Pharmacokinetic and Pharmacodynamic Analysis of Ceftazidime/Avibactam in Critically Ill Patients

Background: The pharmacokinetics, especially the volume of distribution (Vd), of ss-lactam antibiotics can be altered in critically ill patients. This can lead to decreased serum concentrations and a reduction in clinical cures. Ceftazidime/avibactam (CZA) is a new antimicrobial agent utilized in critically ill patients although its pharmacokinetics has not been well defined in these patients. Patients and Methods: In this study, the serum concentrations of CZA from adult patients treated in an intensive care unit (ICU) with standard dosing regimens were measured and both pharmacokinetic and pharmacodynamic parameters were computed. The pharmacodynamic analyses included Monte Carlo simulations to determine the probability of target attainment (PTA: free ceftazidime concentrations exceed the minimum inhibitory concentration [MIC] for 50% of the dosing interval; free avibactam concentrations exceed 1mg/L over the dosing interval) and serum time-kill curves against multi-drug-resistant Enterobacteriaceae susceptible to CZA. Serum concentrations were measured in 10 critically ill patients at two, four, six, and eight hours after multiple doses (infused over two hours) of CZA. Results: A significant linear relation between creatinine clearance and total body clearance was identified for both ceftazidime (R=0.91) and avibactam (R=0.88). The mean clearance, volume of distribution, and half-life for ceftazidime were 6.13.8L/h, 35 +/- 10.5L, and 4.8 +/- 2.15h, respectively. For avibactam, these values were 11.1 +/- 6.8L/h, 50.8 +/- 14.3L, and 4.1 +/- 2.1h, respectively. Ceftazidime/avibactam achieved optimal PTA for bacteria with MICs of 16mg/L or less. Furthermore, time-kill experiments revealed that serum concentrations of CZA, at each collection time, exhibited bactericidal ( 3 log(10) CFU/mL reduction) activity against each of the study isolates. Conclusion: In conclusion, our study results suggest that the current dosing regimens of CZA can provide effective antimicrobial activity in ICU patients against CZA-susceptible (MIC 8mg/L) isolates.