Pharmacokinetic and Pharmacodynamic Analyses of Ceftaroline in Adults with Cystic Fibrosis

Study ObjectiveTo evaluate the pharmacokinetics and pharmacodynamics of ceftaroline in adults with cystic fibrosis (CF). DesignOpen-label, single-center, prospective study. SettingUniversity-affiliated teaching institution. PatientsEight patients with a diagnosis of CF and a history of methicillin-resistant Staphylococcus aureus who were treated with ceftaroline between November 2013 and September 2014. InterventionAll patients received at least three doses of intravenous ceftaroline 600 mg every 12 hours, administered as a 60-minute infusion, to achieve steady-state concentrations before blood sample collection. After an interim analysis of the first four patients' pharmacokinetic data, the remaining four patients received a change in dosage of ceftaroline to 600 mg every 8 hours. Measurements and Main ResultsPatients' blood samples were collected at two time points, 2 and 6 hours after infusion initiation, after administration of at least three doses of ceftaroline. Serum ceftaroline concentrations were determined by using a validated mass spectrometry, with a lower limit of detection of 20 ng/ml. These ceftaroline concentrations were used to estimate patient-specific pharmacokinetic parameters, and 10,000-patient Monte Carlo simulations were performed to determine the pharmacodynamic probability of target attainment (PTA) for ceftaroline in adults with CF. A PTA of 90% or higher for the desired pharmacodynamic target was considered adequate. The PTA for 60% or higher of the dosing interval during which free (unbound) drug concentrations exceed the minimum inhibitory concentration (%fT > MIC) was simulated for various MICs. Compared with values previously reported in other populations, the volume of distribution was increased in the study patients, and the estimated half-life was shorter. Monte Carlo simulations revealed that a dose of ceftaroline 600 mg every 8 hours, infused over 60 minutes, maintained a higher than 90% PTA for %fT > MIC of 60% or higher for an MIC at the susceptibility breakpoint of 1 mg/L. ConclusionThe pharmacokinetics of ceftaroline is altered in adults with CF, which suggests the need for modified dosing in this patient population to achieve adequate %fT > MIC. A dosage of intravenous ceftaroline 600 mg every 8 hours administered as a 60-minute infusion should be considered to achieve 60% fT > MIC.