Dilution susceptibility testing method evaluation for the combination of ceftibuten and avibactam against Enterobacterales

With the increase in antimicrobial resistance and multidrug-resistant infections, the discovery of additional therapeutic options to combat different infection types and treat different patient populations is paramount. Many recently developed antibiotics are administered intravenously, which can needlessly overburden healthcare systems and may not be needed or appropriate for every patient. Extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales infections have increased since 2012 and are resistant to first-line therapies used for many infections including complicated urinary tract infections. To address the need for alternatives to intravenous therapies against ESBL-producing Enterobacterales, a novel combination of ceftibuten and a modified prodrug version of avibactam (ARX-1796) designed for oral administration is being developed to treat serious Gram-negative infections. Because clinicians often prescribe antibiotics to patients based on the susceptibility profile of the bacterium causing their infection-particularly when empiric therapy fails-establishing the parameters for the susceptibility testing is a vital phase of development. To address two key gaps in reference method development for CTB/AVI, this study follows CLSI M23 Tier 1 guidance to investigate the impact of nonstandard testing conditions on broth microdilution testing, as well as the correlation between broth microdilution and agar dilution methods. There was a high correlation between the methods for CTB/AVI (essential agreement ≥90%) when evaluating 153 Enterobacterales isolates, including recent clinical isolates with diverse antimicrobial resistance mechanisms. Besides 100-fold increased inoculum density and pH of 5.0, CTB/AVI activity was largely unaffected by 21 alternate broth microdilution test conditions.IMPORTANCENew antibiotics are desperately needed to combat expanding and new antimicrobial resistance trends globally. While there are antibiotics in the drug development pipeline that target antibiotic-resistant bacteria, most of these new antibiotics are not available in an oral formulation. Ceftibuten in combination with avibactam targets drug-resistant ram-negative organisms, including those that cause complicated urinary tract infections, and is orally administered. This combination fills a gap for clinicians seeking an appropriate oral therapeutic regimen for patients with drug-resistant infections. During anti-infective development, it is important to delineate the variables for susceptibility testing so that clinicians can confidently evaluate whether an infecting organism is resistant or susceptible to a potential therapy. This study evaluated dilution susceptibility testing methods for ceftibuten in combination with avibactam against targeted organisms (Enterobacterales) and found that broth and agar dilution testing methods agree, and this combination is recalcitrant to most variations, aside from low pH and inoculum size, in standard test parameters.