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

Background: Carbapenem-resistant Acinetobacter baumannii (CRAB) infections, driven by metallo- and class D serine β-lactamases, pose significant therapeutic challenges. β-lactam-based combinations offer a promising alternative to agents like colistin and tigecycline, which are associated with toxicity, and to cefiderocol, which is facing emerging resistance.

Methods: The pharmacodynamic activity of ampicillin/sulbactam and ceftazidime/avibactam was evaluated against three CRAB strains: AMA3, AMA133, and AMA205. Genotypic and phenotypic resistance profiles were characterized, and Antibacterial activity was assessed using static concentration time-kill (SCTK) assays. A mechanism-based pharmacodynamic model (MBM) was developed using SCTK data, incorporating Bacterial resistome. This model informed the design of in vitro dynamic Infection model studies, which were subsequently used to validate MBM predictions.

Results: These strains harboring resistance genes including blaOXA-23 (AMA133), blaNDM-1 (AMA3), or both (AMA205) were resistant to ampicillin/sulbactam and ceftazidime/avibactam. However, combination therapy significantly reduced Bacterial burden, achieving ∼90% reduction in the area under the log10-CFU-versus-time curve for AMA133, and ∼50-70% for AMA3 and AMA205. The MBM incorporated sulbactam hydrolysis by NDM-1 and OXA23 Enzymes, along with drug acylation kinetics to penicillin-binding proteins. Potency (EC50) estimates revealed a resistance hierarchy: AMA3>AMA205>AMA133. Avibactam notably enhanced sulbactam's activity. Simulations and experimental validation demonstrated that high-dose ampicillin/sulbactam combinations were required to achieve 4-6 log10-CFU reductions in blaNDM-1 strains, while lower doses sufficed for AMA133.

Conclusion: This study highlights the potential of integrating genomic insights into MBM to optimize Antibiotic regimens. The ampicillin/sulbactam and ceftazidime/avibactam combinations demonstrated promising activity against highly resistant CRAB strains, supporting their potential for clinical application in managing difficult-to-treat infections.

Antimicrobial resistance; Carbapenem-resistant Acinetobacter baumannii; Mechanism-based modeling; Metallo-β-lactamases; Pharmacokinetics/pharmacodynamics.