2121. In vitro Synergy of the Combination of Sulbactam-Durlobactam and Cefepime at Clinically Relevant Concentrations Against A. baumannii, P. aeruginosa, and Enterobacterales

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 ( >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