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 .