Abstract:
Background: Fosfomycin has the potential to be re-purposed as part of a combination therapy to
treat neonatal sepsis where resistance to current standard of care (SOC) is common. Limited data
exist on neonatal fosfomycin pharmacokinetics and estimates of bioavailability and CSF/plasma
ratio in this vulnerable population are lacking.
Objectives: To generate data informing the appropriate dosing of IV and oral fosfomycin in
neonates using a population pharmacokinetic analysis of plasma and CSF data.
Methods: The NeoFosfo study (NCT03453177) was a randomized trial that examined the safety
and pharmacokinetics of fosfomycin comparing SOC versus SOC plus fosfomycin. Sixty-one
neonates received fosfomycin (100 mg/kg IV q12h for 48 h) and then they converted to oral
therapy at the same dose. Two plasma pharmacokinetic samples were taken following the first IV
and oral doses, sample times were randomized to cover the whole pharmacokinetic profile and
opportunistic CSF pharmacokinetic samples were collected. A population pharmacokinetic model
was developed in NONMEM and simulations were performed.
Results: In total, 238 plasma and 15 CSF concentrations were collected. A two-compartment
disposition model, with an additional CSF compartment and first-order absorption, best described
the data. Bioavailability was estimated as 0.48 (95% CI = 0.347-0.775) and the CSF/plasma ratio
as 0.32 (95% CI = 0.272-0.409). Allometric weight and postmenstrual age (PMA) scaling was
applied; additional covariates included postnatal age (PNA) on clearance and CSF protein on
CSF/plasma ratio.
Conclusions: Through this analysis a population pharmacokinetic model has been developed that
can be used alongside currently available pharmacodynamic targets to select a neonatal fosfomycin
dose based on an infant's PMA, PNA and weight.