732. Microbiologic and clinical outcome concordance in the global phase 3 ATTACK trial: Sulbactam-durlobactam (SUL-DUR) versus colistin therapy in patients with Acinetobacter baumannii-calcoaceticus complex (ABC) infections

Abstract

Background SUL-DUR is a β-lactam/β-lactamase inhibitor combination in development for the treatment of ABC, which is a cause of severe infections with substantial mortality. ATTACK evaluated the efficacy and safety of SUL-DUR versus colistin (COL) in patients with serious ABC infections. Methods Part A was a randomized, blinded non-inferiority study (SUL-DUR versus COL) in ABC pneumonia or bacteremia; Part B was an open label study (SUL-DUR only) that enrolled patients with ABC infections who did not tolerate COL or whose pathogens were resistant to COL (COL-R). All subjects received imipenem/cilastatin as background therapy. Primary endpoint included 28-day all-cause mortality (ACM) in Part A patients with carbapenem-resistant ABC at baseline (CRABC m-MITT). Clinical and microbiologic outcomes were measured at the End of Therapy (EOT), Test of Cure (TOC) and Late Follow-up (LFU) visits in CRABC m-MITT patients. In this study, COL-R was defined as MIC ≥ 4 µg/ml and SUL-DUR-non-susceptible (NS) was defined as MIC ≥ 8 µg/ml. Results SUL-DUR was non-inferior to COL in 28-day ACM; 19.0% SUL-DUR versus 32.3% in the COL group (Table 1). SUL-DUR therapy resulted in statistically significant higher clinical cures at EOT and TOC. Similarly, a significant treatment difference in microbiological favorable assessment was observed at EOT and TOC (24.4% and 26.3%, respectively, in Part A). Similar mortality differences were observed in subgroups including infection type, severity of illness, mechanical ventilation, and duration of stay of at least 5 days in the ICU prior to starting study treatment (Table 2). All 149 baseline ABC isolates from CRABC m-MITT patients were multi-drug resistant; the SUL-DUR MIC50/90 was 2/4 µg/ml (range of 0.25 – 8 µg/ml). At baseline 33% of ABC infections were polymicrobial. Conclusion In ATTACK, patients treated with SUL-DUR had lower mortality, higher clinical cure rates and significantly greater microbiologically favorable outcomes than those treated with COL. The correlation between clinical and microbiologic outcomes provides additional evidence that, if approved, SUL-DUR could be an important therapeutic option for Acinetobacter infections including carbapenem-resistant and multidrug-resistant strains. Disclosures David Altarac, MD, MPA, Entasis Therapeutics: Ownership Interest|Entasis Therapeutics: Stocks/Bonds Alita Miller, PhD, Entasis Therapeutics: Employee Sarah McLeod, PhD, Entasis Therapeutics: Employee Adam B. Shapiro, Ph.D, Entasis Therapeutics: Employee|Entasis Therapeutics: Stocks/Bonds Khurram Rana, PharmD, Entasis Therapeutics: Employee|Entasis Therapeutics: Ownership Interest|Entasis Therapeutics: Stocks/Bonds Drew Lewis, MD, MTM&H, Entasis Therapeutics: employee|Entasis Therapeutics: employee|Entasis Therapeutics: Stocks/Bonds|Entasis Therapeutics: Stocks/Bonds Gabrielle Poirier, BS, Entasis Therapeutics: Ownership Interest|Entasis Therapeutics: Stocks/Bonds Daria Chabas, BS, Entasis Therapeutics: Ownership Interest|Entasis Therapeutics: Stocks/Bonds.

Navigating Available Treatment Options for Carbapenem-ResistantAcinetobacter baumannii-calcoaceticusComplex Infections

“…Preliminary results from a phase 3 clinical trial evaluating the safety and efficacy of sulbactam-durlobactam for the treatment of CRAB infections have been reported [ 125 ]. Patients with CRAB infections were randomized to receive sulbactam-durlobactam plus imipenem-cilastatin or the combination of colistin plus imipenem-cilastatin.…”

“…Cefiderocol may not be the paradigm-shifting agent against CRAB that many had once hoped for, but in combination, it offers a well-tolerated, in vitro active β-lactam agent that has been associated with encouraging real-world clinical use in a limited number of patients [ 109 ]. The most promising data for patients with CRAB infections have been reported with sulbactam-durlobactam in a randomized clinical trial [ 125 ]. Other agents demonstrating in vitro activity against CRAB are currently in preclinical development and have been reviewed previously [ 138–140 ].…”

Pathogen-Targeted Clinical Development to Address Unmet Medical Need: Design, Safety, and Efficacy of the ATTACK Trial

“…Furthermore, SUL-DUR was well tolerated in these phase 1 and phase 2 studies [ 28–32 ]. The Acinetobacter Treatment Trial Against Colistin (ATTACK) trial (ClinicalTrials.gov: NCT03894046) was a global, randomized, active-controlled phase 3 noninferiority trial that evaluated the safety and efficacy of SUL-DUR compared with colistin in patients with serious infections from carbapenem-resistant ABC (CRAB) [ 33 ]. The design of this phase 3 trial was in accordance with the FDA guidance for industry on antibacterial therapies for patients with an unmet medical need for the treatment of serious bacterial diseases [ 9 ].…”

Sulbactam-durlobactam: A Step Forward in Treating Carbapenem-Resistant Acinetobacter baumannii (CRAB) Infections

“…SUL-DUR with imipenem-cilastin was well tolerated with no serious adverse events reported, and the pharmacokinetics of SUL-DUR was similar to that observed in healthy volunteers. A recently completed phase 3 trial (ATTACK) compared SUL-DUR with colistin for treating serious infections resulting from carbapenem-resistant A. baumannii – calcoaceticus complex (ABC) [ 23 ]. SUL-DUR met the primary noninferiority endpoint of 28-day all-cause mortality.…”

“…The authors hypothesized that DUR, in addition to providing protection for SUL, may have also enhanced the activity of cefiderocol. The mechanistic basis for this success may also parallel the ATTACK trial, in which combinations and hitting multiple targets enhanced efficacy [ 23 ].…”