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. 2019 May 30;68(12):2045-2052.
doi: 10.1093/cid/ciy825.

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

Morgan Hakki  1 , Romney M Humphries  2 , Peera Hemarajata  3 , Gregory B Tallman  4 , Ryan K Shields  5 , Roberta T Mettus  5 , Yohei Doi  5   6 , James S Lewis  7
Affiliations

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

Morgan Hakki et al. Clin Infect Dis. .

Abstract

Background: In Pseudomonas aeruginosa, fluoroquinolone exposure promotes resistance to carbapenems through upregulation of efflux pumps and transcriptional downregulation 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.

Methods: We retrospectively evaluated episodes of P. aeruginosa bloodstream infections in HM patients or HCT recipients over a 7-year period at our institution. We determined the association of fluoroquinolone prophylaxis at the time of infection with meropenem susceptibility of P. aeruginosa breakthrough isolates and risk factors for meropenem nonsusceptibility. Whole-genome sequencing (WGS) and phenotypic assessments of meropenem efflux pump activity were performed on select isolates to determine the mechanisms of meropenem resistance.

Results: We analyzed 55 episodes of P. aeruginosa bacteremia among 51 patients. Breakthrough bacteremia while on fluoroquinolone prophylaxis was associated with nonsusceptibility to meropenem, but not to antipseudomonal β-lactams or aminoglycosides. The receipt of fluoroquinolone prophylaxis was independently predictive of bacteremia with a meropenem-nonsusceptible isolate. All meropenem-nonsusceptible isolates analyzed by WGS contained oprD inactivating mutations, and all meropenem-nonsusceptible isolates tested demonstrated reductions in the meropenem minimum inhibitory concentration in the presence of an efflux pump inhibitor. A phylogenetic analysis based on WGS revealed several clusters of closely related isolates from different patients.

Conclusions: Fluoroquinolone prophylaxis in HM patients and HCT recipients is associated with breakthrough bacteremia with meropenem-nonsusceptible P. aeruginosa strains, likely due to both mutations increasing efflux pump activity and the epidemiology of P. aeruginosa bloodstream infections in our patient population.

Keywords: Pseudomonas aeruginosa; fluoroquinolone; meropenem; neutropenia; resistance.

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Figures

Figure 1.
Figure 1.
Single-nucleotide variation analysis of Pseudomonas aeruginosa bloodstream clinical isolates selected for whole-genome sequencing using P. aeruginosa PAO1 strain (GenBank sequence AE004091.2) as the reference. Isolates 4 and 7 were obtained from the same patient, and isolates 10 and 14 were obtained from another patient.
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