Azithromycin in severe malaria bacterial co-infection in African children (TABS-PKPD): a phase II randomised controlled trial
Abstract Background African children with severe malaria are at increased risk of non-typhoidal salmonellae co-infection. Broad-spectrum antibiotics are recommended by guidelines but the optimal class and dose have not been established. We investigated the optimal dose of oral dispersible azithromyc...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2024-11-01
|
| Series: | BMC Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12916-024-03712-5 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850195877230018560 |
|---|---|
| author | Roisin Connon Peter Olupot-Olupot Arthur M. A. Pistorius William Okiror Tonny Ssenyondo Rita Muhindo Sophie Uyoga Ayub Mpoya Thomas N. Williams Diana M. Gibb A. Sarah Walker Rob ter Heine Elizabeth C. George Kathryn Maitland |
| author_facet | Roisin Connon Peter Olupot-Olupot Arthur M. A. Pistorius William Okiror Tonny Ssenyondo Rita Muhindo Sophie Uyoga Ayub Mpoya Thomas N. Williams Diana M. Gibb A. Sarah Walker Rob ter Heine Elizabeth C. George Kathryn Maitland |
| author_sort | Roisin Connon |
| collection | DOAJ |
| description | Abstract Background African children with severe malaria are at increased risk of non-typhoidal salmonellae co-infection. Broad-spectrum antibiotics are recommended by guidelines but the optimal class and dose have not been established. We investigated the optimal dose of oral dispersible azithromycin and whether simple clinical criteria and point-of-care biomarkers could target antibiotics to those at greatest risk of bacterial co-infection. Methods We conducted a phase I/II trial in Ugandan children with severe malaria comparing a 5-day course of azithromycin: 10, 15 and 20 mg/kg of azithromycin (prescribed by weight bands) spanning the dose-range effective for other salmonellae infection. We generated relevant pharmacokinetic (PK) data by sparse sampling during dosing intervals and investigated associations between azithromycin exposure and potential mechanisms (PK-pharmacodynamics) using change in C-reactive protein (CRP), a putative marker of sepsis, at 72 h (continuous) and microbiological cure (7-day) (binary), alone and as a composite with 7-day and 90-day survival. To assess whether clinical or biomarkers could identify those at risk of sepsis, a non-severe malaria control was concurrently enrolled. Results Between January 2020 and January 2022, 105 cases were randomised azithromycin doses: 35 to 10 mg/kg, 35 to 15 mg/kg and 35 to 20 mg/kg. Fifty non-severe malaria controls were concurrently enrolled. CRP reduced in all arms by 72 h with a mean reduction of 65.8 mg/L (95% CI 57.1, 74.5) in the 10 mg/kg arm, 64.8 mg/L (95% CI 56.5, 73.1; p = 0.87) in the 20 mg/kg arm and a smaller reduction 51.2 mg/L (95% CI 42.9, 59.5; p = 0.02) in the 15 mg/kg arm. Microbiological cure alone outcome was not analysed as only one pathogen was found among cases. Three events contributed to the composite outcome of 7-day survival and microbiological cure, with no events in the 15 mg/kg arm. The odds ratio comparing 20 vs 10 mg/kg was 0.50 (95% CI 0.04, 5.79); p = 0.58. Due to the low number of pathogens identified, it was not possible to identify better methods for targeting antibiotics including both the cases and controls. Conclusions We found no evidence for an association between systemic azithromycin exposure and reduction in CRP. Further work is needed to better identify children at highest risk from bacterial co-infection. Trial registration ISRCTN49726849 (registered on 27th October 2017). |
| format | Article |
| id | doaj-art-cbba97ce0815400c98c41c5a71cc30bc |
| institution | OA Journals |
| issn | 1741-7015 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj-art-cbba97ce0815400c98c41c5a71cc30bc2025-08-20T02:13:39ZengBMCBMC Medicine1741-70152024-11-0122111510.1186/s12916-024-03712-5Azithromycin in severe malaria bacterial co-infection in African children (TABS-PKPD): a phase II randomised controlled trialRoisin Connon0Peter Olupot-Olupot1Arthur M. A. Pistorius2William Okiror3Tonny Ssenyondo4Rita Muhindo5Sophie Uyoga6Ayub Mpoya7Thomas N. Williams8Diana M. Gibb9A. Sarah Walker10Rob ter Heine11Elizabeth C. George12Kathryn Maitland13MRC Clinical Trials Unit at University College LondonMbale Clinical Research InstituteDepartment of Pharmacy, Research Institute for Medical InnovationMbale Clinical Research InstituteMbale Clinical Research InstituteMbale Clinical Research InstituteKEMRI-Wellcome Trust Research ProgrammeKEMRI-Wellcome Trust Research ProgrammeKEMRI-Wellcome Trust Research ProgrammeMRC Clinical Trials Unit at University College LondonMRC Clinical Trials Unit at University College LondonDepartment of Pharmacy, Research Institute for Medical InnovationMRC Clinical Trials Unit at University College LondonKEMRI-Wellcome Trust Research ProgrammeAbstract Background African children with severe malaria are at increased risk of non-typhoidal salmonellae co-infection. Broad-spectrum antibiotics are recommended by guidelines but the optimal class and dose have not been established. We investigated the optimal dose of oral dispersible azithromycin and whether simple clinical criteria and point-of-care biomarkers could target antibiotics to those at greatest risk of bacterial co-infection. Methods We conducted a phase I/II trial in Ugandan children with severe malaria comparing a 5-day course of azithromycin: 10, 15 and 20 mg/kg of azithromycin (prescribed by weight bands) spanning the dose-range effective for other salmonellae infection. We generated relevant pharmacokinetic (PK) data by sparse sampling during dosing intervals and investigated associations between azithromycin exposure and potential mechanisms (PK-pharmacodynamics) using change in C-reactive protein (CRP), a putative marker of sepsis, at 72 h (continuous) and microbiological cure (7-day) (binary), alone and as a composite with 7-day and 90-day survival. To assess whether clinical or biomarkers could identify those at risk of sepsis, a non-severe malaria control was concurrently enrolled. Results Between January 2020 and January 2022, 105 cases were randomised azithromycin doses: 35 to 10 mg/kg, 35 to 15 mg/kg and 35 to 20 mg/kg. Fifty non-severe malaria controls were concurrently enrolled. CRP reduced in all arms by 72 h with a mean reduction of 65.8 mg/L (95% CI 57.1, 74.5) in the 10 mg/kg arm, 64.8 mg/L (95% CI 56.5, 73.1; p = 0.87) in the 20 mg/kg arm and a smaller reduction 51.2 mg/L (95% CI 42.9, 59.5; p = 0.02) in the 15 mg/kg arm. Microbiological cure alone outcome was not analysed as only one pathogen was found among cases. Three events contributed to the composite outcome of 7-day survival and microbiological cure, with no events in the 15 mg/kg arm. The odds ratio comparing 20 vs 10 mg/kg was 0.50 (95% CI 0.04, 5.79); p = 0.58. Due to the low number of pathogens identified, it was not possible to identify better methods for targeting antibiotics including both the cases and controls. Conclusions We found no evidence for an association between systemic azithromycin exposure and reduction in CRP. Further work is needed to better identify children at highest risk from bacterial co-infection. Trial registration ISRCTN49726849 (registered on 27th October 2017).https://doi.org/10.1186/s12916-024-03712-5Severe malariaAfrican childrenBacterial infectionPharmacokineticsClinical trial |
| spellingShingle | Roisin Connon Peter Olupot-Olupot Arthur M. A. Pistorius William Okiror Tonny Ssenyondo Rita Muhindo Sophie Uyoga Ayub Mpoya Thomas N. Williams Diana M. Gibb A. Sarah Walker Rob ter Heine Elizabeth C. George Kathryn Maitland Azithromycin in severe malaria bacterial co-infection in African children (TABS-PKPD): a phase II randomised controlled trial BMC Medicine Severe malaria African children Bacterial infection Pharmacokinetics Clinical trial |
| title | Azithromycin in severe malaria bacterial co-infection in African children (TABS-PKPD): a phase II randomised controlled trial |
| title_full | Azithromycin in severe malaria bacterial co-infection in African children (TABS-PKPD): a phase II randomised controlled trial |
| title_fullStr | Azithromycin in severe malaria bacterial co-infection in African children (TABS-PKPD): a phase II randomised controlled trial |
| title_full_unstemmed | Azithromycin in severe malaria bacterial co-infection in African children (TABS-PKPD): a phase II randomised controlled trial |
| title_short | Azithromycin in severe malaria bacterial co-infection in African children (TABS-PKPD): a phase II randomised controlled trial |
| title_sort | azithromycin in severe malaria bacterial co infection in african children tabs pkpd a phase ii randomised controlled trial |
| topic | Severe malaria African children Bacterial infection Pharmacokinetics Clinical trial |
| url | https://doi.org/10.1186/s12916-024-03712-5 |
| work_keys_str_mv | AT roisinconnon azithromycininseveremalariabacterialcoinfectioninafricanchildrentabspkpdaphaseiirandomisedcontrolledtrial AT peterolupotolupot azithromycininseveremalariabacterialcoinfectioninafricanchildrentabspkpdaphaseiirandomisedcontrolledtrial AT arthurmapistorius azithromycininseveremalariabacterialcoinfectioninafricanchildrentabspkpdaphaseiirandomisedcontrolledtrial AT williamokiror azithromycininseveremalariabacterialcoinfectioninafricanchildrentabspkpdaphaseiirandomisedcontrolledtrial AT tonnyssenyondo azithromycininseveremalariabacterialcoinfectioninafricanchildrentabspkpdaphaseiirandomisedcontrolledtrial AT ritamuhindo azithromycininseveremalariabacterialcoinfectioninafricanchildrentabspkpdaphaseiirandomisedcontrolledtrial AT sophieuyoga azithromycininseveremalariabacterialcoinfectioninafricanchildrentabspkpdaphaseiirandomisedcontrolledtrial AT ayubmpoya azithromycininseveremalariabacterialcoinfectioninafricanchildrentabspkpdaphaseiirandomisedcontrolledtrial AT thomasnwilliams azithromycininseveremalariabacterialcoinfectioninafricanchildrentabspkpdaphaseiirandomisedcontrolledtrial AT dianamgibb azithromycininseveremalariabacterialcoinfectioninafricanchildrentabspkpdaphaseiirandomisedcontrolledtrial AT asarahwalker azithromycininseveremalariabacterialcoinfectioninafricanchildrentabspkpdaphaseiirandomisedcontrolledtrial AT robterheine azithromycininseveremalariabacterialcoinfectioninafricanchildrentabspkpdaphaseiirandomisedcontrolledtrial AT elizabethcgeorge azithromycininseveremalariabacterialcoinfectioninafricanchildrentabspkpdaphaseiirandomisedcontrolledtrial AT kathrynmaitland azithromycininseveremalariabacterialcoinfectioninafricanchildrentabspkpdaphaseiirandomisedcontrolledtrial |