Simulation in clinical dosing
Using PK data from healthy adults,f T>MICi (%) for aztreonam (0.5 g, 1 g, 2 g) and nacubactam (0.05 g, 0.15 g, 0.5 g, 1 g, 2 g) given in combination every 8 hrs is shown in Table 2. For NDM-1 β-lactamase producing K. pneumoniae ATCC BAA-2473, growth inhibition was achieved at the lowest dose combination (aztreonam 0.5 g q8h and nacubactam 0.05 g q8h), and bactericidal effects were achieved at all other doses. In particular, 2 log10-kill was achieved at doses above nacubactam 0.5 g q8h regardless of aztreonam dosage. A 2 log10-kill was achieved against IMP-6 β-lactamase producing K. pneumoniae MSC 21664 at all simulated doses. For OXA-48 β-lactamase producing K. pneumoniae MSC 21444, bactericidal efficacy was achieved at all doses and 2 log10-kill at doses of nacubactam 0.5 g q8h and above. In all cases, f T>MICi = 100% was reached at doses of nacubactam 1 g q8h and above, suggesting that the combination of aztreonam/nacubactam provides adequate therapeutic efficacy against β-lactamase-producing K. pneumoniae infection in human.
The f T>CT, when aztreonam (0.5 g, 1 g, and 2 g) and nacubactam (0.05 g, 0.15 g, 0.5 g, 1 g, and 2 g) are co-administered every 8 hrs, is also calculated and summarised in Table 3. The CT value with the highestR 2 value at each dose was used in the calculations (Fig. 7). For NDM-1-positive K. pneumoniae ATCC BAA-2473, the minimum combination of aztreonam 0.5 g q8h and nacubactam 0.05 g q8h achieved growth inhibition, and all other doses achieved bactericidal effects.
For IMP-6-positive K. pneumoniae MSC 21664, 2 log10-kill was achieved at all simulated doses as well as f T>MICi. As for OXA-48-positiveK. pneumoniae MSC 21444, all nacubactam dosages achieved growth inhibition when co-administered with aztreonam 0.5 g q8h and 1 log10-kill when co-administered with aztreonam 1 g or 2 g q8h. Interestingly, the bactericidal effect simulated byf T>CT against NDM-1-positiveK. pneumoniae ATCC BAA-2473 and OXA-48-positive K. pneumoniae MSC 21444 was estimated lower thanf T>MICi.