Pharmacokinetics and safety of fosfomycin and flomoxef administered as part of neonatal sepsis treatment (NeoSep1 Part 1).

Neonatal doses for the off-patent antibiotics fosfomycin and flomoxef, which offer coverage against many extended-spectrum beta-lactamase (ESBL)-producing organisms, are based on limited data. We performed a pharmacokinetic (PK) and safety study of fosfomycin and flomoxef to confirm proposed neonatal dosing before further investigation in a trial (NeoSep1, ISRCTN48721236). Neonates with suspected sepsis, weighing more than 1,000 g, were sequentially enrolled into three antibiotic treatment cohorts: fosfomycin and amikacin (Cohort 1), flomoxef and amikacin (Cohort 2), and flomoxef and fosfomycin (Cohort 3), and followed for 28 days. Plasma samples were taken for PK assessment, with population PK modeling and simulations performed. Sixty-two neonates (48/62 [77%] preterm; 48/62 [77%] ≤7 days postnatal age [PNA]) received at least one dose of study antibiotics. Fosfomycin and flomoxef plasma concentrations were best described by a two-compartment and a one-compartment model, respectively, with postmenstrual age and PNA significantly influencing clearance. The probability of target attainment for fosfomycin was 100% for minimum inhibitory concentrations (MICs) of up to 8 mg/L, and for flomoxef, it was 100% for MICs of up to 0.5 mg/L. Adverse events (AEs) were common in this critically ill cohort. Thirteen (21%) neonates developed 19 trial antibiotic-related AEs (17 with grade ≤2, and 2 of grade 3), none of which required modification or discontinuation of allocated treatment. Seven neonates (11.6%) died. In this predominately preterm population, fosfomycin and flomoxef were safe, with drug exposures similar to published studies supporting the proposed doses for the larger, randomized NeoSep1 trial.This study is registered with ISRCTN48721236.