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

Abstract

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 outcomes and measures: 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.

Keywords: neonatology; pharmacology; sepsis.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1

Trial flow chart. This original figure was created by CWO for this manuscript. CPR, cardiopulmonary resuscitation; HIE, hypoxic ischaemic encephalopathy; IV, intravenous; SOC, standard of care; SOC-F, standard of care plus fosfomycin. *Reasons include mother postcaesarean section (46) or seriously ill (6), absconded from hospital (3), discharged against advice (3), abandoned by mother (1) and already enrolled into another study (1). †One SOC-F participant died after completing follow-up (on day 106).

Figure 2

Probability target attainment for intravenous fosfomycin dosing. Neonatal subpopulations. Group 1: WT >1.5 kg +PNA ≤7 days (n=4391), group 2: WT >1.5 kg +PNA >7 days (n=2798), group 3: WT ≤1.5 kg +PNA ≤7 days (n=1534), group 4: WT ≤1.5 kg +PNA >7 days (n=1277). Groups 1 and 2 represent patients similar to those fitting our inclusion criteria. Groups 3 and 4 represent an extrapolation to preterm neonates that were not studied in our population. This original figure was created by ZK for this manuscript. BID, two times per day; IV, intravenous; MIC, minimum inhibitory concentration; PNA, postnatal age; WT, weight.

Figure 3

Probability target attainment for oral fosfomycin dosing. Neonatal subpopulations. Group 1: WT >1.5 kg +PNA ≤7 days (n=4391), group 2: WT >1.5 kg +PNA >7 days (n=2798), group 3: WT ≤1.5 kg +PNA ≤7 days (n=1534), group 4: WT ≤1.5 kg +PNA >7 days (n=1277). Groups 1 and 2 represent patients similar to those fitting our inclusion criteria. Groups 3 and 4 represent an extrapolation to preterm neonates using external data that were not studied in our population. This original figure was created by ZK for this manuscript. BID, two times per day; MIC, minimum inhibitory concentration; PNA, postnatal age; PO, oral; WT, weight.