Restoring cefepime activity against multidrug-resistant KPC-producing Klebsiella pneumoniae by combination with boronic acid inhibitors, MB076 and S02030.

Abstract

Foremost in the design of new β-lactamase inhibitors (BLIs) are the boronic acid transition state inhibitors (BATSIs). Two highly potent BATSIs being developed are S02030 and MB076 strategically designed to be active against cephalosporinases and carbapenemases, especially KPC. When combined with cefepime, S02030 and MB076 demonstrated potent antimicrobial activity against laboratory and clinical strains of Enterobacterales expressing a variety of class A and class C β-lactamases, including bla_KPC-2 and bla_KPC-3. Static time-kill assays revealed the bactericidal activity of cefepime in combination with S02030 and MB076 against a multidrug-resistant KPC-producing K. pneumoniae (KPC-Kpn-1), in which a ≥ 3-log₁₀ decrease in the bacterial density was observed by 6 h. In vivo efficacy of MB076 in combination with cefepime was evaluated in a lung infection model where male C57BL/6 mice were infected intranasally with KPC-Kpn-1. Cefepime alone administered at 2 h post infection resulted in a 1.07 log₁₀ CFU reduction at 24 h, while cefepime in combination with MB076 resulted in an enhanced reduction of 2.70 log₁₀ CFU (P < 0.0001) compared to the no treatment control group. In a survival analysis where mice were infected via the tail vein with KPC-Kpn-1, all mice treated with placebo or cefepime alone (100 mg/kg) died, whereas those treated with a 1:4 molar ratio of cefepime-MB076 survived. Our data demonstrate bactericidal activity and in vivo efficacy of cefepime-MB076 comparable to ceftazidime-avibactam and support the continued development of this combination as a new treatment option for infections caused by class A carbapenemase producing Enterobacterales, particularly KPC-Kpn.