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. 2025 Feb 3;80(2):547-553.
doi: 10.1093/jac/dkae443.

Simulated achievement rate of β-lactams/nacubactam treatment in humans using instantaneous MIC-based PK/PD analysis

Yuki Igarashi  1 , Kazuaki Taguchi  1 , Yuki Enoki  1 , Victor Tuan Giam Chuang  2 , Kazuaki Matsumoto  1
Affiliations

Simulated achievement rate of β-lactams/nacubactam treatment in humans using instantaneous MIC-based PK/PD analysis

Yuki Igarashi et al. J Antimicrob Chemother. .

Abstract

Background: Nacubactam (NAC), a new diazabicyclooctane β-lactamase inhibitor, is being developed for use together with aztreonam (AZT) and cefepime (CFPM). However, the effective clinical dosages of AZT/NAC and CFPM/NAC have not yet been established. We have previously shown that free time above instantaneous MIC (fT > MICi) is a valuable pharmacokinetic (PK)/pharmacodynamic parameter for β-lactam (BL)/NAC in a mouse thigh infection model.

Objectives: This study simulated the fT > MICi (%) for AZT/NAC and CFPM/NAC against carbapenemase-producing Enterobacterales (CPE) with different MIC in humans to estimate the clinical efficacy at practically achievable combination doses of AZT/NAC and CFPM/NAC.

Methods: Using previously reported PK parameters of each drug in humans and chequerboard MIC data, we calculated the fT > MICi (%) for AZT/NAC and CFPM/NAC in 10 000 simulated patients to predict the percentages of target attainment of bacteriostatic and bactericidal efficacies at various combined doses.

Results: The results predicted that both BL/NAC combinations could achieve 100% 2 log10-kill against CPE strains at the lowest combination dose (0.5 g/0.5 g q8h). Additionally, in MIC studies examining BLs/NAC at a 1:1 ratio, the dosage regimen for strains with MICcomb ≤ 1 mg/L was expected to offer 100% bactericidal efficacy (2 log10-kill) at 0.5 g/0.5 g q8h or higher doses. For strains with 1 mg/L < MICcomb ≤ 16 mg/L, BLs/NAC at a 2 g/2 g q8h was predicted to produce bactericidal efficacy (1 log10-kill). At MICcomb = 32 mg/L, some bacteriostatic effect was expected at high BL doses.

Conclusions: AZT/NAC and CFPM/NAC are bactericidal against CPE at practically achievable dosages.

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Figures

Figure 1.
Figure 1.
Estimation of the fT > MICi of AZT or CFPM. (a) Chequerboard MIC assay of AZT/NAC of CFPM/NAC. (b) Dose–response curve of the AZT or CFPM MIC to NAC concentration. (c) Simulated free plasma NAC PK profile. (d) Calculated AZT or CFPM MICi transition after the administration of NAC. (e) Superimposition of the free plasma AZT or CFPM PK profile and AZT or CFPM MICi transition. The fT > MICi (%) is the percentage of time that the free plasma AZT or CFPM concentration exceeded the AZT or CFPM MICi.
Figure 2.
Figure 2.
Simulated MIC curves. MIC curves predicted when BL and NAC were used together at a 1:1 ratio with MICcomb values of (a) 0.5, (b) 1, (c) 2, (d) 4, (e) 8, (f) 16, (g) 32 and (h) 64 mg/L.
Figure 3.
Figure 3.
PTAs for each MICcomb of AZT/NAC (a–c) or CFPM/NAC (d–f).
See this image and copyright information in PMC

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