Pharmacokinetics and pharmacodynamics of azithromycin in severe malaria bacterial co-infection in African children

Can children with severe malaria and bacterial co-infection be accurately identified using clinical criteria (or in combination with a rapid test) compared to those without co-infection and what dose of azithromycin is adequate?

What is this study about?

This is a Phase II trial looking at the pharmacokinetics and pharmacodynamics (PKPD) of azithromycin in severe malaria bacterial co-infection in African children using three different doses. It is also examining if children with severe malaria with culture-proven bacteraemia can be accurately identified using clinical criteria alone or in combination with rapid diagnostic biomarker tests, in comparison with a control cohort of children hospitalized with severe malaria but not meeting Teule criteria, at low risk of bacterial co-infection. The primary outcome is change in c-reactive protein (CRP) which is a putative marker of sepsis at 72 hours (for the PKPD study) and microbiological cure and survival at 7 days.

Establishing which children with malaria are at greatest risk of bacteraemia is critical to pragmatically inform a policy for targeted antibiotic therapy that could substantially reduce malaria-associated mortality while minimising the risks of excess antibiotic prescribing. This trial, designed to inform a key research gap, proposes targeted and appropriate antimicrobial treatment of children with severe malaria at greatest risk of bacterial co-infection. Incorporated in the design are experimental data to demonstrate that the mechanisms that azithromycin is targeting are biologically reasonable, that the dosing is providing the right exposure, and that there is a PKPD link between azithromycin exposure and the potential mechanisms for reducing both short-term and microbiological cure (7-day) and longer-term mortality (28-day). Sub-group analyses will also enable us to identify whether antimicrobial treatment can be further targeted.

Type of study

Randomised trial

Who is funding the study?

Global Health Trials Development grant by the MRC and Wellcome Trust.

When is it taking place?

September 2020 - March 2022

Where is it taking place?

Uganda (Mbale Regional Referral Hospital and Soroti Regional Referral Hospital) and Kenya (Kilifi Hospital)

Who is included?

105 children (6 months to 12 years) with temperature >38°C or <36°C and evidence of severe malaria will be included in azithromycin randomisation. An additional 50 children without severe malaria (but with temperature >38°C or <36°C) will be enrolled to a control group that receive standard of care.