Using a hollow fiber infection model to investigate the role of ceftazidime-avibactam in combination with meropenem in the prevention and treatment of mutant KPC-producing infections - Ceftazidime-avibactam (CAZ-......................-................-lactamase inhibitor (BL-BLI) that is a preferred treatment for KPC-producing Enterobacterales infections. KPC-producing infections represent a significant health threat associated with upwards of 40% mortality. AVI, as a BLI, binds to and inhibits the active site (i.e., ..-loop) of the KPC enzyme, enabling CAZ to evade hydrolysis from KPC enzymes and successfully reach its target – PBP3. Regrettably, simultaneous with its availability, emergence of CAZ-AVI resistance was recognized and clinical reports of resistance emerging during treatment continue to accumulate. Mutant KPCs (i.e., those exhibiting resistance to CAZ-AVI) result from amino acid modifications in the ..-loop region of the KPC enzyme leading to conformational changes that enable the “trapping” of CAZ in the ..-loop, a reduction in affinity for AVI, and unfettered CAZ hydrolysis. The emergence of resistance of KPC-producing Enterobacterales to CAZAVI, even with a single treatment course, has been described in approximately 15% of isolates. Remarkably, when amino acid modifications occur (rendering CAZ-AVI inactive), a lowering of carbapenem (e.g., meropenem) MICs is observed, frequently resulting in a reversion of meropenem resistance to susceptibility. It remains unknown, however, if reduced carbapenem MICs render carbapenems effective therapy for mutant KPC infections. This question is critical to investigate as CAZ-AVI is often the only KPC-active ..-lactam antibiotic in many hospitals. Moreover, several BL-BLI in development are cephalosporin-based (e.g., cefepime-taniborbactam, cefepime-zidebactam, cefiderocol-xeruborbactam). Given their structural similarities with CAZ, they are also at risk of being inactive against mutant KPC. The goal of this proposal is to investigate (1) the molecular mechanisms of resistance to ceftazidimeavibactam, (2) the frequency of emergence of resistance to ceftazidime-avibactam, (3) the likelihood of crossresistance between ceftazidime-avibactam and cephalosporin-based agents in advanced stages of development, and (4) modifiable risk factors such as duration, dosage, and frequency of ceftazidime-avibactam administration on preventing the emergence of resistance to ceftazidime-avibactam in a cohort of 500 patients with KPC-producing Enterobacterales infections. Moreover, as KPC-producing isolates that develop resistance to ceftazidime-resistance frequently have susceptibility to meropenem reinstated - a hollow-fiber infection model using humanized dosing over a 14-day period will explore (1) the combination of ceftazidime-avibactam and meropenem as a treatment option for mutant KPC (i.e., isolates exhibiting resistance to ceftazidimeavibactam) infections and (2) the combination of ceftazidime-avibactam and meropenem as an option for the prevention of the emergence of resistance of KPC-producing isolates to ceftazidime-avibactam. As antimicrobial resistance continues to escalate and therapeutic options are limited, rational mechanisticallyinformed treatment options are needed to preserve the activity of available antibiotic options.
