Pharmacodynamic Target Attainment for Various Ceftazidime Dosing Schemes in High-Flux Hemodialysis

• Authors: Angela S. Loo, New York-Presbyterian/Weill Cornell Medical Center; Michael Neely, USC Keck School of Medicine; Evan Anderson, Emory University; Cybele Ghossein, Northwestern Memorial Hospital; Milena M. McLaughlin, Northwestern Memorial Hospital; Marc H. Scheetz, Northwestern Memorial Hospital
• Journal Title: Antimicrobial Agents and Chemotherapy
• Volume: Volume 57, Number 12
• Publisher: American Society for Microbiology | 2013-12-01, Pages 5854-5859
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1128/AAC.00474-13
• Subjects: Health Sciences, Pharmacy; Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Life Sciences & Biomedicine; Microbiology; Pharmacology & Pharmacy; MICROBIOLOGY; PHARMACOLOGY & PHARMACY; ANTIMICROBIAL SURVEILLANCE PROGRAM; BROAD-SPECTRUM CEPHALOSPORINS; AMERICAN MEDICAL-CENTERS; IMPAIRED RENAL-FUNCTION; PSEUDOMONAS-AERUGINOSA; UNITED-STATES; PHARMACOKINETICS; INFECTIONS; SIMULATION; RESISTANCE

Abstract

Ceftazidime is a broad-spectrum cephalosporin with high-level activity against a variety of Gram-negative pathogens, including Pseudomonas aeruginosa. Improved outcomes are associated with cumulative percentages of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (%T MIC ) of > 45 to 70% of the dosing interval. Optimal dosing to achieve a 90% probability of target attainment (PTA) in patients receiving high-flux hemodialysis (HFHD) is unknown. We used existing data from six anephric adults receiving hemodialysis to construct a population model with the Pmetrics package for R. From the final model's joint probability density, we simulated the PTA for various ceftazidime dosing regimens, HFHD schedules, and organism MICs. For HFHD every 48 h and 1 g of ceftazidime given posthemodialysis, the PTA exceeds 90% for all isolates with MICs of≤8 μg/ml, assuming a goal of 70%T MIC . For 72-h dialysis intervals, postdialysis dosing of 1 g is adequate for achievement of the 70%T MIC goal only for organisms with MICs of≤4 μg/ml, while 2 g is adequate for organisms with MICs of≤8 μg/ml. A dose of 500 mg once daily, regardless of HFHD schedule, has a 90% PTA for organisms with MICs of≤16 μg/ml, while 1 g once daily may achieve 100% PTA even for resistant organisms with a MIC of 32 μg/ml. Therefore, to ensure maximal ceftazidime activity, once-daily dosing of 500 mg to 1 g ceftazidime in patients receiving HFHD may be preferable for critically ill patients when MIC data are unavailable and for more resistant organisms with ceftazidime MICs of 16 to 32 μg/ml.