Sarah M. McLeod

Zoliflodacin is a first-in-class spiropyrimidinetrione, oral, single-dose antibacterial recently approved by the US FDA for treatment of uncomplicated urogenital gonorrhea. Isolates of Neisseria gonorrhoeae ( n = 322) collected in the United States in 2020–2022 by the Centers for Disease Control and Prevention, as well as two ceftriaxone-resistant isolates, were tested for susceptibility to zoliflodacin. All isolates were susceptible to zoliflodacin with MIC _50/90 values of 0.12 µg/mL. Zoliflodacin activity was consistent over time and against ceftriaxone-, ciprofloxacin-, and tetracycline-resistant and azithromycin-non-susceptible isolates.

Acinetobacter baumannii-calcoaceticu s complex (ABC) causes severe, difficult-to-treat infections that are frequently antibiotic resistant. Sulbactam-durlobactam (SUL-DUR) is a targeted β-lactam/β-lactamase inhibitor combination antibiotic designed to treat ABC infections, including those caused by multidrug-resistant strains. In a global, pathogen-specific, randomized, controlled phase 3 trial (ATTACK), the efficacy and safety of SUL-DUR were compared to colistin, both dosed with imipenem-cilastatin as background therapy, in patients with serious infections caused by carbapenem-resistant ABC. Results from ATTACK showed that SUL-DUR met the criteria for non-inferiority to colistin for the primary efficacy endpoint of 28-day all-cause mortality with improved clinical and microbiological outcomes compared to colistin. This report describes the characterization of the baseline ABC isolates from patients enrolled in ATTACK, including an analysis of the correlation of microbiological outcomes with SUL-DUR MIC values and the molecular drivers of SUL-DUR resistance.

In a previous study, the efficacy and safety of sulbactam-durlobactam vs. colistin for the treatment of patients with carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (CRABC) infections were evaluated in a randomized, controlled, Phase 3 trial. Both arms were dosed on a background of imipenem-cilastatin to treat co-infecting Gram-negative pathogens. Thirty-six percent of infections in the primary efficacy population were polymicrobial. A subset analysis was performed to compare clinical and microbiological outcomes at Test of Cure (7 ± 2 days after the last dose) for patients with monomicrobial and polymicrobial CRABC infections. Minimal inhibitory concentrations of antibiotics against baseline isolates were determined by broth microdilution using CLSI methodology. 28-day all-cause mortality, clinical cure and microbiological outcomes were similar for patients in the sulbactam-durlobactam treatment arm with either monomicrobial or polymicrobial ABC infections. Patients in the colistin arm with monomicrobial CRABC infections had higher mortality rates with worse clinical and microbiological outcomes compared to those with polymicrobial infections. For patients who received sulbactam-durlobactam, imipenem susceptibility of co-infecting Gram-negative pathogens trended with clinical benefit for patients with polymicrobial ABC infections. When tested in vitro, durlobactam restored imipenem susceptibility to the majority of co-infecting Gram-negative pathogens from the sulbactam-durlobactam arm. This phenotype appeared to be related to the clinical outcome in 13 of 15 evaluable cases. These results suggest that the use of sulbactam-durlobactam plus a carbapenem could be an effective approach to treat polymicrobial infections that include CRABC, but additional clinical data are needed to demonstrate efficacy.

Acinetobacter baumannii is a difficult-to-treat healthcare-associated pathogen due to its propensity for environmental contamination and multidrug resistance. The Centers for Disease Control and Pr...

Sulbactam-durlobactam is a β-lactam/β-lactamase inhibitor combination developed to treat hospital-acquired and ventilator-associated bacterial pneumonia caused by Acinetobacter baumannii-calcoaceticus complex (ABC). Durlobactam is a diazabicyclooctane β-lactamase inhibitor with potent activity against Ambler classes A, C, and D serine β-lactamases and restores sulbactam activity against multidrug-resistant ABC. Studies were conducted to establish sulbactam-durlobactam antimicrobial susceptibility testing methods for both broth microdilution minimal inhibitory concentration (MIC) and disk diffusion tests as well as quality control (QC) ranges. To establish the MIC test method, combinations of sulbactam and durlobactam were evaluated using a panel of genetically characterized A. baumannii isolates which were categorized as predicted to be susceptible or resistant based on the spectrum of β-lactamase inhibition by durlobactam. MIC testing with doubling dilutions of sulbactam with a fixed concentration of 4 µg/mL of durlobactam resulted in the greatest discrimination of the pre-defined susceptible and resistant strains. Similarly, the sulbactam/durlobactam 10/10 µg disk concentration showed the best discrimination as well as correlation with the MIC test. A. baumannii NCTC 13304 was selected for QC purposes because it assesses the activity of both sulbactam and durlobactam with clear endpoints. Multi-laboratory QC studies were conducted according to CLSI M23 Tier 2 criteria. A sulbactam-durlobactam broth MIC QC range of 0.5/4–2/4 µg/mL and a zone diameter QC range of 24–30 mm were determined for A. baumannii NCTC 13304 and have been approved by CLSI. These studies will enable clinical laboratories to perform susceptibility tests with accurate and reproducible methods.

Recently, a global, active-controlled Phase 3 trial evaluated the efficacy and safety of SUL-DUR vs. COL for patients with Acinetobacter baumannii-calcoaceticus complex (ABC) infections, including multidrug resistant strains. Both arms were dosed on a background of imipenem/cilastatin (IMI) to treat co-infecting Gram-negative pathogens. 33% of infections in the primary efficacy population were polymicrobial. The minimal inhibitory concentrations (MICs) of SUL-DUR, colistin and imipenem against baseline isolates were determined by broth microdilution using CLSI guidelines. The primary efficacy endpoint was 28-day all-cause mortality (ACM) in patients with carbapenem-resistant ABC at baseline (CRABC m-MITT). Clinical and microbiological outcomes were evaluated at Test of Cure (TOC). SUL-DUR was equally efficacious in patients with monomicrobial vs. polymicrobial ABC baseline infections and an equal percentage of deaths (33%) were attributable to the index infection in each sub-group. Although fewer patients in the COL arm died with polymicrobial ABC infections (5 of 20, 25%) than monomicrobial ABC infections (15 of 20, 75%), 60% of the former (3 of 5) were attributable to polymicrobial ABC infections while 46.7% of the latter (7 of 15) were attributable to monomicrobial ABC infections. These results suggest that, if approved, the use of SUL-DUR plus a carbapenem could be an effective approach to treat polymicrobial infections that include ABC. Alita Miller, PhD, Entasis Therapeutics: employee|Entasis Therapeutics: Stocks/Bonds Sarah McLeod, PhD, Innoviva Specialty Therapeutics: Employee|Innoviva Specialty Therapeutics: Employee|Innoviva Specialty Therapeutics: Stocks/Bonds|Innoviva Specialty Therapeutics: Stocks/Bonds Adam B. Shapiro, Ph.D, Innoviva Specialty Therapeutics: Employee|Innoviva Specialty Therapeutics: Stocks/Bonds Khurram Rana, PharmD, Innoviva Specialty Therapeutics: Employee|Innoviva Specialty Therapeutics: Stocks/Bonds David Altarac, MD, MPA, Entasis Therapeutics: Full Time Employee

Acinetobacter baumannii-calcoaceticuscomplex (ABC) causes severe infections that are difficult to treat due to pre-existing antibiotic resistance. Sulbactam-durlobactam (SUL-DUR) is a targeted β-lactam/β-lactamase inhibitor combination antibiotic designed to treat serious infections caused byAcinetobacter, including multidrug- and carbapenem-resistant strains. In a recent global surveillance study of 5,032 ABC clinical isolates collected from 2016 to 2021, less than 2% of ABC isolates had SUL-DUR MIC values >4 µg/mL. Molecular characterization of these isolates confirmed the primary drivers of resistance are metallo-β-lactamases or penicillin-binding protein 3 (PBP3) mutations, as previously described. In addition, this study shows that certain common PBP3 variants, such as A515V, are insufficient to confer sulbactam resistance and that the efflux of durlobactam by AdeIJK is likely to play a role in a subset of strains.

The incidence of infections caused by multidrug-resistant (MDR) Acinetobacter baumannii (Ab) is increasing at an alarming rate in certain regions of the world, including the Middle East. Sulbactam (SUL) has intrinsic antibacterial activity against Ab; however, the prevalence of β-lactamases in Ab has limited its therapeutic utility. Durlobactam (DUR, formerly ETX2514) is a diazabicyclooctenone β-lactamase inhibitor with broad-spectrum activity against Ambler class A, C and D β-lactamases that restores SUL activity in vitro against MDR Ab. SUL-DUR is an antibiotic designed to treat serious infections caused by Acinetobacter, including multidrug-resistant strains, that is currently in Phase 3 clinical development. In global surveillance studies of >3600 isolates from 2012-2017, the MIC₉₀ of SUL-DUR was 2 mg/L. Although surveillance systems to monitor MDR infections in the Middle East are currently being established, quantitative, prevalence-based data are not yet available. Therefore, the potency of SUL-DUR was determined against 190 recent, diverse Ab clinical isolates from this region. 190 Ab isolates were collected between 2016 - 2018 from medical centers located in Israel (N = 47), Jordan (N = 36), Qatar (N = 13), Kuwait (N = 42), Lebanon (N = 8), Saudi Arabia (N = 24) and United Arab Emirates (N = 20). Seventy-five percent and 20.5% of these isolates were from respiratory and blood stream infections, respectively. Susceptibility to SUL-DUR and comparator agents was performed according to CLSI guidelines, and data analysis was performed using CLSI and EUCAST breakpoint criteria where available. This collection of isolates was 86% carbapenem-resistant and 90% sulbactam-resistant (based on a breakpoint of 4 mg/L). The addition of SUL-DUR (fixed at 4 mg/L) decreased the sulbactam MIC₉₀ from 64 mg/L to 4 mg/L. Only 3 isolates (1.6%) had SUL-DUR MIC values of > 4 mg/L. This potency was consistent across countries, sources of infection and subsets of resistance phenotypes. SUL-DUR demonstrated potent antibacterial activity against recent clinical isolates of Ab from the Middle East, including MDR isolates. These data support the global development of SUL-DUR for the treatment of MDR Ab infections. Alita Miller, PhD, Entasis Therapeutics (Employee) Sarah McLeod, PhD, Entasis Therapeutics (Employee) Samir Moussa, PhD, Entasis Therapeutics (Employee)