Senthil Natesan1, Manjunath P Pai2, Thomas P Lodise3. 1. Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WA, USA. 2. Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI, USA. 3. Albany College of Pharmacy and Health Sciences, Albany, NY, USA.
Abstract
Background: Optimization of the antibiotics for patients with infections due to MDR Pseudomonas aeruginosa (MDR-PA) often requires consideration of alternate dose and infusion times that can be influenced by renal function. Objectives: We sought to identify ceftolozane/tazobactam dosing schemes that optimized the probability of target attainment (PTA) against infections due to MDR-PA with ceftolozane/tazobactam MICs between 4 and 32 mg/L across different categories of renal function. Methods: A prior validated ceftolozane/tazobactam population pharmacokinetic model was used for Monte Carlo simulation of 128 alternate permutations of dose, infusion time and renal function in 5000 cases/permutation. Four ceftolozane/tazobactam doses (250/125 mg to 2/1 g) every 8 h with infusion durations of 1-7 h and as continuous infusions were simulated. The model simulated ceftolozane/tazobactam clearance as a function of creatinine clearance (CLCR) within four categories of estimated renal function: 15-29, 30-50, 51-120 and 121-180 mL/min. The PTA was benchmarked on 40% free ceftolozane/tazobactam concentration time above the MIC. Results: The 512 alternate scenarios identified the current ceftolozane/tazobactam dose of 1/0.5 g to be optimal for MICs ≤32 mg/L (CLCR 15-50 mL/min), ≤16 mg/L (CLCR 51-120 mL/min) and ≤8 mg/L (CLCR 121-180 mL/min). Extended infusion of 4-5 h had a higher PTA than shorter and continuous infusions in simulations of augmented renal clearance across infections with MICs of 4-32 mg/L. Conclusions: Extended infusion ceftolozane/tazobactam regimens should be investigated as a potential dosing solution to improve the PTA against infections due to MDR-PA with higher ceftolozane/tazobactam MICs.
Background: Optimization of the antibiotics for patients with infections due to MDR Pseudomonas aeruginosa (MDR-PA) often requires consideration of alternate dose and infusion times that can be influenced by renal function. Objectives: We sought to identify ceftolozane/tazobactam dosing schemes that optimized the probability of target attainment (PTA) against infections due to MDR-PA with ceftolozane/tazobactam MICs between 4 and 32 mg/L across different categories of renal function. Methods: A prior validated ceftolozane/tazobactam population pharmacokinetic model was used for Monte Carlo simulation of 128 alternate permutations of dose, infusion time and renal function in 5000 cases/permutation. Four ceftolozane/tazobactam doses (250/125 mg to 2/1 g) every 8 h with infusion durations of 1-7 h and as continuous infusions were simulated. The model simulated ceftolozane/tazobactam clearance as a function of creatinine clearance (CLCR) within four categories of estimated renal function: 15-29, 30-50, 51-120 and 121-180 mL/min. The PTA was benchmarked on 40% free ceftolozane/tazobactam concentration time above the MIC. Results: The 512 alternate scenarios identified the current ceftolozane/tazobactam dose of 1/0.5 g to be optimal for MICs ≤32 mg/L (CLCR 15-50 mL/min), ≤16 mg/L (CLCR 51-120 mL/min) and ≤8 mg/L (CLCR 121-180 mL/min). Extended infusion of 4-5 h had a higher PTA than shorter and continuous infusions in simulations of augmented renal clearance across infections with MICs of 4-32 mg/L. Conclusions: Extended infusion ceftolozane/tazobactam regimens should be investigated as a potential dosing solution to improve the PTA against infections due to MDR-PA with higher ceftolozane/tazobactam MICs.
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