The growing problem of antimicrobial resistance is well recognized. Infections with multi-drug resistant organisms are challenging to treat, and are associated with increased morbidity, mortality, and expenditure of healthcare resources. While much attention has been directed at understanding the epidemiology of resistance in Gram-positive organisms, especially methicillin-resistant Staphylococcus aureus, much less is known about the epidemiology of multi-drug resistance in Gram-negative organisms, particularly in pediatrics. Our preliminary data demonstrate statistically significant and very worrisome increases in plasmid-borne, broad-spectrum 2-lactam resistance (PBLR) in Enterobacteriaceae at our pediatric center. This type of resistance includes plasmid-borne AmpC-, ESBL-, and carbapenemase-type determinants, and is concerning both because it limits the antimicrobials available to treat infections and because plasmids are readily transferable between organisms, creating a threat for rapid spread of resistance. We propose a multicenter pilot project to describe national molecular and epidemiological trends in pediatric PBLR in Enterobacteriaceae .
Aims 1. To estimate the prevalence of plasmid-borne, broad-spectrum 2-lactam resistance (PBLR), and to describe frequency distributions of the respective molecular determinants and plasmid types, among clinical pediatric Enterobacteriaceae isolates from 4 medical centers across the U.S. over time. 2. To define the clonal background and virulence properties of E. coli isolates demonstrating PBLR versus control E. coli isolates without PBLR. 3. To define the demographic, clinical, and bacterial factors associated with PBLR in Enterobacteriaceae infections in pediatric patients. Methods. A consortium of 4 pediatric hospitals is involved in this project. Each site, through routine clinical care, will identify Enterobacteriaceae with resistance patterns potentially indicative of PBLR. These isolates (along with non-PBLR control isolates) and demographic and clinical data from the infected patients will be sent to Seattle Children's, where further characterization of the organisms and data analyses will take place. Expected Outcomes of the Project. This project will define the scope of PBLR resistance in pediatrics on a national scale. This information has the potential to inform treatment, especially empiric treatment, of serious bacterial infections in children. It will also provide novel information from integrated analyses of clinical data from the human host, strain background and virulence of the bacterial host, and the molecular determinants of resistance. This will provide needed information for the design of future interventional studies aimed at preventing PBLR resistance.

Public Health Relevance

We propose to study antibiotic resistance in Enterobacteriaceae bacteria (such as Escherichia coli and Klebsiella pneumoniae) that produce urinary tract and bloodstream infections in children, by analyzing clinical isolates from 4 children's hospitals across the country. Having already demonstrated a statistically significant increase in the frequency of specific resistance genes among clinical isolates at our medical center, we describe an expanded approach that features geographically broader sampling as well as a powerful set of molecular tools that can highlight key epidemiologic differences between resistant strains and still-susceptible strains. This data will fill a critical gap in the pediatric literature, and provide the foundation for design of intervention studies to reduce the spread of this resistance, and guide changes in treatment to reduce the morbidity and mortality of such infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI083413-03
Application #
8294778
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Korpela, Jukka K
Project Start
2010-06-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$579,344
Indirect Cost
$160,786
Name
Seattle Children's Hospital
Department
Type
DUNS #
048682157
City
Seattle
State
WA
Country
United States
Zip Code
98105
Zerr, Danielle M; Qin, Xuan; Oron, Assaf P et al. (2014) Pediatric infection and intestinal carriage due to extended-spectrum-cephalosporin-resistant Enterobacteriaceae. Antimicrob Agents Chemother 58:3997-4004
Kronman, Matthew P; Zerr, Danielle M; Qin, Xuan et al. (2014) Intestinal decontamination of multidrug-resistant Klebsiella pneumoniae after recurrent infections in an immunocompromised host. Diagn Microbiol Infect Dis 80:87-9
Weissman, Scott J; Adler, Amanda; Qin, Xuan et al. (2013) Emergence of extended-spectrum *-lactam resistance among Escherichia coli at a US academic children's hospital is clonal at the sequence type level for CTX-M-15, but not for CMY-2. Int J Antimicrob Agents 41:414-20