New Therapy OK'd for Drug-Resistant Pneumonia

The FDA has approved sulbactam-durlobactam (Xacduro) for healthcare-acquired bacterial pneumonia caused by certain strains of Acinetobacter baumannii-calcoaceticus complex (A. baumannii), the agency announced late on Tuesday.

An intravenous treatment, sulbactam-durlobactam is specifically indicated for adults with hospital-acquired and ventilator-associated pneumonias caused by susceptible isolates of A. baumannii, including carbapenem‐resistant organisms.

"Today's approval helps address a high unmet medical need by providing an additional treatment option for some of the sickest patients in our nation's hospitals," Peter Kim, MD, MS, director of the Division of Anti-Infectives at FDA's Center for Drug Evaluation and Research, said in a statement.

According to the CDC, more than 29,000 people in the U.S. died in 2020 from antimicrobial-resistant infections commonly linked to healthcare, with nearly 40% acquired during hospital stays.

After decreasing in prior years, deaths related to carbapenem-resistant Acinetobacter infections -- which the agency has categorized as an "urgent threat" pathogen -- increased by 78% from 2019 to 2020.The difficult-to-treat bacteria also places among the World Health Organization's critical group of pathogens identified as being a top priority for antibiotic development.

Sulbactam is an established derivative of penicillin, while durlobactam is a beta-lactamase inhibitor that "protects sulbactam from being degraded by enzymes that may be produced" by A. baumannii, the FDA explained.

Approval of the co-packaged combination was supported by findings from the phase III ATTACK trial, a non-inferiority study that included 177 patients with hospital-acquired and ventilator-associated pneumonias caused by A. baumannii. All patients received imipenem/cilastatin as background antibiotic therapy for cases potentially caused by other pathogens.

Among the subset with laboratory-confirmed carbapenem-resistant cases, all-cause mortality at 28 days -- the trial's primary endpoint -- was 19% for the group receiving sulbactam-durlobactam and 32% for those randomized to colistin, a 13.2% difference (95% CI -30.0 to 3.5) that fell within the bounds of non-inferiority.

Clinical cure rates were significantly higher in the sulbactam-durlobactam arm compared with the placebo arm (75% vs 45%, respectively, at the end of therapy and 62% vs 40% at the test of cure visit). The combination was well tolerated in this critically ill patient population, according to the investigators.

Those findings were enough to sway members of the Antimicrobial Drugs Advisory Committee, who unanimously agreed in April that the risk-benefit assessment for sulbactam-durlobactam was favorable in light of the great unmet need for options to treat bacterial pneumonia cases caused by carbapenem‐resistant A. baumannii infections.

Drugmaker Innoviva said the co-packaged injection drug -- administered via a 3-hour IV infusion every 6 hours (1 g of each drug) -- will be available later this year.

"Physicians will soon have a novel therapeutic option that may help to address this urgent public health threat," said ATTACK investigator Andrew Shorr, MD, MPH, MBA, of Georgetown University School of Medicine in Washington, D.C., in a press release from the company.

"Acinetobacter poses a significant danger to hospitalized patients, who are generally very ill and particularly susceptible to infections," he continued. "Effectively treating infections caused by drug-resistant Acinetobacter is a challenge and makes this patient population in high need of new, effective treatment options."

The bacteria has acquired resistance genes for almost all antibiotics used against Gram-negative bacteria (e.g., aminoglycosides, carbapenems, cephalosporins, fluoroquinolones).

In trials, common adverse events with sulbactam-durlobactam included liver test abnormalities in 19%, diarrhea in 17%, anemia in 13%, and hypokalemia in 12%. Labeling for the drug includes warnings and precautions about hypersensitivity reactions and about the risk for Clostridioides difficile-associated diarrhea.

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