Morgan Hakki1, Romney M Humphries2, Peera Hemarajata3, Gregory B Tallman4, Ryan K Shields5, Roberta T Mettus5, Yohei Doi5,6, James S Lewis7. 1. Division of Infectious Diseases, Oregon Health and Science University, Portland. 2. Accelerate Diagnostics, Tucson, Arizona. 3. Los Angeles County Department of Public Health, California. 4. Department of Pharmacy Practice, Oregon State University/Oregon Health and Science University College of Pharmacy, Portland. 5. Division of Infectious Diseases, Center for Innovative Antimicrobial Therapy, University of Pittsburgh School of Medicine, Pennsylvania. 6. Departments of Microbiology and Infectious Diseases, Fujita Health University School of Medicine, Toyoake, Aichi, Japan. 7. Department of Pharmacy Services, Oregon Health and Science University, Portland.
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.
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.
Authors: Ebbing Lautenbach; Mark G Weiner; Irving Nachamkin; Warren B Bilker; Angela Sheridan; Neil O Fishman Journal: Infect Control Hosp Epidemiol Date: 2006-08-21 Impact factor: 3.254
Authors: Winfried V Kern; Petra Steinke; Anja Schumacher; Sabine Schuster; Heike von Baum; Jürgen A Bohnert Journal: J Antimicrob Chemother Date: 2005-12-14 Impact factor: 5.790
Authors: Daniel J Wolter; Dee Acquazzino; Richard V Goering; Paul Sammut; Noha Khalaf; Nancy D Hanson Journal: Clin Infect Dis Date: 2008-06-15 Impact factor: 9.079
Authors: Natalija Karabasevic; Jason A Roberts; Luke Stronach; Saiyuri Naicker; Steven C Wallis; Fredrik Sjövall; Fekade Sime Journal: Antimicrob Agents Chemother Date: 2022-04-07 Impact factor: 5.938
Authors: C Gudiol; A Albasanz-Puig; J Laporte-Amargós; N Pallarès; A Mussetti; I Ruiz-Camps; P Puerta-Alcalde; E Abdala; C Oltolini; M Akova; M Montejo; M Mikulska; P Martín-Dávila; F Herrera; O Gasch; L Drgona; H Paz Morales; A-S Brunel; E García; B Isler; W V Kern; I Morales; G Maestro-de la Calle; M Montero; S S Kanj; O R Sipahi; S Calik; I Márquez-Gómez; J I Marin; M Z R Gomes; P Hemmatti; R Araos; M Peghin; J L Del Pozo; L Yáñez; R Tilley; A Manzur; A Novo; J Carratalà Journal: Antimicrob Agents Chemother Date: 2020-03-24 Impact factor: 5.191
Authors: Annika Y Classen; Larissa Henze; Marie von Lilienfeld-Toal; Georg Maschmeyer; Michael Sandherr; Luisa Durán Graeff; Nael Alakel; Maximilian Christopeit; Stefan W Krause; Karin Mayer; Silke Neumann; Oliver A Cornely; Olaf Penack; Florian Weißinger; Hans-Heinrich Wolf; Jörg Janne Vehreschild Journal: Ann Hematol Date: 2021-04-13 Impact factor: 3.673
Authors: Justin G Horowitz; Gerard W Gawrys; Grace C Lee; Brittney A Ramirez; Carole M Elledge; Paul J Shaughnessy Journal: Transpl Infect Dis Date: 2021-07-30