1959. Determination of Alternative Ceftolozane/Tazobactam (C/T) Dosing Regimens for Patients with Infections Due to Pseudomonas aeruginosa with high (C/T) MIC values
Session: Poster Abstract Session: Antimicrobial Pharmacokinetics and Pharmacodynamics
Saturday, October 29, 2016
Room: Poster Hall
Background: Multidrug resistant P. aeruginosa (MDR-PA) related infections are increasing worldwide. This investigation simulated standard and alternative C/T dosing schemes to optimize the free concentration time above the MIC (fT>MIC) of C/T against PA with higher C/T MIC values in populations with normal and augmented clearance (CL). Methods: A previously published C/T population PK model (J Clin Pharmacol. 2015; 55:230-239) was used to generate distributions of concentration-time profiles (n=5000/simulation) through Monte Carlo simulation (ADAPT 5). Briefly, the structural model for C-CL is a function of creatinine clearance (CLcr) and volume of the central compartment is a function of weight. The weight simulations were set to the original population distribution with a mean (range) of 79.6 (43-173) kg. Two mean (range) CLcr distributions were simulated that included a normal group [85 (50-120) mL/min] and an augmented group [150 (121-180) mL/min]. C (T was not simulated as it does not affect activity of C against PA) 1 to 2 g IV Q8H as 1-, 2-, 3-, 4-, 5-, 6-, 7-H and continuous infusion (inf) regimens were simulated. Free C concentrations were based on a fixed protein binding estimate (21%). The fraction of simulated subjects who achieved 40% fT>MIC between 16H-24H (after the 3rddose) was calculated for PA infections with MICs between 4-32 mg/L. Results: All simulated C 1g regimens had a high probability of achieving 40% fT>MIC for PA infections with MICs ≤ 16 mg/L in subjects with normal CLcr. For isolates with a MIC of 32 mg/L, C 2 g IV Q8H (1-H inf) was required to achieve >90% of achieving 40% fT>MIC in normal CLcr group. All C 1 g regimens were also optimal for isolates with MICs ≤ 8 mg/L in the augment CLcr group. For isolates with MIC of 16 mg/L, C 1 g IV Q8H as a 4-H inf had >90% of achieving 40% fT>MIC in the augment CLcr group. For isolates with a MIC of 32 mg/L, C 2 g IV Q8H as a 4-H inf conferred a >90% of achieving 40% fT>MIC in the augment CLcr group. Conclusion: Among populations with normal renal function, the results suggest that 1gC/0.5T g IV Q8H achieves optimal fT>MIC in the blood for PA infection with C/T MICs ≤ 16 mg/L but 2gC/1gT g IV Q8H may be required for PA infections with C/T MICs of 32 mg/L. Extended interval infusions of C/T may also be relevant in populations with augmented CL, and should be validated clinically.
Senthil Natesan, PhD, Manjunath P. Pai, PharmD and Thomas P. Lodise, PharmD, PhD, Albany College of Pharmacy and Health Sciences, Albany, NY


S. Natesan, None

M. P. Pai, merck: Grant Investigator , Grant recipient

T. P. Lodise, merck: Grant Investigator and Speaker's Bureau , Grant recipient and Speaker honorarium

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