TABS PKPD

TABS-PKPD Study

Full title

Pharmacokinetics and Pharmacodynamics of Azithromycin in Severe Malaria Bacterial Co-infection in African Children

Study overview

Children admitted to hospital with severe malaria may also have serious bacterial infections. These co-infections, particularly those caused by non-typhoidal Salmonella and other Gram-negative bacteria, substantially increase the risk of death.

Because severe malaria and bacterial sepsis can present with similar clinical features, it is often difficult to identify which children require antibiotics. Many African hospitals also have limited access to reliable blood-culture services. Consequently, antibiotics may be prescribed to all children with suspected severe malaria, contributing to unnecessary medicine use and antimicrobial resistance.

The TABS-PKPD Study investigated whether oral dispersible azithromycin could provide effective additional treatment for bacterial co-infection in children with severe malaria. It also examined how azithromycin is absorbed, distributed and eliminated in severely ill children.

Study objectives

The study aimed to:

• Determine an appropriate oral azithromycin dose for children with severe malaria.
• Describe the pharmacokinetics of azithromycin in severely ill African children.
• Examine the relationship between azithromycin exposure and clinical or laboratory responses.
• Assess the safety and tolerability of different azithromycin doses.
• Investigate whether clinical signs and point-of-care biomarkers could identify children at increased risk of bacterial co-infection.
• Generate evidence to inform a future Phase III trial of antibiotic treatment in severe malaria.
• Support targeted antibiotic treatment and reduce unnecessary antimicrobial use.

Study design

TABS-PKPD was an open-label, randomised Phase I/II clinical trial with an additional observational control group.

Children with severe malaria who were considered at increased risk of bacterial co-infection were randomly allocated in equal proportions to receive one of three azithromycin doses:

• 10 mg/kg once daily
• 15 mg/kg once daily
• 20 mg/kg once daily

Azithromycin was administered orally for five days using 100 mg dispersible tablets and weight-band dosing.

A separate group of children with non-severe malaria was enrolled as a control cohort. These children received standard clinical care and were not included in the azithromycin randomisation.

Study population

The study enrolled children aged six months to 12 years with confirmed malaria and either fever or abnormally low body temperature.

Children enrolled in the randomised trial also had at least one feature associated with an increased risk of bacterial co-infection:

• Impaired consciousness
• Prostration or unconsciousness
• Respiratory distress
• Severe anaemia, defined as haemoglobin below 5 g/dL
• HIV infection

Children with major contraindications to azithromycin or taking medicines with important azithromycin interactions were excluded.

Study site

The study was conducted at Mbale Regional Referral Hospital in Eastern Uganda, an area with a high malaria burden.

Mbale Clinical Research Institute participated in study implementation, including clinical research, participant follow-up, laboratory activities and collaboration with national and international research partners.

Study intervention

Children in the randomised trial received oral dispersible azithromycin once daily for five days. The medicine was administered according to predefined weight bands, with doses rounded to the nearest 50 mg to facilitate practical use.

All children with severe malaria also received standard antimalarial treatment, including parenteral artesunate. Clinicians could prescribe other antibiotics when clinically indicated and in accordance with national treatment guidelines.

The azithromycin used in the study was donated by Cipla Limited.

Pharmacokinetic and pharmacodynamic assessments

Pharmacokinetics describes what the body does to a medicine, including its absorption, distribution and elimination. Pharmacodynamics examines the relationship between medicine exposure and its effects on infection or clinical outcomes.

Blood samples were collected at selected times to measure azithromycin concentrations. These measurements were used to develop a population pharmacokinetic model and assess whether children of different weights achieved appropriate medicine exposure.

The pharmacodynamic analysis examined the relationship between azithromycin exposure and:

• Changes in C-reactive protein within 72 hours
• Microbiological cure by day seven
• Survival at day seven
• Survival up to day 90
• Clinical recovery
• Length of hospital stay
• Hospital readmission

Study outcomes

The co-primary outcomes were:

• Change in C-reactive protein from enrolment to 72 hours
• Microbiological cure by day seven, assessed independently and together with seven-day survival

Secondary outcomes included:

• Mortality within 48 hours
• Mortality by days 28 and 90
• Length of hospital stay
• Hospital readmission by day 90
• Serious adverse events
• Severe adverse events
• Adverse events related to azithromycin
• Azithromycin pharmacokinetic exposure
• Identification of clinical or laboratory predictors of bacterial co-infection

Participant enrolment

The study enrolled:

• 105 children with severe malaria, with 35 allocated to each azithromycin dose
• 50 children with non-severe malaria in the observational control group

Recruitment was completed in 2021, and the final participant follow-up took place in January 2022. The study is therefore classified as completed.

Main findings

All three azithromycin doses were generally safe and well tolerated. No serious adverse events were considered related to azithromycin, and only 9% of children required a repeat dose because of vomiting.

C-reactive protein concentrations declined in all three treatment groups. However, the researchers found no evidence that higher systemic azithromycin exposure produced a greater reduction in C-reactive protein.

Only one bacterial pathogen was isolated among the severe-malaria participants. This unexpectedly low number meant that the researchers could not reliably compare microbiological cure between the dose groups or identify clinical and laboratory markers that accurately predicted bacterial co-infection.

Survival, length of hospital stay and readmission were similar across the three treatment groups. The study was not designed or statistically powered to determine whether azithromycin reduced mortality.

Dosing findings

The study found that conventional milligram-per-kilogram dosing did not produce consistent azithromycin exposure across all weight groups. Children with lower body weights tended to have lower predicted exposure, while heavier children could have comparatively higher exposure.

On average, the 15 mg/kg dose achieved an exposure similar to the reference exposure observed in adults. However, pharmacokinetic modelling indicated that an allometric dosing schedule based on WHO weight bands would provide more consistent exposure across children of different sizes.

These findings provide useful dosing information for future clinical trials but do not, by themselves, establish azithromycin as routine treatment for all children with severe malaria.

Interpretation of the findings

The study demonstrated that oral dispersible azithromycin can be safely administered to children with severe malaria and provided valuable information about its pharmacokinetics during severe illness.

However, the low prevalence of confirmed bacterial infection prevented the study from determining whether azithromycin improved microbiological or clinical outcomes. The investigators concluded that further research is required to identify children with severe malaria who are genuinely at high risk of bacterial co-infection.

The findings support the development of better diagnostic approaches and more targeted antibiotic strategies rather than routine, indiscriminate antibiotic use.

Importance of the study

TABS-PKPD addressed an important clinical and public-health challenge. Giving antibiotics to every child with suspected severe malaria may expose many children to medicines they do not require and may contribute to antimicrobial resistance. Conversely, failing to treat bacterial co-infection can lead to preventable deaths.

The study generated evidence that can help researchers design future antibiotic trials, refine paediatric azithromycin dosing and develop practical approaches for identifying children who are most likely to benefit from antibiotic treatment.

Study leadership and collaborating institutions

The study’s Principal Investigator was Professor Kathryn Maitland. Professor Peter Olupot-Olupot and the Mbale-based research team played leading roles in the design, implementation and publication of the study.

Collaborating institutions included:

• Imperial College London
• Mbale Clinical Research Institute
• Mbale Regional Referral Hospital
• Busitema University Faculty of Health Sciences
• MRC Clinical Trials Unit at University College London
• KEMRI-Wellcome Trust Research Programme
• Radboud University Medical Centre
• Wellcome Trust

Funding

The study was funded by the UK Medical Research Council under grant reference MR/P021492/1. The funded project ran from June 2017 to April 2022 and is recorded as closed. View the UKRI project record.

Ethical approval and consent

The study received ethical approval from:

• Imperial College Research Ethics Committee: 17IC3965
• Mbale Regional Referral Hospital Research Ethics Committee: MRRH-REC 095/2017

Written informed consent was obtained from parents or legal guardians. An approved deferred-consent procedure was available for emergency situations in which delaying treatment to complete the full consent process could have placed the child at risk.

Trial registration

The TABS-PKPD Study was registered as:

ISRCTN49726849

The trial was registered on 27 October 2017.

Publications

The main results were published in BMC Medicine in November 2024:

Azithromycin in severe malaria bacterial co-infection in African children: a Phase II randomised controlled trial

The study protocol was published in Wellcome Open Research:

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