By Stan Deresinski, MD, FACP, FIDSA
Clinical Professor of Medicine, Stanford University
SYNOPSIS: Sulbactam-durlobactam is non-inferior to colistin in the treatment of serious bacterial infections caused by Acinetobacter baumannii-calcoaceticus complex organisms.
SOURCE: Kaye KS, Shorr AF, Wunderink RG, et al. 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). Lancet Infect Dis 2023;23:1072-1084.
Kaye and colleagues performed a randomized clinical trial at 59 clinical sites in 16 countries evaluating antibiotic treatment of patients with serious infections due to Acinetobacter baumannii-calcoaceticus complex (ABC) organisms. All the patients received imipenem-cilastatin (1 g each every six hours over one hour) and were randomized to also receive sulbactam-durlobactam (1 g each over three hours every six hours) or colistin (2.5 mg/kg over 30 minutes every 12 hours).
Of the 181 patients randomized, 176 had bacterial pneumonia (hospital-acquired pneumonia, ventilator-associated pneumonia, ventilated pneumonia) while five had bacteremia. The primary study endpoint was 28-day all-cause mortality in the 128 patients with carbapenem-resistant ABC infection. This mortality endpoint occurred in 12/63 (19%) of those who received sulbactam-durlobactam and 20/62 (32%) given colistin for a difference of -13.2% (95% confidence interval [CI], -30.0 to 3.5), meeting the predetermined non-inferiority criterion of an upper bound of the difference of less than +20%. Furthermore (and as expected), nephrotoxicity in colistin recipients was more frequent, occurring in 32/85 (38%) compared to only 12/91 (13%; P < 0.001) given sulbactam-durlobactam.
COMMENTARY
The Food and Drug Administration approved sulbactam-durlobactam in May 2023 for use in patients 18 years of age and older for treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) caused by susceptible isolates of ABC. This action was largely based on the trial by Kaye and colleagues.
Sulbactam is a beta-lactamase inhibitor (BLI) with antibacterial activity against Acinetobacter, targeting PB1 and PBP3, and often has been used in the treatment of Acinetobacter infections.
In the United States, sulbactam had only been available in combination with ampicillin (as Unasyn) and this has been given in high dose (e.g., 24 g ampicillin over 24 hours) — often with colistin, especially with infections due to carbapenem-resistant isolates. Carbapenem resistance in Acinetobacter has become a serious problem in many geographic regions.
The combination of sulbactam and durlobactam represents a significant advance in the treatment of ABC infections. In a large collection of ABC isolates, only 2.3% were resistant to this combination, although 3.7% of those resistant to colistin were resistant to sulbactam-durloactam.
Finally, it is interesting to note that this combination represents a circumstance in which BLI protects a BLI — although one of them has significant direct antibacterial activity.
