Sulbactam-durlobactam: a β-lactam/β-lactamase inhibitor combination targeting Acinetobacter baumannii

Abstract

Sulbactam-durlobactam is a pathogen-targeted β-lactam/β-lactamase inhibitor combination that has been approved by the US FDA for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex (ABC) in patients 18 years of age and older. Sulbactam is a penicillin derivative with antibacterial activity against Acinetobacter but is prone to hydrolysis by β-lactamases encoded by contemporary isolates. Durlobactam is a diazabicyclooctane β-lactamase inhibitor with activity against Ambler classes A, C and D serine β-lactamases that restores sulbactam activity both in vitro and in vivo against multidrug-resistant ABC. Sulbactam-durlobactam is a promising alternative therapy for the treatment of serious Acinetobacter infections, which can have high rates of mortality.

Keywords: Acinetobacter baumannii; carbapenem resistance; pneumonia; sulbactam–durlobactam; β-lactamase inhibitor.

Figure 1.

Sulbactam–durlobactam and sulbactam MIC distributions for 5032 global, clinical isolates of ABC collected from 2016 to 2021. Number of isolates at each MIC is depicted for sulbactam–durlobactam (black bars) and sulbactam (gray bars). S = susceptible interpretive criteria for sulbactam–durlobactam (MIC ≤4 μg/ml); I = intermediate interpretive criteria for sulbactam–durlobactam (MIC = 8 μg/ml); R = interpretive criteria for sulbactam–durlobactam (MIC ≥16 μg/ml), as approved by the US FDA [25]. Adapted from [22].

Figure 2.

Sulbactam–durlobactam MIC distribution of non-susceptible metallo-β-lactamase-positive and metallo-β-lactamase-negative Acinetobacter spp. Number of isolates at each sulbactam–durlobactam MIC is depicted for metallo-β-lactamase-encoding isolates (black bars) and metallo-β-lactamase negative isolates that encode for PBP3 mutations (gray bars). I: intermediate interpretive criteria for sulbactam–durlobactam of 8 μg/ml; R: interpretive criteria for sulbactam–durlobactam of ≥16 μg/ml, as approved by the US FDA [25]. Adapted from [28].

Figure 3.

Design of pivotal phase III trial for sulbactam–durlobactam versus colistin. ABC: Acinetobacter baumannii-calcoaceticus complex; BSI: Bacteremia; HABP: Hospital-acquired bacterial pneumonia; IMI: Imipenem/cilastatin; SUL-DUR: Sulbactam–durlobactam; VABP: Ventilator-associated bacterial pneumonia. Information taken from [46].

Figure 4.

All-cause mortality from pivotal phase III trial comparing sulbactam–durlobactam to colistin. ACM: All-cause mortality; CRABC m-MITT: Carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex microbiologically modified intent-to-treat population (primary efficacy analysis population); SUL-DUR: Sulbactam–durlobactam. Adapted from [46].