Development of an Optimised Pharmacokinetics/Pharmacodynamics analysis
method of β-lactam/nacubactam against Carbapenemase-Producing K.
pneumoniae
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-producing
Klebsiella 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 by
in vivo PD study was plotted based on
%fT>MICi and analysed using the
Inhibitory Effect Sigmoid Imax Model. Key
Results: fT>MICi calculated from
the PK experiments showed a high correlation with the bactericidal
effect obtained in the PD experiments, 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. 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 vivo therapeutic effect against
carbapenemase-producing K. pneumoniae, particularly NDM-producing
K. pneumoniae.