2121. In vitro Synergy of the Combination of Sulbactam-Durlobactam and Cefepime at Clinically Relevant Concentrations Against A. baumannii, P. aeruginosa, and Enterobacterales
Authors: Fouad Aliaa , Nicolau David P , Gill Christian M 
Published: November 2023

Abstract

Background
Due to the incidence of polymicrobial nosocomial infections, effective therapies with activity against Acinetobacter baumannii (ACB), P. aeruginosa (PSA) and Enterobacterales are needed. Sulbactam-durlobactam (SUL-DUR) has potent, selective activity against ACB. Cefepime (FEP) is a common first-line therapy for hospital/ventilator associated pneumonia caused by non-ACB Gram-negative pathogens, but resistance to FEP is increasing. This study investigated the in vitro synergy of SUL-DUR + FEP against relevant pathogens.

Methods
Static time-kills were performed in duplicate against fourteen FEP-resistant isolates (ACB, n=4; PSA, n=4; E. coli, n=3; K. pneumoniae, n=3). One wild type K. pneumoniae isolate was included. Antibiotic concentrations simulated the free-steady state average concentration of clinically administered doses in patients (SUL-DUR 1g-1g q6h, FEP 2g q8h).

Results
SUL-DUR alone showed significant activity against ACB consistent with the MIC for isolates at 8 mg/L and lower (range: 0.91-2.14 log10 reduction in CFU/mL relative to 0h control). SUL-DUR plus FEP showed synergy (2.96 log10 reduction in CFU/mL relative to SUL-DUR alone) against one ACB isolate with an elevated MIC to SUL-DUR (32 mg/L). SUL-DUR plus FEP showed synergy vs. all PSA isolates (range: 2.93-3.27 log10 reduction in CFU/mL relative to SUL-DUR alone). Against Enterobacterales, combination therapy was indifferent due to significant kill from SUL-DUR (due to the intrinsic antibacterial activity of DUR alone vs. Enterobacterales) with ∼ 4 log10 kill relative to 0h. SUL-DUR plus FEP was synergistic (5.82 log10 reduction in CFU/mL relative to SUL-DUR alone) vs. one E. coli isolate with an elevated MIC to SUL-DUR ( &gt;128 mg/L). SUL-DUR plus FEP showed synergy against one of the K. pneumoniae with 2.97 log10 CFU/mL reduction relative to SUL-DUR and an additive effect against the other two K. pneumoniae tested (range: 1.82-1.94 log10 reduction in CFU/mL relative to SUL-DUR alone). No antagonism was observed in any isolates.

Conclusion
Synergy and no antagonism was observed with the combination of SUL-DUR and FEP. Further pharmacokinetic/pharmacodynamic studies conducted in vivo to verify these results are warranted.

Disclosures
David P. Nicolau, PharmD, Allergan: Advisor/Consultant|Allergan: Grant/Research Support|Cepheid: Advisor/Consultant|Cepheid: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Tetraphase: Advisor/Consultant|Tetraphase: Grant/Research Support|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support|Wockhardt: Advisor/Consultant|Wockhardt: Grant/Research Support Christian M. Gill, PharmD, Cepheid: Grant/Research Support|Entasis therapeutics: Grant/Research Support|Everest Medicines: Grant/Research Support|Shionogi: Grant/Research Support