Randomised controlled trial of fosfomycin in neonatal sepsis: pharmacokinetics and safety in relation to sodium overload

Abstract

ObjectiveTo assess pharmacokinetics and changes to sodium levels in addition to adverse events (AEs) associated with fosfomycin among neonates with clinical sepsis.DesignA single-centre open-label randomised controlled trial.SettingKilifi County Hospital, Kenya.Patients120 neonates aged ≤28 days admitted being treated with standard-of-care (SOC) antibiotics for sepsis: ampicillin and gentamicin between March 2018 and February 2019.InterventionWe 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.Results61 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 relevanceFosfomycin 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 numberNCT03453177.

Prevalence and whole genome phylogenetic analysis reveal genetic relatedness between antibiotic resistance Salmonella in hatchlings and older chickens from farms in Nigeria

“…Notably, 34.4% of isolates belonging to S. Stanleyville, S. Menston and S. Haelsingborg were shown to contain fosfomycin resistance genes, however we did not test for phenotypic resistance against this drug. Fosfomycin is a broad spectrum antimicrobial that is often used as drug of last resort in the treatment of chronic bacterial infections in human and is presently being promoted as a treatment of choice for life-threatening sepsis in African settings ( Falagas et al, 2016 ; Kane et al, 2021 ; Obiero et al, 2022 ). Detection of fosfomycin resistance in day-old chicks is worrisome, because it indicates possible administration of this antimicrobial to day-old chicks or grandparent stock.…”

New ways of using old antibiotics in pediatrics: Focus on fosfomycin

“…There was no difference in rate of adverse events between SOC-F and SOC, 2.2 events/100 infant-days and 3.2 events/100 infant days (95% TRAN exposure and rate of adverse events in combination with SOC regimen (ampicillin plus gentamicin). 25 Additionally, four 23,29,30,33 of the six studies with reported outcomes for UTI were observational in nature and the remaining two 31,32 randomized controlled studies examined fosfomycin as a single dose for lower UTI. Although more research is needed to further define the optimal PD target, as well as PK, safety and outcomes for repeated oral and IV dosing in infants and children, fosfomycin tromethamine offers an important option for pediatric patients, particularly for treatment of MDR UTI in the United States.…”

“…21,22 The first PK and clinical experience of fosfomycin tromethamine in children reported a mean peak serum concentration (C max ) and area under concentration-time curve (AUC) ranged from 11.3 to 25.3 mcg/mL and 53.7 to 139 mcg × h/mL, respectively, following a single dose of 19tients with neonatal sepsis 24,25. The reported mean gestational age (GA), post-natal age (PNA), and weight was 39.8 weeks, 2.7 days, and 2.872 kg, respectively.…”

Developmental Pharmacokinetics of Antibiotics Used in Neonatal ICU: Focus on Preterm Infants

“…Fosfomycin has a negligible PPB rate and change in plasma protein concentration is not an important factor here [ 172 ]. Other antibiotics with very low PPB rates include aminoglycosides, so change in PPB is not expected in neonates [ 20 ].…”