Use of site-specific pharmacokinetics to optimize antibiotic combinations and prevent the emergence of resistance against CRE

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ABSTRACT Carbapenem-resistant Enterobacteriaceae (CRE) continue to be a global public health threat and priority for antimicrobial development efforts. Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (KPC-Kp) is the predominant pathogen; however, prevalence rates have decreased in endemic regions resulting in a more diverse CRE landscape that includes both KPC and non-KPC producing pathogens. Ceftazidime-avibactam (CAZ-AVI), a novel β-lactam/β-lactamase inhibitor (BL/BLI) that has become the front- line treatment of CRE infections, resulting in superior efficacy and safety compared to prior salvage regimens. Despite these encouraging findings, CAZ-AVI resistance emerged in 10% of patients following courses of 7 – 19 days. We identified mutations in blaKPC-3 encoding variant KPC-3 enzymes responsible for resistance. Variant KPC enzymes displayed reverted susceptibility to carbapenems. Two newer BL/BLI agents, meropenem- vaborbactam (MER-VAB) and imipenem-relebactam (IMI-REL) feature a carbapenem backbone that may provide stability against blaKPC mutations; however, we have showed that their activity against CRE is compromised by porin gene mutations that decrease outer membrane permeability. It is unclear how frequently resistance will emerge to each of the new BL/BLI agents. Antibiotic combination therapy is a common strategy to treat CRE infections; however, ideal BL/BLI combination regimens are not defined, nor are dosing regimens that optimize activity and reduce the selection of resistant mutants. Our primary objectives in this project are to understand mechanisms by which CRE develop resistance to CAZ-AVI, MER-VAB, and IMI-REL, and to identify strategies that effectively suppress the emergence of resistance. To accomplish these objectives we will investigate new and previously defined resistance mechanisms and suppression of resistance by partnering BL/BLI agents with other recently-approved agents that offer complimentary mechanisms or dual BL agents with each BLI. In specific aim 1, we will determine the frequency (aim 1a) and mechanisms (aim 1b) by which resistance emerges against BL/BLI agents in a dynamic hollow-fiber infection model. BL/BLI exposures will be modeled using serum and epithelial lining fluid (ELF) pharmacokinetics that are achieved during bacteremia and pneumonia, respectively. In specific aim 2, we will define BL/BLI combination regimens that suppress the emergence of resistance in hollow-fiber (aim 2a) and murine pneumonia (aim 2b) models. To do so, we will screen novel combination regimens in time-kill analyses by partnering BL/BLI agents with eravacycline, fosfomycin, and plazomicin, or CAZ-AVI plus MER or IMI and CAZ plus MER-VAB or IMI-REL. The most active combinations will be validated against representative CRE clinical isolates with diverse mechanisms. The results of this study will generate timely, clinically-relevant data that provides new information on optimized treatment regimens in the face of a rapidly changing CRE landscape. Moreover, we will define novel mechanisms of resistance, and use these data to better define the therapeutic niche of each newly-approved, CRE-active agent.