Pharmacodynamic target attainment for various ceftazidime dosing schemes in high-flux hemodialysis

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 (%TMIC) 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%TMIC. For 72-h dialysis intervals, postdialysis dosing of 1 g is adequate for achievement of the 70%TMIC 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.

Figures

Fig 1

Concentration-time profiles for 6 patients after receiving a 2-g ceftazidime dose (27).

Fig 2

Two-compartment models of observed versus predicted serum concentrations of ceftazidime (R2 = 0.803 and 0.988). Predictions are based on the median population parameter values (left) and median individual Bayesian posterior parameter values (right).

Fig 3

Probability of target attainment for 48-h dialysis.

Fig 4

Probability of target attainment for 72-h dialysis.

Fig 5

Simulated concentration-time curves for free ceftazidime for hemodialysis every 72 h (5th, 50th, and 95th percentiles are shown).