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CRAB Treatment Updates
Attack of the Finicky Foe: Updates on Carbapenem-Resistant Acinetobacter baumannii Treatment

Released: August 08, 2023

Emily Heil
Emily Heil, PharmD, MS, BCIDP, AAHIVP
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Key Takeaways
  • Combination therapy consisting of high-dose ampicillin/sulbactam—even if nonsusceptibility is demonstrated—and at least 1 additional active agent (eg, polymyxin, tetracycline derivative [minocycline, tigecycline], or cefiderocol) is recommended for the treatment of moderate to severe carbapenem-resistant Acinetobacter baumannii‒calcoaceticus complex (CRAB) infections.
  • Sulbactam/durlobactam—a recently FDA-approved antibiotic—was found to be noninferior to colistin for the treatment of CRAB infections in ATTACK, a randomized phase III study, and may change the landscape of how CRAB is treated.

Carbapenem-resistant Acinetobacter baumannii‒calcoaceticus complex (CRAB) is notoriously known as a tricky pathogen to treat. Even in the recently updated Infectious Diseases Society of America (IDSA) guidance on the treatment of antimicrobial-resistant gram-negative infections, no clear standard-of-care regimen exists for the treatment of moderate to severe CRAB infections.

It is suggested that healthcare professionals use combination therapy consisting of high-dose ampicillin/sulbactam—even if nonsusceptibility is demonstrated—and at least 1 additional active agent, such as polymyxin, tetracycline derivatives (minocycline, tigecycline), or cefiderocol . Initial use of monotherapy is not advised but can be considered when clinical improvement is observed.

Sulbactam/Durlobactam
Near the time the IDSA guidance update was released , a new drug—sulbactam/durlobactam—was approved by the FDA for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) caused by A. baumannii‒calcoaceticus complex and is expected to be available for purchase in the fall of 2023.

The drug combines 2 β-lactamase inhibitors: sulbactam and durlobactam. Durlobactam, a novel β-lactamase inhibitor, is a potent inhibitor of Ambler class A and C serine β-lactamases and was chemically optimized to inhibit class D OXA carbapenemases, providing potent activity against CRAB.

ATTACK
Sulbactam/durlobactam was studied in ATTACK, a randomized, multicenter, open-label, noninferiority phase III study of patients with HABP, VABP, ventilated pneumonia, or bloodstream infections caused by A . baumannii‒calcoaceticus complex. In total, 181 patients were randomized to receive sulbactam/durlobactam (1 g/1 g over 3 hours every 6 hours) or colistin (2.5 mg/kg over 30 minutes every 12 hours). All patients received imipenem/cilastatin as background therapy to cover other potential organisms.

Among patients in the microbiologic intention-to-treat group (n = 125) with laboratory-confirmed CRAB, 28-day all-cause mortality was 19% in the sulbactam/durlobactam group and 32% in the colistin group (-13.2%; 95% CI: 30% to 3.5%), meeting the prespecified noninferiority criteria. Not surprisingly, incidence of nephrotoxicity in the overall study population was significantly lower in the sulbactam/durlobactam group compared with the colistin group (13% vs 38%; P <.001).

Place in Therapy
For years, the treatment of CRAB has been guided by observational studies; thus, the development of sulbactam/durlobactam—a CRAB-focused agent—and the randomized, controlled study (ATTACK) represent exciting advancements.

What remains to be seen is how sulbactam/durlobactam will change the treatment of CRAB, including if it will become a standard-of-care regimen. Although the role of sulbactam/durlobactam has not yet been added to the IDSA guidance, a recent review by Shields and colleagues recommended that CRAB be treated with a sulbactam backbone, whether that be the combination of sulbactam/durlobactam or sulbactam (in ampicillin/sulbactam) plus 1 or more in vitro active agents.

The Unknowns
Despite the excitement surrounding sulbactam/durlobactam, many questions remain. First, sulbactam/durlobactam was studied in combination with imipenem/cilastatin. Although it was primarily added to cover pathogens other than CRAB, it is unclear if additional inhibition was provided with imipenem. More data are needed to understand the role of imipenem/cilastatin, if any, and if alternate agents would be suitable for use in combination.

In addition, it should be noted that the mortality rate in the sulbactam/durlobactam arm in ATTACK (19%) was similar to the best available therapy arm —which primarily consisted of colistin-based regimens—in the subgroup of patients with CRAB infections enrolled in the randomized, open-label phase III CREDIBLE-CR trial (18%), which compared cefiderocol vs best available therapy for serious carbapenem-resistant gram-negative bacterial infections. Although we certainly cannot compare apples and oranges between these trials, it reminds us that even with a novel drug designed specifically for CRAB, CRAB remains a finicky foe.

Learn More
To learn more about the IDSA guidance updates on the treatment of antimicrobial-resistant gram-negative infections and the potential role of sulbactam/durlobactam in the treatment of CRAB infections, join me and a panel of experts at our live symposium at IDWeek 2023 in Boston, Massachusetts. You can participate in person or via live simulcast.

Unable to make it to the IDWeek 2023 meeting? Check out our encore virtual symposium here.

Your Thoughts?
How will your management of CRAB infections change with the approval of sulbactam/durlobactam? Join the discussion by posting a comment.