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)

• Published in: The Lancet infectious diseases 2023-09, Vol.23 (9), p.1072-1084
• Main Authors: Kaye, Keith S, Shorr, Andrew F, Wunderink, Richard G, Du, Bin, Poirier, Gabrielle E, Rana, Khurram, Miller, Alita, Lewis, Drew, O'Donnell, John, Chen, Lan, Reinhart, Harald, Srinivasan, Subasree, Isaacs, Robin, Altarac, David
• Format: Article
• Language: English
• Subjects: Acinetobacter baumannii; Active control; Adverse events; Amides; Antibiotics; Antimicrobial agents; Bacteria; Clinical trials; Colistin; Creatinine; Criteria; Drug dosages; Drug resistance; Effectiveness; End-stage renal disease; Glomerular filtration rate; Health services; Hospitals; Imipenem; Infectious diseases; Kidney diseases; Mortality; Multidrug resistance; Pathogens; Patients; Penicillin; Pharmacokinetics; Pneumonia; Renal failure; Safety; Strains (organisms); Sulbactam; Upper bounds; Urinary tract diseases; Urinary tract infections; Urogenital system; Ventilators; β Lactamase; β-Lactam antibiotics
• ISSN: 1473-3099; 1474-4457
• DOI: 10.1016/S1473-3099(23)00184-6

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. 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. 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