Abstract
Background and Purpose: No pharmacokinetics/pharmacodynamics (PK/PD) analysis method has been established for combination therapy that comprehensively reflects the efficacy of both antibiotics. Recently, nacubactam, which is a DBO-type new β-lactamase inhibitor and has antibacterial activity, is being developed as a single drug to be co-administered with cefepime or aztreonam. This study attempted to establish a PK/PD analysis method for β-lactam/β-lactamase inhibitors that incorporates instantaneous MIC (MICi) to determine practical PK/PD parameters for aztreonam/nacubactam.
Experimental Approach: Based on Checkerboard MIC measurements, MICi of aztreonam against carbapenemase-producingKlebsiella pneumoniae in the presence of nacubactam was simulated. In vivo PD effect was evaluated by the bacterial count of thigh-infected mice after administered a combination of nacubactam and aztreonam. The mean change in the bacterial count obtained byin vivo PD study was plotted based on %f T>MICi and analysed using the Inhibitory Effect Sigmoid I max Model.
Key Results: f T>MICicalculated from the PK experiments showed a high correlation with the bactericidal effect obtained in the PD experiments, suggesting thatf T>MICi is the optimal PK/PD parameter for aztreonam/nacubactam. The target values off T>MICi achieving growth inhibition, 1 log10-kill and 2 log10-kill, were 22, 38 and 75%, respectively.
Conclusion and Implications: The PK/PD analysis method proposed in this study is promising for determining practical PK/PD parameters in a combination antimicrobial therapy. In addition, this is the first report of aztreonam/nacubactam showing a potent in vivotherapeutic effect against carbapenemase-producing K. pneumoniae , particularly NDM-producing K. pneumoniae .