Fluoroquinolone Prophylaxis Selects for Meropenem-nonsusceptible Pseudomonas aeruginosa in Patients With Hematologic Malignancies and Hematopoietic Cell Transplant Recipients

Abstract

In Pseudomonas aeruginosa, fluoroquinolone exposure promotes resistance to carbapenems through up-regulation of efflux pumps and transcriptional down-regulation of the porin OprD. Evidence of this effect among hematologic malignancy (HM) patients or hematopoietic-cell transplant (HCT) recipients receiving fluoroquinolone prophylaxis for neutropenia is lacking. We retrospectively evaluated episodes of P. aeruginosa bloodstream infections in HM patients or HCT recipients over a 7-year period at our institution. The association of fluoroquinolone prophylaxis at the time of infection with meropenem susceptibility of P. aeruginosa breakthrough isolates and risk factors for meropenem non-susceptibility were determined. Whole genome sequencing (WGS) and phenotypic assessment of meropenem efflux pump activity were performed on select isolates to determine the mechanisms of meropenem resistance. Fifty-five episodes of P. aeruginosa bacteremia among 51 patients were analyzed. Breakthrough bacteremia while on fluoroquinolone prophylaxis was associated with non-susceptibility to meropenem but not to anti-pseudomonal β-lactams or aminoglycosides. Receipt of fluoroquinolone prophylaxis was independently predictive of bacteremia with a meropenem non-susceptible isolate. All meropenem non-susceptible isolates analyzed by WGS contained oprD inactivating mutations, and all meropenem non-susceptible isolates tested demonstrated reduction in the meropenem MIC in the presence of an efflux pump inhibitor. Phylogenetic analysis based on WGS revealed several clusters of closely related isolates from different patients. Fluoroquinolone prophylaxis in HM patients and HCT recipients is associated with breakthrough bacteremia with meropenem non-susceptible P. aeruginosa strains, likely due to both mutations increasing efflux pump activity and the epidemiology of P. aeruginosa bloodstream infections in our patient population.