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ABSTRACTAcinetobacter baumannii is characterized by its exceptional ability to acquire multidrug resistance, spread amonghospitalized patients and cause difficult-to-treat infections in health care settings. While colonization withoutinfection is common with A. baumannii, invasive infections such as bacteremia and ventilator-associatedpneumonia do occur and are associated with infection-related deaths. Treatment options for infections causedby carbapenem-resistant A. baumannii (CRAb) are limited, and there is a dearth of clinical data regarding CRAb,ranging from its clinical epidemiology, overall and syndrome-specific clinical outcome of infected patients and itsrisk factors. Due to these knowledge gaps, it is currently not known how patients with CRAb can be bestassessed and managed to prevent morbidity and mortality. We have previously shown that clonal complex (CC)2 accounts for the majority of CRAb in hospitals across the U.S, and our preliminary work on patient outcome-based proteomic screening of virulence factors of A. baumannii has yielded several potential virulence factorswith potential clinical relevance. Leveraging the infrastructure of the highly successful CRACKLE consortiumwhich have provided seminal data regarding the epidemiology, risk factors and treatment outcome ofcarbapenem-resistant Enterobacteriaceae infections, we propose to establish the Study Network ofAcinetobacter as a Carbapenem-Resistant Pathogen (SNAP) as a platform to integrate these two successfulresearch platforms to deepen our understanding of this formidable drug-resistant pathogen. We hypothesize thatspecific clades of CRAb within epidemic clonal complexes such as CC2 are associated with fatal invasiveinfections, and that certain virulence factors such as OmpA and peptidyl-prolyl cis-trans isomerase aredifferentially expressed in the virulent clades, conferring clinically relevant pathogenicity. To test thesehypotheses, we propose the following Specific Aims: (i) to determine CRAb clades responsible for fatal invasiveinfections, and (ii) to identify virulence factors associated with fatal CRAb infections. Capitalizing on existingclinical and laboratory research infrastructure and capabilities, SNAP will provide the initial clinical description ofCRAb infections in the U.S., identify high-risk clades at the genomic level and elucidate clinically relevantvirulence factors that constitute potential therapeutic targets. Upon successful completion of the proposed study,SNAP can be readily expanded nationally and internationally as the next step in investigation utilizing the studysites and infrastructure of the growing CRACKLE consortium.

Doi, Yohei
University of Pittsburgh
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