Fosfomycin as a potential treatment for neonatal sepsis An open label randomised clinical trial evaluating safety and pharmacokinetics
Objective To assess pharmacokinetics and changes to sodium levels in addition to adverse events (AEs) associated with fosfomycin among neonates with clinical sepsis. Design A single-centre open-label randomised controlled trial. Setting Kilifi County Hospital, Kenya. Patients 120 neonates aged ≤2...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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BMJ Publishing Group
2022
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| _version_ | 1826308490235215872 |
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| author | Obiero, C Williams, P Murunga, S Thitiri, J Omollo, R Walker, AS Egondi, T Nyoake, B Correia, E Kane, Z Gastine, S Kipper, K Standing, J Ellis, S Sharland, M Berkley, J |
| author_facet | Obiero, C Williams, P Murunga, S Thitiri, J Omollo, R Walker, AS Egondi, T Nyoake, B Correia, E Kane, Z Gastine, S Kipper, K Standing, J Ellis, S Sharland, M Berkley, J |
| author_sort | Obiero, C |
| collection | OXFORD |
| description | Objective To assess pharmacokinetics and changes to sodium levels in addition to adverse events (AEs) associated with fosfomycin among neonates with clinical sepsis.
Design A single-centre open-label randomised controlled trial.
Setting Kilifi County Hospital, Kenya.
Patients 120 neonates aged ≤28 days admitted being treated with standard-of-care (SOC) antibiotics for sepsis: ampicillin and gentamicin between March 2018 and February 2019.
Intervention We randomly assigned half the participants to receive additional intravenous then oral fosfomycin at 100 mg/kg two times per day for up to 7 days (SOC-F) and followed up for 28 days.
Main outcome(s) and measure(s) Serum sodium, AEs and fosfomycin pharmacokinetics.
Results 61 and 59 infants aged 0–23 days were assigned to SOC-F and SOC, respectively. There was no evidence of impact of fosfomycin on serum sodium or gastrointestinal side effects. We observed 35 AEs among 25 SOC-F participants and 50 AEs among 34 SOC participants during 1560 and 1565 infant-days observation, respectively (2.2 vs 3.2 events/100 infant-days; incidence rate difference −0.95 events/100 infant-days (95% CI −2.1 to 0.20)). Four SOC-F and 3 SOC participants died. From 238 pharmacokinetic samples, modelling suggests an intravenous dose of 150 mg/kg two times per day is required for pharmacodynamic target attainment in most children, reduced to 100 mg/kg two times per day in neonates aged <7 days or weighing <1500 g.
Conclusion and relevance Fosfomycin offers potential as an affordable regimen with a simple dosing schedule for neonatal sepsis. Further research on its safety is needed in larger cohorts of hospitalised neonates, including very preterm neonates or those critically ill. Resistance suppression would only be achieved for the most sensitive of organisms so fosfomycin is recommended to be used in combination with another antimicrobial.
Trial registration number NCT03453177.
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| first_indexed | 2024-03-07T07:20:15Z |
| format | Journal article |
| id | oxford-uuid:bbdfae20-d435-464d-b343-e383730688d0 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:20:15Z |
| publishDate | 2022 |
| publisher | BMJ Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:bbdfae20-d435-464d-b343-e383730688d02022-09-29T09:10:22ZFosfomycin as a potential treatment for neonatal sepsis An open label randomised clinical trial evaluating safety and pharmacokineticsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:bbdfae20-d435-464d-b343-e383730688d0EnglishSymplectic ElementsBMJ Publishing Group2022Obiero, CWilliams, PMurunga, SThitiri, JOmollo, RWalker, ASEgondi, TNyoake, BCorreia, EKane, ZGastine, SKipper, KStanding, JEllis, SSharland, MBerkley, JObjective To assess pharmacokinetics and changes to sodium levels in addition to adverse events (AEs) associated with fosfomycin among neonates with clinical sepsis. Design A single-centre open-label randomised controlled trial. Setting Kilifi County Hospital, Kenya. Patients 120 neonates aged ≤28 days admitted being treated with standard-of-care (SOC) antibiotics for sepsis: ampicillin and gentamicin between March 2018 and February 2019. Intervention We randomly assigned half the participants to receive additional intravenous then oral fosfomycin at 100 mg/kg two times per day for up to 7 days (SOC-F) and followed up for 28 days. Main outcome(s) and measure(s) Serum sodium, AEs and fosfomycin pharmacokinetics. Results 61 and 59 infants aged 0–23 days were assigned to SOC-F and SOC, respectively. There was no evidence of impact of fosfomycin on serum sodium or gastrointestinal side effects. We observed 35 AEs among 25 SOC-F participants and 50 AEs among 34 SOC participants during 1560 and 1565 infant-days observation, respectively (2.2 vs 3.2 events/100 infant-days; incidence rate difference −0.95 events/100 infant-days (95% CI −2.1 to 0.20)). Four SOC-F and 3 SOC participants died. From 238 pharmacokinetic samples, modelling suggests an intravenous dose of 150 mg/kg two times per day is required for pharmacodynamic target attainment in most children, reduced to 100 mg/kg two times per day in neonates aged <7 days or weighing <1500 g. Conclusion and relevance Fosfomycin offers potential as an affordable regimen with a simple dosing schedule for neonatal sepsis. Further research on its safety is needed in larger cohorts of hospitalised neonates, including very preterm neonates or those critically ill. Resistance suppression would only be achieved for the most sensitive of organisms so fosfomycin is recommended to be used in combination with another antimicrobial. Trial registration number NCT03453177. |
| spellingShingle | Obiero, C Williams, P Murunga, S Thitiri, J Omollo, R Walker, AS Egondi, T Nyoake, B Correia, E Kane, Z Gastine, S Kipper, K Standing, J Ellis, S Sharland, M Berkley, J Fosfomycin as a potential treatment for neonatal sepsis An open label randomised clinical trial evaluating safety and pharmacokinetics |
| title | Fosfomycin as a potential treatment for neonatal sepsis An open label randomised clinical trial evaluating safety and pharmacokinetics |
| title_full | Fosfomycin as a potential treatment for neonatal sepsis An open label randomised clinical trial evaluating safety and pharmacokinetics |
| title_fullStr | Fosfomycin as a potential treatment for neonatal sepsis An open label randomised clinical trial evaluating safety and pharmacokinetics |
| title_full_unstemmed | Fosfomycin as a potential treatment for neonatal sepsis An open label randomised clinical trial evaluating safety and pharmacokinetics |
| title_short | Fosfomycin as a potential treatment for neonatal sepsis An open label randomised clinical trial evaluating safety and pharmacokinetics |
| title_sort | fosfomycin as a potential treatment for neonatal sepsis an open label randomised clinical trial evaluating safety and pharmacokinetics |
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