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

Luzelena Caro, David P Nicolau, Jan J De Waele, Joseph L Kuti, Kajal B Larson, Elaine Gadzicki, Brian Yu, Zhen Zeng, Adedayo Adedoyin, Elizabeth G Rhee, Luzelena Caro, David P Nicolau, Jan J De Waele, Joseph L Kuti, Kajal B Larson, Elaine Gadzicki, Brian Yu, Zhen Zeng, Adedayo Adedoyin, Elizabeth G Rhee

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.

© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

Figures

Figure 1.
Figure 1.
Arithmetic mean (±SD) total concentration–time profiles in plasma [first dose (n = 25 patients) and last dose (n = 24 patients)] and ELF (last dose; n = 22 patients) for (a) ceftolozane and (b) tazobactam. Note: curves are slightly offset around each timepoint in order to achieve separation of error bars.
Figure 2.
Figure 2.
Individual unbound plasma concentration–time profiles for first (n = 25) and last (n = 24) doses, with target concentrations shown as horizontal lines, among patients included in the plasma PK analyses, for (a) ceftolozane first dose, (b) ceftolozane last dose, (c) tazobactam first dose and (d) tazobactam last dose.

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