Gram-negative bloodstream infections (BSIs) cause severe morbidity and mortality in neutropenic patients. Fluoroquinolones (FQs) are used to prevent Gram-negative BSI during neutropenia, but the extent to which FQ resistance threatens the effectiveness of FQ prophylaxis is unknown. The objectives of this proposal are to de- termine the prevalence of colonization with FQ-resistant Enterobacteriaceae (FQRE) in neutropenic patients and the impact of FQRE colonization density and the gut microbiome on the risk of Gram-negative BSI in pa- tients who receive FQ prophylaxis, and to develop a rapid diagnostic test to detect colonization with resistant enteric bacteria. The central hypothesis is that rapid identification of dense colonization with FQRE via multi- plexed PCR identifies neutropenic patients at high risk of developing FQRE BSI despite FQ prophylaxis. The rationale for this proposal is that knowledge of the impact of FQRE colonization and the gut microbiome on the effectiveness of FQ prophylaxis would lead to novel personalized infection prevention strategies.
The specific aims of this project are: 1) Determine the prevalence and clinical significance of FQRE colonization in neutro- penic patients across large geographically-diverse cancer centers; 2) Identify which FQRE-colonized patients are at highest risk for developing Gram-negative BSI while receiving FQ prophylaxis; and 3) Develop and verify a molecular assay to rapidly identify colonization with enteric bacteria that are resistant to FQs and other po- tential prophylactic antibiotics. In this study, 900 patients receiving intensive chemotherapy for acute leukemia or hematopoietic cell transplantation at four cancer centers will be screened for colonization with FQRE by weekly perianal swab cultures. The prevalence of FQRE colonization will be identified and the risk of Gram- negative BSI in FQRE-colonized patients and non-colonized patients will be compared. A predictive risk model for Gram-negative BSI will then be constructed for FQRE-colonized patients that incorporates FQRE coloniza- tion density, gut microbial diversity, abundance of commensal bacteria, and host factors. Additionally, the per- formance of a multiplexed PCR platform that identifies genetic resistance determinants to FQs and ?-lactam agents will be compared to the gold standards of selective culture and antimicrobial susceptibility testing. The contributions of this proposal are that we will determine the nationwide prevalence of FQRE colonization and the risk of Gram-negative BSI in colonized neutropenic patients who receive FQ prophylaxis, develop a model to identify which FQRE-colonized patients are at highest risk of FQRE BSI, and develop a rapid, easy-to-use molecular test to diagnose colonization with FQRE and ?-lactam-resistant enteric bacteria. These contributions will be significant and innovative because they will directly lead to the design of a potentially practice-changing clinical trial in which neutropenic patients are randomized to an individualized strategy of antibacterial prophy- laxis, based on screening for colonization with FQRE and enteric bacteria that are resistant to other potential prophylactic agents, or to the current ?one-size-fits-all? approach of universal administration of FQ prophylaxis.
Patients with hematologic malignancies are uniquely susceptible to life-threatening bloodstream infections (BSIs) from Gram-negative enteric bacteria when they are neutropenic after chemotherapy. The administration of fluoroquinolones (FQs) prophylactically decreases the risk of Gram-negative BSI, but increasing FQ re- sistance threatens the effectiveness of this approach. The proposed research is relevant to public health and NIAID's mission because understanding the impact that colonization with fluoroquinolone (FQ)-resistant and commensal gut bacteria have on the effectiveness of FQ prophylaxis in preventing Gram-negative BSIs during neutropenia and establishing an easy-to-use diagnostic tool to detect colonization with resistant enteric bacte- ria would lead to the design of novel individualized strategies to prevent infections in this vulnerable patient population.