Pharmacokinetics/pharmacodynamics (PK/PD) targets of antibiotics are critical for optimizing their dosage regimens to maximize efficacy, minimize toxicity, and delay the emergence of resistance. Furthermore, a high heterogeneity is presented in patients that are known to exhibit variations in antimicrobial PK. Therefore, therapeutic drug monitoring of CAZ and AVI to evaluate the PK/PD targets and PK/PD-based dosage adjustment in patients are beneficial for rational use of these drugs. Herein, we developed and validated a simple method for the simultaneous determination of CAZ and AVI in human plasma using LC–MS/MS. Finally, the established and validated method was successfully applied to the determination of CAZ and AVI in plasma for patients. The results showed considerable PK variations in patients, demonstrating the great significance of TDM in the clinic.
Abstract
What is Known and Objective
Carbapenem-resistant Gram-negative bacterial pathogens continue to threaten public health. Avibactam (AVI), a novel non-β-lactam β-lactamase inhibitor, has been approved for use with ceftazidime (CAZ) mainly against carbapenem-resistant Enterobacteriaceae. Therapeutic drug monitoring (TDM) is urgently needed to optimize dosage regimens to maximize efficacy, minimize toxicity, and delay the emergence of resistance. This study aims to develop and validate a rapid, simple, and economical LC–MS/MS method for simultaneous determination of CAZ/AVI in human plasma.
Methods
Samples were processed by simple protein precipitation, and gradient elution strategy was applied to separate CAZ and AVI on a reverse-phase C18 column; with subsequent detection by the mass spectrometer in a positive and negative ion switching mode. Plasma samples from patients were analysed.
Results and Discussion
A 4-min run of LC–MS/MS was developed. The precision, trueness, matrix effect, extraction recovery, carry-over, dilution integrity, and stability were all acceptable for a bioanalytical method. The method was successfully applied to the determination of CAZ and AVI in patients, and a considerable PK variability of CAZ/AVI was observed among patients.
What is New and Conclusion
A robust, rapid, simple, and economical LC–MS/MS method for the simultaneous determination of CAZ and AVI was developed. The considerable PK variability of CAZ/AVI among patients demonstrates the clinical significance of TDM.
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