PD study
An in vivo dose fractionation study in neutropenic mice infected with K. pneumoniae ATCC BAA-2473 thighs showed that aztreonam and nacubactam alone hardly reduced viable bacterial counts. However, the aztreonam/nacubactam combination showed a nacubactam dose-dependent bacterial count reduction and a strong bactericidal effect of up to 2 log10 CFU thigh-1 compared to the control group (Fig. 4).
The in vivo dose-ranging study of aztreonam/nacubactam was assessed in neutropenic thigh-infected mice with K. pneumoniaeMSC 21664 and K. pneumoniae MSC 21444, administering aztreonam/nacubactam at various doses every 2 hrs (Fig. 5). In both strains, nacubactam and aztreonam alone showed a slight reduction in bacterial counts, but the combination of both antibiotics provided a potent bactericidal effect. The maximum bactericidal effect in neutropenic mice infected with K. pneumoniae MSC 21664 andK. pneumoniae MSC 21444 was about 3 log10 and 1 log10 CFU thigh-1, respectively.
PK/PD analysis withfT>MICi
The values of f T>MICi in each dose group calculated from the PK data were plotted against the change in bacterial counts obtained in the PD study (Fig. 6). The results showed a high correlation (R 2=0.868) between the change in viable bacterial counts andf T>MICi following aztreonam/nacubactam administration. The growth inhibition and bactericidal effect target values were further analysed using the Inhibitory Effect Sigmoid I max Model. The target values of f T>MICi required to achieve growth inhibition, 1 log10-kill and 2 log10-kill, were 22%, 38%, and 75%, respectively.