Development of an optimized and practical pharmacokinetics/pharmacodynamics analysis method for aztreonam/nacubactam against carbapenemase-producing K. pneumoniae

Abstract

Background: Nacubactam, a new β-lactamase inhibitor with antibacterial activity, is being developed as a single drug to be co-administered with cefepime or aztreonam. However, determining pharmacokinetics/pharmacodynamics (PK/PD) parameters in β-lactam/β-lactamase inhibitor combinations remains challenging. We aimed to establish a practical PK/PD analysis method for aztreonam/nacubactam that incorporates instantaneous MIC (MICi). Methods: Based on chequerboard MIC measurements, MICi of aztreonam against carbapenemase-producing Klebsiella pneumoniae in the presence of nacubactam was simulated. Results: The mean change in the bacterial count of thigh-infected mice in an in vivo PD study was plotted based on %fT>MICi and analysed using the inhibitory effect sigmoid Imax model. fT>MICi calculated from the PK experiments showed a high correlation with the in vivo bactericidal effect, suggesting that fT>MICi is the optimal PK/PD parameter for aztreonam/nacubactam. The target values of fT>MICi achieving growth inhibition, 1 log10 kill and 2 log10 kill, were 22, 38% and 75%, respectively. Conclusions: The PK/PD analysis method proposed in this study is promising for determining practical PK/PD parameters in combination therapy. In addition, this is the first report of aztreonam/nacubactam showing a potent in vivo therapeutic effect against NDM-producing K. pneumoniae.