Acinetobacter baumannii is characterized by its exceptional ability to acquire multidrug resistance, spread among hospitalized patients and cause difficult-to-treat infections in health care settings. While colonization without infection is common with A. baumannii, invasive infections such as bacteremia and ventilator-associated pneumonia do occur and are associated with infection-related deaths. Treatment options for infections caused by 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 its risk factors. Due to these knowledge gaps, it is currently not known how patients with CRAb can be best assessed 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 factors with potential clinical relevance. Leveraging the infrastructure of the highly successful CRACKLE consortium which have provided seminal data regarding the epidemiology, risk factors and treatment outcome of carbapenem-resistant Enterobacteriaceae infections, we propose to establish the Study Network of Acinetobacter as a Carbapenem-Resistant Pathogen (SNAP) as a platform to integrate these two successful research platforms to deepen our understanding of this formidable drug-resistant pathogen. We hypothesize that specific clades of CRAb within epidemic clonal complexes such as CC2 are associated with fatal invasive infections, and that certain virulence factors such as OmpA and peptidyl-prolyl cis-trans isomerase are differentially expressed in the virulent clades, conferring clinically relevant pathogenicity. To test these hypotheses, we propose the following Specific Aims: (i) to determine CRAb clades responsible for fatal invasive infections, and (ii) to identify virulence factors associated with fatal CRAb infections. Capitalizing on existing clinical and laboratory research infrastructure and capabilities, SNAP will provide the initial clinical description of CRAb infections in the U.S., identify high-risk clades at the genomic level and elucidate clinically relevant virulence 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 study sites and infrastructure of the growing CRACKLE consortium.
Acinetobacter baumannii is an antibiotic-resistant bacterial pathogen that spreads among hospitalized patients and causes difficult-to-treat infections. A. baumannii strains resistant to carbapenems (CRAb) are particularly problematic. The project will provide the initial clinical description of CRAb infections in the U.S., identify high- risk clades at the genomic level and elucidate clinically relevant virulence factors that constitute potential therapeutic targets.
| Ballaben, Anelise S; Andrade, Leonardo N; Galetti, Renata et al. (2018) Diversity of High-Level Aminoglycoside Resistance Mechanisms among Gram-Negative Nosocomial Pathogens in Brazil. Antimicrob Agents Chemother 62: |
