VENOUS: A translational study of enterococcal bacteremia

ABSTRACT
Enterococci are one of the most recalcitrant hospital-associated pathogens due to resistance to many
antibiotics used in clinical practice with some untreatable infections occurring in immunocompromised
individuals. The CDC conservatively estimates that vancomycin-resistant enterococci (VRE) are associated
with 20,000 infections and 1,300 deaths per year in the US alone. VRE typically affect patients who have
multiple comorbidities or with important compromise of the immune system, including solid organ transplant
patients and those with hematological malignancies, among others. Surprisingly, despite the frequent
occurrence of VRE in these vulnerable populations, prospective studies assessing the actual clinical impact of
infections due to these organisms are scarce, limiting the availability of clinical information to guide treatment
for these recalcitrant infections. Furthermore, the paucity of reliable antimicrobial options to treat severe
disease is of major concern. Indeed, enterococci have developed resistance to virtually all anti-enterococcal
antibiotics available in clinical practice. Currently, the lipopetide antibiotic daptomycin (DAP) has become the
first-line therapy due to its bactericidal activity and safety profile, despite lacking FDA approval for this
indication. However, uncertainties on the performance of MIC testing, DAP breakpoint and appropriate dosing
for enterococci are major limitations for using this antibiotic against VRE. Additionally, resistance and tolerance
to DAP readily emerge during therapy via chromosomal mutations in genes encoding the LiaFSR system, a
three component regulatory system that controls the enterococcal cell membrane stress response. In order to
fill this major vacuum in knowledge and optimize the management of enterococcal bacteremia, we have
assembled the VENOUS cohort (Vancomycin-Resistant ENterococci OUtcomes Study), a unique prospective
cohort of patients with enterococcal bacteremia currently recruiting in 17 hospitals in the USA (7 cities) and
additional 4 hospitals in South America (n=2) and Europe (n=2). Our overarching hypothesis is that a deep
understanding of the clinical and microbiological aspects of VRE bloodstream infections and dynamics of the
population structure of infecting isolates is crucial to help design novel diagnostic approaches and treatment
regimens to improve the outcomes of these difficult-to-treat infections. Using the VENOUS study we propose to
i) characterize the clinical impact of VRE bacteremia, ii) dissect the population structure of VRE causing
bloodstream infections and, iii) develop a new minimal inhibitory concentration (MIC)-independent diagnostic
test to assess DAP susceptibility, seeking to guide clinicians with a novel tool to allow accurate identification of
DAP-susceptible isolates and improve the use of DAP and combination with β-lactams against these
organisms. The results of this proposal are likely to provide much needed and robust data to optimize the
treatment of VRE infections, deliver the necessary information to plan future interventional studies and develop
innovative diagnostic approaches to revolutionize the management of these life-threatening infections.

Grant Number: 5R01AI148342-05
NIH Institute/Center: NIH
Principal Investigator: Cesar Arias