycin dose in severe malaria and investigate azithromycin exposure to change in C-reactive protein, a putative marker of sepsis at 72 hours, and microbiological cure (seven-day), alone and as a composite with seven-day survival. We will also evaluate whether a combination of clinical, point-of-care diagnostic tests, and/or biomarkers can accurately identify the sub-group of severe malaria with culture-proven bacteraemia by comparison with a control cohort of children hospitalized with severe malaria at low risk of bacterial co-infection. Discussion: We plan to study azithromycin because of its favourable microbiological spectrum, its inherent antimalarial and immunomodulatory properties and dosing and safety profile. This study will generate new data to inform the design and sample size for definitive Phase III trial evaluation. Registration: ISRCTN49726849 (27 (th) October 2017). F1000 Research Limited 2023-01-10 /pmc/articles/PMC10382785/ /pubmed/37519413 http://dx.doi.org/10.12688/wellcomeopenres.16968.2 Text en Copyright: © 2023 Olupot-Olupot P et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Study Protocol Olupot-Olupot, Peter Okiror, William Mnjalla, Hellen Muhindo, Rita Uyoga, Sophie Mpoya, Ayub Williams, Thomas N terHeine, Rob Burger, David M Urban, Britta Connon, Roisin George, Elizabeth C Gibb, Diana M Walker, A Sarah Maitland, Kathryn Pharmacokinetics and pharmacodynamics of azithromycin in severe malaria bacterial co-infection in African children (TABS-PKPD): a protocol for a Phase II randomised controlled trial |
title | Pharmacokinetics and pharmacodynamics of azithromycin in severe malaria bacterial co-infection in African children (TABS-PKPD): a protocol for a Phase II randomised controlled trial |
title_full | Pharmacokinetics and pharmacodynamics of azithromycin in severe malaria bacterial co-infection in African children (TABS-PKPD): a protocol for a Phase II randomised controlled trial |
title_fullStr | Pharmacokinetics and pharmacodynamics of azithromycin in severe malaria bacterial co-infection in African children (TABS-PKPD): a protocol for a Phase II randomised controlled trial |
title_full_unstemmed | Pharmacokinetics and pharmacodynamics of azithromycin in severe malaria bacterial co-infection in African children (TABS-PKPD): a protocol for a Phase II randomised controlled trial |
title_short | Pharmacokinetics and pharmacodynamics of azithromycin in severe malaria bacterial co-infection in African children (TABS-PKPD): a protocol for a Phase II randomised controlled trial |
title_sort | pharmacokinetics and pharmacodynamics of azithromycin in severe malaria bacterial co-infection in african children (tabs-pkpd): a protocol for a phase ii randomised controlled trial |
topic | Study Protocol |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10382785/ https://www.ncbi.nlm.nih.gov/pubmed/37519413 http://dx.doi.org/10.12688/wellcomeopenres.16968.2 |
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