A common theme in bacterial evolution is how the acquisition of antibiotic resistance can rapidly change the epidemiologic landscape of major human pathogens. Carbapenem Resistant Klebsiella pneumoniae (CRKp), first documented in 1996, is now epidemic in New York City (NYC) hospitals and is reported globally. CRKp infections often result in poor therapeutic indices; thus curbing the incidence of CRKp infections is now a national priority. Currently, three overlapping CRKp epidemics with three different classes of carbapenemases are spreading in different continents. Accelerating these epidemics is the ability of carbapenemase genes, harbored on conjugative plasmids, to spread across the Enterobacteriaceae family. A critical, poorly understood aspect of the CRKp epidemic is the relative contribution of plasmid-mediated transfer and clonal dissemination to driving the regional and global epidemiology. Previously, we used whole genome sequencing (WGS) to dissect the molecular epidemiology and evolution of the main US epidemic CRKp sequence type (ST) 258. Interrogating strains and resistance harboring plasmids within our network of NYC hospitals we found that the majority of ST258 CRKp strains harbor one of three common plasmids carrying a particular class of carbapenemase enzyme, KPC. These data suggest the spread of CRKp is likely the consequence of plasmid-mediated gene transfer and subsequent clonal spread. We therefore hypothesize that this epidemic is primarily due to transmission of resistance harboring plasmids uniquely adapted to specific host genetic backgrounds.
In Aim 1, we expand our NYC network to include a large US consortium and to examine the genomic epidemiology of CRKp strains and plasmids across the US.
Aim 2 builds on the insights and techniques developed in our previous studies to interrogate the global epidemiology of CRKp via a large clinical isolate collection from over 62 countries, with the goal of constructing a phylogeographic map of strains, plasmids and carbapenemase genes. In this Aim we will also directly test the basis of CRKp strain-plasmid association by comparative transmission efficiency studies of different carbapenemase gene-harboring plasmids into diverse strain backgrounds. Using robust CRKp genomic data obtained in Aims 1 and 2, we will develop a rapid molecular detection assay to identify and track CRKp strains and plasmids in clinical settings.
Aim 3 will characterize non-carbapenemase factors that contribute to high-level carbapenemase resistance in CRKp isolates, such as mutations in outer membrane proteins, which result in very poor clinical outcomes. Based on this characterization, some of these highly carbapenemase resistant strains will be selected to build a new, well-curated panel of strains for testing novel antibiotic agents. Taken together, ours is an innovative approach with the potential to make a substantial impact in the field of CRKp epidemiology, develop critically needed diagnostic platforms, and explore efficacy of novel antibiotics against these organisms.

Public Health Relevance

Carbapenem resistant Klebsiella pneumoniae (CRKp) is epidemic in New York City hospitals and now reported globally. CRKp infections present a major clinical challenge often resulting in poor therapeutic indices; however, the epidemiology and molecular basis driving the epidemic remains poorly understood. Our studies proposed herein are designed to decipher the nature of an expanding epidemic, both from a local/global epidemiological and biologic perspective, and identify genetic and/or phenotypic traits catalyzing this epidemic.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI090155-07A1
Application #
9238126
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Ernst, Nancy L
Project Start
2011-03-15
Project End
2021-11-30
Budget Start
2016-12-16
Budget End
2017-11-30
Support Year
7
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Rutgers University
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
078795851
City
Newark
State
NJ
Country
United States
Zip Code
07103
Huang, Bin; He, Yuting; Ma, Xingyan et al. (2018) Promoter Variation and Gene Expression of mcr-1-Harboring Plasmids in Clinical Isolates of Escherichia coli and Klebsiella pneumoniae from a Chinese Hospital. Antimicrob Agents Chemother 62:
Kanwar, Anubhav; Marshall, Steven H; Perez, Federico et al. (2018) Emergence of Resistance to Colistin During the Treatment of Bloodstream Infection Caused by Klebsiella pneumoniae Carbapenemase-Producing Klebsiella pneumoniae. Open Forum Infect Dis 5:ofy054
Shields, Ryan K; Nguyen, M Hong; Chen, Liang et al. (2018) Pneumonia and Renal Replacement Therapy Are Risk Factors for Ceftazidime-Avibactam Treatment Failures and Resistance among Patients with Carbapenem-Resistant Enterobacteriaceae Infections. Antimicrob Agents Chemother 62:
Yu, Fangyou; Lv, Jingnan; Niu, Siqiang et al. (2018) In Vitro Activity of Ceftazidime-Avibactam against Carbapenem-Resistant and Hypervirulent Klebsiella pneumoniae Isolates. Antimicrob Agents Chemother 62:
Kobayashi, Scott D; Porter, Adeline R; Freedman, Brett et al. (2018) Antibody-Mediated Killing of Carbapenem-Resistant ST258 Klebsiella pneumoniae by Human Neutrophils. MBio 9:
Chavda, Bhakti; Lv, Jingnan; Hou, Mengyun et al. (2018) Coidentification of mcr-4.3 and blaNDM-1 in a Clinical Enterobacter cloacae Isolate from China. Antimicrob Agents Chemother 62:
Yu, Fangyou; Lv, Jingnan; Niu, Siqiang et al. (2018) Multiplex PCR Analysis for Rapid Detection of Klebsiella pneumoniae Carbapenem-Resistant (Sequence Type 258 [ST258] and ST11) and Hypervirulent (ST23, ST65, ST86, and ST375) Strains. J Clin Microbiol 56:
Peirano, Gisele; Matsumura, Yasufumi; Adams, Mark D et al. (2018) Genomic Epidemiology of Global Carbapenemase-Producing Enterobacter spp., 2008-2014. Emerg Infect Dis 24:1010-1019
Shields, Ryan K; Clancy, Cornelius J; Pasculle, A William et al. (2018) Verification of Ceftazidime-Avibactam and Ceftolozane-Tazobactam Susceptibility Testing Methods against Carbapenem-Resistant Enterobacteriaceae and Pseudomonas aeruginosa. J Clin Microbiol 56:
Satlin, Michael J; Chen, Liang; Patel, Gopi et al. (2017) Multicenter Clinical and Molecular Epidemiological Analysis of Bacteremia Due to Carbapenem-Resistant Enterobacteriaceae (CRE) in the CRE Epicenter of the United States. Antimicrob Agents Chemother 61:

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