Intrapulmonary concentrations of ceftobiprole high doses administered by continuous infusion in critically ill patients with community-acquired pneumonia

Optimal antimicrobial drug exposure in the lung is required for ensuring successful treatment of community-acquired pneumonia (CAP). Little is known about the intrapulmonary pharmacokinetics (PK) of ceftobiprole when administered by continuous infusion (CI). To determine the PK of high doses (3 g/day) CI of ceftobiprole in the plasma and epithelial lining fluid (ELF) in mechanically ventilated patients with CAP. Patients receiving a CI of ceftobiprole (2.5 g daily after a 0.5 g bolus loading dose) for the treatment of severe CAP were eligible. Plasma and ELF samples were collected over 3 days of therapy. Concentrations were analysed by HPLC-UV, and population PK modelling was conducted using Monolix™. Monte Carlo simulations were performed to estimate the probability of target attaining a free ELF concentration of 100% of time above MIC. Twelve patients, 2 female, median (IQR) age 67 (58-71), were enrolled with 108 plasma and 12 ELF concentrations included in the population analysis. The median (min-max) lung penetration ratio was 30 (15-45) % after 3 doses of ceftobiprole. In the Monte Carlo simulations, higher doses given as CI (3 g/day) may be necessary for MICs up to 2 mg/L in patients with normal renal function. The final PK model using a 4 × MIC plasma target may help to approximate ELF target attainment. The use of high doses of ceftobiprole given by CI may be necessary to achieve PK/pharmacodynamic targets in ELF in critically ill patients with CAP and normal renal function, especially when less susceptible pathogen is suspected or identified.