Lung penetration, bronchopulmonary pharmacokinetic/pharmacodynamic profile and safety of 3 g of ceftolozane/tazobactam administered to ventilated, critically ill patients with pneumonia

Abstract

Objectives Ceftolozane/tazobactam is approved for hospital-acquired/ventilator-associated bacterial pneumonia at double the dose (i.e. 2 g/1 g) recommended for other indications. We evaluated the bronchopulmonary pharmacokinetic/pharmacodynamic profile of this 3 g ceftolozane/tazobactam regimen in ventilated pneumonia patients. Methods This was an open-label, multicentre, Phase 1 trial (clinicaltrials.gov: NCT02387372). Mechanically ventilated patients with proven/suspected pneumonia received four to six doses of 3 g of ceftolozane/tazobactam (adjusted for renal function) q8h. Serial plasma samples were collected after the first and last doses. One bronchoalveolar lavage sample per patient was collected at 1, 2, 4, 6 or 8 h after the last dose and epithelial lining fluid (ELF) drug concentrations were determined. Pharmacokinetic parameters were estimated by non-compartmental analysis and pharmacodynamic analyses were conducted to graphically evaluate achievement of target exposures (plasma and ELF ceftolozane concentrations >4 mg/L and tazobactam concentrations >1 mg/L; target in plasma: ≥30% and ≥20% of the dosing interval, respectively). Results Twenty-six patients received four to six doses of study drug; 22 were included in the ELF analyses. Ceftolozane and tazobactam Tmax (6 and 2 h, respectively) were delayed in ELF compared with plasma (1 h). Lung penetration, expressed as the ratio of mean drug exposure (AUC) in ELF to plasma, was 50% (ceftolozane) and 62% (tazobactam). Mean ceftolozane and tazobactam ELF concentrations remained >4 mg/L and >1 mg/L, respectively, for 100% of the dosing interval. There were no deaths or adverse event-related study discontinuations. Conclusions In ventilated pneumonia patients, 3 g of ceftolozane/tazobactam q8h yielded ELF exposures considered adequate to cover ceftolozane/tazobactam-susceptible respiratory pathogens.

Population Pharmacokinetic Analyses for Omadacycline Using Phase 1 and 3 Data

“…However, despite the first limitation, the estimation of omadacycline ELF exposure using a population PK model, which was developed by comodeling plasma and ELF concentration data, represented a robust approach. With regard to the second limitation, while data evaluating ELF exposures for antimicrobial agents in infected patients are limited (24)(25)(26)(27)(28) and more challenging to obtain, future studies in omadacycline-treated patients would be useful to determine if ELF exposure in patients is different from that in healthy volunteers.…”

Augmented Renal Clearance and How to Augment Antibiotic Dosing

“…Interim safety results from a Phase 1 PK study reported that twice the standard dosing of ceftolozane/tazobactam, or 3 g every 8 h, was safe and generated sufficient exposure in twelve critically ill pneumonia patients with a mean creatinine clearance of 134.6 mL/min [ 70 ]. The exposures from this increased regimen were confirmed to be adequate upon completion of this study [ 71 ]. A population pharmacokinetic analysis that took ARC into consideration was performed for imipenem/relebactam [ 72 ].…”

Population Pharmacokinetic Analysis for Plasma and Epithelial Lining Fluid Ceftolozane/Tazobactam Concentrations in Patients With Ventilated Nosocomial Pneumonia

“…Of these, 1481 and 1455 ceftolozane and tazobactam plasma observations, respectively, were obtained from 305 adult patients participating in the ASPECT‐NP study (MK7625A‐008, Supplemental Table S1). ELF data were obtained from 2 phase 1 studies: 1 study was conducted in healthy volunteers (CXA‐ELF‐10‐03) 22 and the other in critically ill patients with confirmed or suspected pneumonia (CXA‐ICU‐14‐01) 24 . In addition to plasma samples, these 2 studies collected bronchoalveolar lavage samples to measure ceftolozane and tazobactam concentrations in ELF from each patient at 1 of 5 predefined times (1, 2, 4, 6, or 8 hours after the start of infusion).…”

“…Model 2 assumed an ELF compartment with mass transfer between the plasma and ELF compartments, and model 3 was a hypothetical link model without mass transfer and assumed an influx rate constant from plasma‐to‐ELF compartments (K 1E ), an elimination rate constant from the ELF compartment (K E0 ), and that V3 was equal to V1. An exploratory data analysis suggested that plasma and ELF data were more variable in critically ill patients with confirmed or suspected pneumonia compared with healthy participants 22,24 . As a result, the base structural models for ceftolozane and tazobactam were refined further by estimating IIV with K 1E separately for healthy participants and patients with pneumonia.…”