Determination of Alternative Ceftolozane/Tazobactam (C/T) Dosing Regimens for Patients with Infections Due to Pseudomonas aeruginosa with high (C/T) MIC values

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.