Methods: 16 ventilated swine were infected with Pseudomonas aeruginosa to establish pneumonia and then treated for 72 hours with ceftolozane/tazobactam (C/T) 50mg/kg q8h (n=8) or piperacillin/tazobactam (TZP) 200mg/kg q8h (n=8). Plasma and BAL concentrations were measured in each swine at 1, 2, 4, 6, and 8 hours after the first dose. Urea correction was used to calculate ELF values. Ceftolozane and piperacillin plasma and ELF data were fitted to a two compartment model using the nonparametric adaptive grid program in Pmetrics. Hypothetical models were refitted after randomly selecting either 1B or 2B sampling time points from each swine. A 5,000 subject Monte Carlo simulation was performed for each model to define PTA (60% free time above the MIC) and ELF penetration [area under the curve in ELF (AUCELF) vs. free AUCplasma]. The KS-test was used to analyze distribution differences, reporting maximum vertical deviation (D) as percent difference; D<20% was defined as negligible.
Results: 32 C/T and 34 TZP plasma samples and 29 and 32 BAL samples were available for the full model, respectively; 1B and 2B sampling models used 8 and 16 BAL samples. All models adequately fitted the data. C/T PTA at 4 mg/L was 94.8, 96.1, and 98.0%, for the full, 1B and 2B models. TZP PTA at 16 mg/L was 55.8, 46.8, and 46.7%, respectively. C/T median [interquartile range] penetration differences were negligible between the full (65% [25 – 109]) and 1B (72% [45 – 125], D=15%) or 2B models (62% [32 – 111], D=6%). TZP penetration differences were also minimal between the full (32% [9 – 67]) and 1B (17% [5 – 49], D=18%) or 2B models (27% [9 – 44], D=15%).
Conclusion: These data suggest that antibiotic ELF models constructed from a single BAL time point result in similar exposure estimates to full ELF profiles.
G. Li Bassi, MSD: Grant Investigator , Grant recipient .
A. Torres, MSD: Grant Investigator , Grant recipient .
D. P. Nicolau, None