A specific group of Escherichia coli, sequence type ST131 is a newly recognized, widely disseminated cause of multi-drug-resistant (MDR extraintestinal infections that appears to represent an important emerging health threat in urgent need of study. Therefore, we propose to test the following Hypotheses by accomplishing the following Specific Aims: 1. ST131 has emerged in the past ten years as the predominant FQ-R E. coli clonal group in the US, including among veterans.
Aim 1. Assess the annual prevalence of ST131 in the US among FQ-R and FQ-S E. coli in the SENTRY and TRUST collections (1999-2009) and from VA medical centers nationwide (2009). 2. ST131 is more fit than other E. coli in the pathogenic and commensal niches, and is present in foods. 2.a. In humans, ST131 causes more severe infections, in less compromised hosts, than other E. coli.
Aim 2. a. Compare clinical presentation (syndrome and severity), illness outcome, and host compromise status among veterans with ST131 vs. non-ST131 E. coli clinical isolates. 2.b. In mice, ST131 is more virulent (UTI, sepsis) than other E. coli, including classic ExPEC strains.
Aim 2. b. Compare the virulence of ST131 isolates, non-ST131 clinical isolates, and classic ExPEC strains. 2.c. ST131 exhibits enhanced intestinal colonization and host-to-host transmission, vs. other E.
coli Aim 2. c.1. In humans, assess the prevalence of intestinal co-colonization among household members of index patients with ST131 vs. non-ST131 FQ-R E. coli clinical isolates.
Aim 2. c.2. In mice, compare ST131 with non-ST131 E. coli for establishment of intestinal colonization after direct challenge or indirect exposure. 2.d. ST131 is present in retail foods, consistent with foodborne transmission.
Aim 2. d.1. Determine the prevalence of ST131 in diverse retail foods.
Aim 2. d.2. Assess the similarity of food-source versus human-source ST131 isolates according to genomic background, virulence genotype, and resistance profile. 3. Specific host characteristics predict ST131 infection.
Aim 3. Compare demographics and exposures among veterans with ST131 infection versus concurrent controls with non-ST131 E. coli infection. 4. ST131 is more receptive to CTX-M-15-encoding genetic elements than are other E. coli.
Aim 4. Compare transfer frequencies for CTX-M-15 (vs. other ESBL)-encoding elements from ST131 (vs. non-ST131) donors to ST131 (vs. non-ST131) recipients.

Public Health Relevance

Relevance to Veterans Health. Veterans commonly suffer from UTI and diverse other E. coli infections (e.g. of lung, abdomen, and wounds) [16]. Emerging antimicrobial resistance in E. coli increases the risk that veterans will receive inappropriate initial antimicrobial therapy, and makes appropriate therapy more expensive, potentially toxic, and difficult to administer.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01CX000192-04
Application #
8390429
Study Section
Infectious Diseases B (INFB)
Project Start
2009-04-01
Project End
2013-09-30
Budget Start
2012-10-01
Budget End
2013-09-30
Support Year
4
Fiscal Year
2013
Total Cost
Indirect Cost
Name
Minneapolis VA Medical Center
Department
Type
DUNS #
071774624
City
Minneapolis
State
MN
Country
United States
Zip Code
55417