Pharmacodynamics of aztreonam/ceftazidime/avibactam and polymyxin B versus New Delhi MBL-producing Acinetobacter baumannii

Background: Acinetobacter baumannii has become an increasingly urgent public health concern among global health agencies due to high rates of carbapenem resistance. Carbapenem-resistant A. baumannii (CRAB) that express both oxacillinases and MBLs is especially problematic due to resistance to all β-lactams. Methods: Two clinical A. baumannii isolates, AR-0033 and AR-0083, harbouring bla_NDM-1 (for both isolates MIC_aztreonam >64 mg/L, MIC_{ceftazidime/avibactam} >128/4 mg/L, MIC_{polymyxin B} = 1 mg/L, MIC_cefiderocol  ≥16 mg/L) were treated with mono- or combination therapies of aztreonam/ceftazidime/avibactam and polymyxin B (PMB) in static time–kill studies over 24 h. Replicate time–kills were analysed by integrating the area under the cfu/mL-versus-time curve using the linear-trapezoidal method and normalizing to the growth control to produce the log-ratio area (LRA). The LRA was mathematically modelled as a function of aztreonam concentrations using a Hill-type function to identify the IC₅₀ values for aztreonam. Results: Treatment with aztreonam/ceftazidime/avibactam achieved <2 log₁₀ cfu/mL reduction by 24 h for all concentrations in both isolates. Monotherapies of PMB at 0.75, 1.5, 3.0 and 6.0 mg/L displayed maximum killing by 6 h against AR-0033. Monte Carlo simulations of human pharmacokinetics of aztreonam showed that package insert dosing resulted in a average free steady-state concentration above the target aztreonam IC₅₀ values for AR-0033 ≥96% of time when in combination with ceftazidime/avibactam and PMB. Conclusions: This study supports the potential utility of low-dose PMB therapy in combination with β-lactams to combat NDM-producing CRAB.