Ampicillin/Sulbactam in Combination with Ceftazidime/Avibactam against Metallo-β-Lactamase-Producing Carbapenem-Resistant Acinetobacter baumannii: A Genomics-Informed Mechanism-Based Model

AbstractCarbapenem-resistant Acinetobacter baumannii (CRAB) infections, driven by metallo- and class D serine β-lactamases, present significant treatment challenges due to limited therapeutic options. β-lactam combinations emerge as a promising strategy, given the toxicity and limited efficacy of agents like colistin, tigecycline, and cefiderocol. We evaluated the pharmacodynamic activity of ampicillin/sulbactam (AMP/SUL) and ceftazidime/avibactam (CAZ/AVI) against three CRAB strains: AMA3, AMA133, and AMA205, which carry resistance genes blaOXA-23 (AMA133), blaNDM-1 (AMA3), or both (AMA205). Notably, AMA205 has a lpxA gene mutation that enhances drug permeability through the bacterial outer membrane. Phenotypic susceptibility testing revealed high resistance to AMP/SUL and CAZ/AVI alone, but avibactam significantly restored sulbactam activity. Static concentration time-kill (SCTK) assays showed no bacterial killing with either drug as monotherapy, whereas combination therapy resulted in ~90% reduction in the area under the colony forming unit versus-time curve for AMA133 and ~50–70% reductions for AMA3 and AMA205. A mechanism-based model, built from SCTK data and strain resistomes, included SUL hydrolysis by NDM-1 and OXA23 enzymes along with drug acylation rates to penicillin-binding proteins (PBPs). The model’s potency parameter indicated resistance as AMA3 > AMA205 > AMA133. Avibactam’s PBP2 inhibition significantly increased SUL’s potency, indicating strong synergy. Model-based simulations informed an in vitro dynamic infection model, showing that high dose AMP/SUL based combinations were necessary for blaNDM-1 strains, while lower doses were effective for AMA133, validating SCTK and model predictions. The AMP/SUL and CAZ/AVI combination shows potential against difficult-to-treat CRAB infections by targeting multiple PBPs and β-lactamases.