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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.

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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.
Authors: Olupot-Olupot, Peter1,2, Okiror, William1,2, Mnjalla, Hellen3, Muhindo, Rita1,2, Uyoga, Sophie3, Mpoya, Ayub3, Williams, Thomas N.3,4, terHeine, Rob5, Burger, David M5, Urban, Britta6, Connon, Roisin7, George, Elizabeth C.7, Gibb, Diana M.7, Walker, A. Sarah7, Maitland, Kathryn3,4 k.maitland@imperial.ac.uk
Source: Wellcome Open Research. 2023, p1-24. 24p.
Subject Terms: *Malaria, *Bacterial communities, Pharmacokinetics, Pharmacodynamics, Azithromycin
Abstract: 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. [ABSTRACT FROM AUTHOR]
Copyright of Wellcome Open Research is the property of Wellcome Trust and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: 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.
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  Data: <searchLink fieldCode="AR" term="%22Olupot-Olupot%2C+Peter%22">Olupot-Olupot, Peter</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Okiror%2C+William%22">Okiror, William</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Mnjalla%2C+Hellen%22">Mnjalla, Hellen</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Muhindo%2C+Rita%22">Muhindo, Rita</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Uyoga%2C+Sophie%22">Uyoga, Sophie</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Mpoya%2C+Ayub%22">Mpoya, Ayub</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Williams%2C+Thomas+N%2E%22">Williams, Thomas N.</searchLink><relatesTo>3,4</relatesTo><br /><searchLink fieldCode="AR" term="%22terHeine%2C+Rob%22">terHeine, Rob</searchLink><relatesTo>5</relatesTo><br /><searchLink fieldCode="AR" term="%22Burger%2C+David+M%22">Burger, David M</searchLink><relatesTo>5</relatesTo><br /><searchLink fieldCode="AR" term="%22Urban%2C+Britta%22">Urban, Britta</searchLink><relatesTo>6</relatesTo><br /><searchLink fieldCode="AR" term="%22Connon%2C+Roisin%22">Connon, Roisin</searchLink><relatesTo>7</relatesTo><br /><searchLink fieldCode="AR" term="%22George%2C+Elizabeth+C%2E%22">George, Elizabeth C.</searchLink><relatesTo>7</relatesTo><br /><searchLink fieldCode="AR" term="%22Gibb%2C+Diana+M%2E%22">Gibb, Diana M.</searchLink><relatesTo>7</relatesTo><br /><searchLink fieldCode="AR" term="%22Walker%2C+A%2E+Sarah%22">Walker, A. Sarah</searchLink><relatesTo>7</relatesTo><br /><searchLink fieldCode="AR" term="%22Maitland%2C+Kathryn%22">Maitland, Kathryn</searchLink><relatesTo>3,4</relatesTo><i> k.maitland@imperial.ac.uk</i>
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  Data: <searchLink fieldCode="JN" term="%22Wellcome+Open+Research%22">Wellcome Open Research</searchLink>. 2023, p1-24. 24p.
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  Data: *<searchLink fieldCode="DE" term="%22Malaria%22">Malaria</searchLink><br />*<searchLink fieldCode="DE" term="%22Bacterial+communities%22">Bacterial communities</searchLink><br /><searchLink fieldCode="DE" term="%22Pharmacokinetics%22">Pharmacokinetics</searchLink><br /><searchLink fieldCode="DE" term="%22Pharmacodynamics%22">Pharmacodynamics</searchLink><br /><searchLink fieldCode="DE" term="%22Azithromycin%22">Azithromycin</searchLink>
– Name: Abstract
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  Data: 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. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Wellcome Open Research is the property of Wellcome Trust and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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      – Type: doi
        Value: 10.12688/wellcomeopenres.16968.2
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      – Code: eng
        Text: English
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        PageCount: 24
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    Subjects:
      – SubjectFull: Malaria
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      – SubjectFull: Bacterial communities
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      – SubjectFull: Pharmacokinetics
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      – SubjectFull: Pharmacodynamics
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      – SubjectFull: Azithromycin
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      – TitleFull: 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.
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              Text: 2023
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