Pharmacokinetics, Safety and Tolerability of Single-dose or Multiple-dose Cefiderocol in Hospitalized Pediatric Patients Three Months to Less Than Eighteen Years Old With Infections Treated With Standard-of-care Antibiotics in the PEDI-CEFI Phase 2 Study.

Abstract

Background: Multidrug-resistant Gram-negative bacterial infections are increasing globally in neonates, infants and children; antibiotic options are limited.

Methods: This international, multicenter, open-label phase 2 study, investigated the pharmacokinetics, safety and tolerability of single-dose and multiple-dose cefiderocol [as a 3-hour infusion (every 8 hours) dosed at 2000 mg for body weight ≥34 kg and at 60 mg/kg for body weight <34 kg], over a range of renal function, in hospitalized pediatric patients with aerobic Gram-negative bacterial infection; multiple-dose patients required standard-of-care systemic antibiotics for 5-14 days. Four cohorts of pediatric patients were enrolled (cohort 1: 12 to <18 years, cohort 2: 6 to <12 years, cohort 3: 2 to <6 years and cohort 4: 3 months to <2 years).

Results: A total of 53 patients (median age: 73.5 months) were enrolled. Plasma concentration profiles were similar with single-dose (n = 24) and multiple-dose (n = 29) cefiderocol, irrespective of age and body weight in those with normal renal function or mild renal impairment. Geometric mean concentrations at the end of infusion ranged between 72.7 and 97.1 μg/mL for single-dose cefiderocol and between 88.8 and 106.0 μg/mL after multiple doses. At 8 hours, corresponding trough concentrations ranged from 7.86 to 10.8 μg/mL with single-dose cefiderocol and from 9.64 to 18.1 μg/mL with multiple doses. There were no deaths, no cefiderocol-related serious adverse events, significant related laboratory abnormalities or discontinuations.

Conclusions: Multiple-dose cefiderocol, administered for 5-14 days and according to body weight, achieved steady-state plasma concentrations that remained above the susceptibility breakpoints of Gram-negative bacteria throughout the dosing period. Cefiderocol was well tolerated.