Efficacy and safety of sulbactam–durlobactam versus colistin for the treatment of patients with serious infections caused by Acinetobacter baumannii–calcoaceticus complex: a multicentre, randomised, active-controlled, phase 3, non-inferiority clinical trial (ATTACK)

Background: An urgent need exists for antibiotics to treat infections caused by carbapenem-resistant Acinetobacter baumannii–calcoaceticus complex (ABC). Sulbactam–durlobactam is a β-lactam–β-lactamase inhibitor combination with activity against Acinetobacter, including multidrug-resistant strains. In a phase 3, pathogen-specific, randomised controlled trial, we compared the efficacy and safety of sulbactam–durlobactam versus colistin, both in combination with imipenem–cilastatin as background therapy, in patients with serious infections caused by carbapenem-resistant ABC. Methods: The ATTACK trial was done at 59 clinical sites in 16 countries. Adults aged 18 years or older with ABC-confirmed hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, ventilated pneumonia, or bloodstream infections were randomised 1:1 using a block size of four to sulbactam–durlobactam (1·0 g of each drug in combination over 3 h every 6 h) or colistin (2·5 mg/kg over 30 min every 12 h) for 7–14 days. All patients received imipenem–cilastatin (1·0 g of each drug in combination over 1 h every 6 h) as background therapy. The primary efficacy endpoint was 28-day all-cause mortality in patients with laboratory-confirmed carbapenem-resistant ABC (the carbapenem-resistant ABC microbiologically modified intention-to-treat population). Non-inferiority was concluded if the upper bound of the 95% CI for the treatment difference was less than +20%. The primary safety endpoint was incidence of nephrotoxicity assessed using modified Risk, Injury, Failure, Loss, End-stage renal disease criteria measured by creatinine level or glomerular filtration rate through day 42. This trial is registered at ClinicalTrials.gov, NCT03894046. Findings: Between Sep 5, 2019, and July 26, 2021, 181 patients were randomly assigned to sulbactam–durlobactam or colistin (176 hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, or ventilated pneumonia; and five bloodstream infections); 125 patients with laboratory-confirmed carbapenem-resistant ABC isolates were included in the primary efficacy analysis. 28-day all-cause mortality was 12 (19%) of 63 in the sulbactam–durlobactam group and 20 (32%) of 62 in the colistin group, a difference of –13·2% (95% CI –30·0 to 3·5), which met criteria for non-inferiority. Incidence of nephrotoxicity was significantly (p<0·001) lower with sulbactam–durlobactam than colistin (12 [13%] of 91 vs 32 [38%] of 85). Serious adverse events were reported in 36 (40%) of 91 patients in the sulbactam–durlobactam group and 42 (49%) of 86 patients in the colistin group. Treatment-related adverse events leading to study drug discontinuation were reported in ten (11%) of 91 patients in the sulbactam–durlobactam group and 14 (16%) of 86 patients in the colistin group. Interpretation: Our data show that sulbactam–durlobactam was non-inferior to colistin, both agents given in combination with imipenem–cilastatin, for the primary endpoint of 28-day all-cause mortality. Sulbactam–durlobactam was well tolerated and could be an effective intervention to reduce mortality from serious infections caused by carbapenem-resistant ABC, including multidrug-resistant strains. Funding: Entasis Therapeutics and Zai Lab.