1882. Pharmacokinetics (PK)/Pharmacodynamics (PD) and Safety of 3 g Ceftolozane/Tazobactam (TOL/TAZ) in Ventilated, Critically-Ill Patients
Session: Poster Abstract Session: Clinical Study with New Antibiotics and Antifungals
Saturday, October 7, 2017
Room: Poster Hall CD
Posters
  • Caro IDWeek_90x42@200_printreadyR.pdf (1.1 MB)
  • Background: TOL/TAZ is an antipseudomonal cephalosporin/β-lactamase inhibitor combination approved for complicated intra-abdominal and urinary tract infections in adults at a 1.5g (1g/0.5g) dose q8h. TOL/TAZ is being studied at a higher 3g (2g/1g) q8h dose in a Phase 3 trial in nosocomial pneumonia (NP) patients. PK and safety data from an ongoing Phase 1 study of 3g TOL/TAZ in ventilated, critically ill patients are presented.

    Methods: Mechanically ventilated patients with proven or suspected pneumonia received 4-6 doses of 3g TOL/TAZ q8h, adjusted for renal function; safety was evaluated. Plasma PK samples were collected after the first and last doses and PK parameters were calculated using non-compartmental analysis. Probability of target attainment (PTA) was assessed by the percent of patients achieving PK/PD targets: free TOL concentrations above minimum inhibitory concentrations of 4 and 8 µg/mL for ≥40% of the dosing interval (pneumonia breakpoint is 4), free TAZ concentrations above 1 μg/mL for ≥20% of the dosing interval. Baseline creatinine clearance (CrCL) was assessed by Cockroft-Gault (C-G) and compared to urine-derived values.

    Results: The 18 patients (11 male) were 21-82 years old with a mean (range) BMI of 26.5 (13.8-55.5) kg/m2 and estimated CrCL of 116 (38-238) mL/min. TOL and TAZ plasma clearances were ~5 and ~16 L/h, respectively; TOL and TAZ steady-state volumes of distribution were ~30 and ~40 L, respectively. The individual percent of time above the PK/PD targets after the first and last doses ranged from 74-100% at 4 μg/mL and 56-100% at 8 μg/mL for TOL and 47-100% at 1 μg/mL for TAZ. There were 27 adverse events (AEs) in 12 patients, with one AE (diarrhea) related to study drug, with no serious AEs reported. Exploratory analyses show a robust correlation between baseline CrCL by C-G and urine (Pearson correlation coefficient 0.626; P=0.0054; P=0.0039, adjusting for weight).

    Conclusion: Results from 18 ventilated pneumonia patients demonstrate that 3g TOL/TAZ was well tolerated. All patients achieved the TOL and TAZ PK/PD targets after the first and last doses (100% PTA), suggesting this dose provides adequate exposure from the initiation of therapy. These data support the 3g TOL/TAZ dose and regimen selected for the ongoing Phase 3 NP trial.

    Luzelena Caro, PhD1, Kajal Larson, PhD2, David P. Nicolau, PharmD, FCCP, FIDSA3, Jan De Waele, MD PhD4, Joseph L. Kuti, PharmD3, Elaine Gadzicki, BS2, Adedayo Adedoyin, PhD2, Zhen Zeng, Ph.D.2, Bernardino Mosquera, MD, MPH2, Ramanatha Saralaya, MPharm5 and Elizabeth Rhee, MD2, (1)Merck & Co., Inc., Kenilworth, NJ, (2)Merck & Co. Inc., Kenilworth, NJ, (3)Hartford Hospital, Hartford, CT, (4)Ghent University Hospital, Gent, Belgium, (5)Cytel, Hyderabad, India

    Disclosures:

    L. Caro, Merck: Employee , Salary

    K. Larson, Merck: Employee , Salary

    D. P. Nicolau, Merck: Investigator and Speaker's Bureau , Research support

    J. De Waele, Merck: Speaker's Bureau , Speaker honorarium

    J. L. Kuti, None

    E. Gadzicki, Merck: Employee , Salary

    A. Adedoyin, Merck: Employee , Salary

    Z. Zeng, Merck: Employee , Salary

    B. Mosquera, Merck: Employee , Salary

    R. Saralaya, Merck: Research Contractor , Cytel contracted

    E. Rhee, Merck: Employee , Salary

    Findings in the abstracts are embargoed until 12:01 a.m. PDT, Wednesday Oct. 4th with the exception of research findings presented at the IDWeek press conferences.