Molecular Epidemiology, Emergence of Resistance, and Clinical Outcomes of NDM-E Infections

About This Grant

PROJECT ABSTRACT New Delhi metallo-β-lactamase-producing Enterobacterales (NDM-E) are the fastest growing carbapenemase threat in the United States, with mortality exceeding 40% and treatment options remaining limited. Clinicians often approach NDM-E as if resistance mechanisms are uniform, yet accumulating evidence shows that allelic variation (e.g., NDM-1, NDM-5) and co-resistance mechanisms profoundly alter antibiotic efficacy. The absence of allele-level therapeutic guidance undermines precision treatment strategies and compromises outcomes. This proposal addresses this gap by integrating genotype, phenotype, and patient-level outcomes to inform care. Aim 1 defines the genetic epidemiology of NDM-E and links allele-specific diversity to susceptibility of cefiderocol (FDC), aztreonam-avibactam (A-A), and late-stage investigational agents cefepime-taniborbactam (C-T), cefepime-zidebactam (C-Z), and cefepime-nacubactam (C-N), generating an “NDM-allele antibiogram” to guide therapy. Aim 2 identifies mechanisms of resistance to NDM-directed antibiotics by evaluating resistant organisms with susceptible reference isolates and performing comparative genomics to elucidate resistance emergence. Aim 3 compares outcomes of FDC- versus A-A-treated patients with NDM-E infections, evaluating 30-day mortality and 90-day resistance emergence, with propensity score methodology mitigating confounding. A collection of approximately 800 isolates from Northwestern University, Johns Hopkins University, and the University of Pennsylvania will undergo broth microdilution, short- and long- read sequencing, and bioinformatic analysis, with patient data linked to allele-specific resistance correlates. Career development is central to this award: Dr. Hareza will receive structured training in whole-genome sequencing, bioinformatics, and high-dimensional statistical methods, reinforced by formal coursework in advanced biostatistics and causal inference and by immersive laboratory rotations with expert microbiologists. Mentorship from Drs. Pranita Tamma and Alan Hauser, supported by a multidisciplinary advisory team, will ensure both methodological rigor and clinical relevance. Northwestern University provides an ideal training environment with state-of-the-art genomics facilities, nationally recognized infectious diseases expertise, and robust bioinformatics and biostatistical cores, while protected effort ensures dedicated time for mentored research and training. The long-term goal is to position Dr. Hareza as an independent investigator leading an R01-funded program in precision-guided management of antimicrobial resistance. Ultimately, this project will advance patient care by translating allele-level resistance mechanisms into actionable therapeutic guidance while launching his independent research career in antimicrobial resistance.