Multifactorial resistance mechanisms associated with resistance to ceftazidime-avibactam in clinical Pseudomonas aeruginosa isolates from Switzerland
BackgroundIncreasing reports of multidrug resistance (MDR) in clinical Pseudomonas aeruginosa have led to a necessity for new antimicrobials. Ceftazidime-avibactam (CZA) is indicated for use against MDR P. aeruginosa across a broad range of infection types and particularly those that are carbapenem...
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Frontiers Media S.A.
2023-04-01
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| Series: | Frontiers in Cellular and Infection Microbiology |
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| author | Baharak Babouee Flury Baharak Babouee Flury Baharak Babouee Flury Anja Bösch Anja Bösch Valentin Gisler Valentin Gisler Adrian Egli Salome N. Seiffert Oliver Nolte Jacqueline Findlay |
| author_facet | Baharak Babouee Flury Baharak Babouee Flury Baharak Babouee Flury Anja Bösch Anja Bösch Valentin Gisler Valentin Gisler Adrian Egli Salome N. Seiffert Oliver Nolte Jacqueline Findlay |
| author_sort | Baharak Babouee Flury |
| collection | DOAJ |
| description | BackgroundIncreasing reports of multidrug resistance (MDR) in clinical Pseudomonas aeruginosa have led to a necessity for new antimicrobials. Ceftazidime-avibactam (CZA) is indicated for use against MDR P. aeruginosa across a broad range of infection types and particularly those that are carbapenem resistant. This study sought to determine the molecular mechanisms of CZA and imipenem (IPM)-resistance in clinical P. aeruginosa isolates obtained from Swiss hospitals.MethodsClinical P. aeruginosa isolates were obtained from inpatients in three hospitals in Switzerland. Susceptibility was determined by either antibiotic disc testing or broth microdilution according to EUCAST methodology. AmpC activity was determined using cloxacillin and efflux activity was determined using phenylalanine-arginine β-naphthylamide, in agar plates. Whole Genome Sequencing was performed on 18 clinical isolates. Sequence types (STs) and resistance genes were ascertained using the Centre for Genomic Epidemiology platform. Genes of interest were extracted from sequenced isolates and compared to reference strain P. aeruginosa PAO1.ResultsSixteen different STs were identified amongst the 18 isolates in this study indicating a high degree of genomic diversity. No carbapenemases were detected but one isolate did harbor the ESBL blaPER-1. Eight isolates were CZA-resistant with MICs ranging from 16-64 mg/L, and the remaining ten isolates had either low/wildtype MICs (n=6; 1-2 mg/L) or elevated, but still susceptible, MICs (n=4; 4-8 mg/L). Ten isolates were IPM-resistant, seven of which had mutations resulting in truncations of OprD, and the remaining nine IPM-susceptible isolates had intact oprD genes. Within CZA-R isolates, and those with reduced susceptibility, mutations resulting in ampC derepression, OprD loss, mexAB overexpression and ESBL (blaPER-1) carriage were observed in various combinations and one harbored a truncation of the PBP4 dacB gene. Within the six isolates with wildtype-resistance levels, five had no mutations that would affect any antimicrobial resistance (AMR) genes of interest when compared to PAO1.ConclusionThis preliminary study highlights that CZA-resistance in P. aeruginosa is multifactorial and could be caused by the interplay between different resistance mechanisms including ESBL carriage, increased efflux, loss of permeability and derepression of its intrinsic ampC. |
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| publishDate | 2023-04-01 |
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| spelling | doaj-art-9d91d3da22a2407a904a1c64a07c9ba72025-07-10T15:05:59ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882023-04-011310.3389/fcimb.2023.10989441098944Multifactorial resistance mechanisms associated with resistance to ceftazidime-avibactam in clinical Pseudomonas aeruginosa isolates from SwitzerlandBaharak Babouee Flury0Baharak Babouee Flury1Baharak Babouee Flury2Anja Bösch3Anja Bösch4Valentin Gisler5Valentin Gisler6Adrian Egli7Salome N. Seiffert8Oliver Nolte9Jacqueline Findlay10Medical Research Center, Kantonspital St. Gallen, St. Gallen, SwitzerlandDivision of Infectious Diseases and Hospital Epidemiology, Kantonsspital St. Gallen, St. Gallen, SwitzerlandDepartment of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandMedical Research Center, Kantonspital St. Gallen, St. Gallen, SwitzerlandDivision of Infectious Diseases and Hospital Epidemiology, Kantonsspital St. Gallen, St. Gallen, SwitzerlandClinic of Infectious Diseases and Hospital Hygiene, Kantonsspital Aarau, Aarau, SwitzerlandDepartment of Microbiology, Institute for Laboratory Medicine, Kantonsspital Aarau, Aarau, SwitzerlandInstitute of Medical Microbiology, University of Zurich, Zurich, SwitzerlandDivision of Human Microbiology, Centre for Laboratory Medicine, St. Gallen, SwitzerlandDivision of Human Microbiology, Centre for Laboratory Medicine, St. Gallen, SwitzerlandMedical and Molecular Microbiology, Faculty of Science and Medicine, University of Fribourg, Fribourg, SwitzerlandBackgroundIncreasing reports of multidrug resistance (MDR) in clinical Pseudomonas aeruginosa have led to a necessity for new antimicrobials. Ceftazidime-avibactam (CZA) is indicated for use against MDR P. aeruginosa across a broad range of infection types and particularly those that are carbapenem resistant. This study sought to determine the molecular mechanisms of CZA and imipenem (IPM)-resistance in clinical P. aeruginosa isolates obtained from Swiss hospitals.MethodsClinical P. aeruginosa isolates were obtained from inpatients in three hospitals in Switzerland. Susceptibility was determined by either antibiotic disc testing or broth microdilution according to EUCAST methodology. AmpC activity was determined using cloxacillin and efflux activity was determined using phenylalanine-arginine β-naphthylamide, in agar plates. Whole Genome Sequencing was performed on 18 clinical isolates. Sequence types (STs) and resistance genes were ascertained using the Centre for Genomic Epidemiology platform. Genes of interest were extracted from sequenced isolates and compared to reference strain P. aeruginosa PAO1.ResultsSixteen different STs were identified amongst the 18 isolates in this study indicating a high degree of genomic diversity. No carbapenemases were detected but one isolate did harbor the ESBL blaPER-1. Eight isolates were CZA-resistant with MICs ranging from 16-64 mg/L, and the remaining ten isolates had either low/wildtype MICs (n=6; 1-2 mg/L) or elevated, but still susceptible, MICs (n=4; 4-8 mg/L). Ten isolates were IPM-resistant, seven of which had mutations resulting in truncations of OprD, and the remaining nine IPM-susceptible isolates had intact oprD genes. Within CZA-R isolates, and those with reduced susceptibility, mutations resulting in ampC derepression, OprD loss, mexAB overexpression and ESBL (blaPER-1) carriage were observed in various combinations and one harbored a truncation of the PBP4 dacB gene. Within the six isolates with wildtype-resistance levels, five had no mutations that would affect any antimicrobial resistance (AMR) genes of interest when compared to PAO1.ConclusionThis preliminary study highlights that CZA-resistance in P. aeruginosa is multifactorial and could be caused by the interplay between different resistance mechanisms including ESBL carriage, increased efflux, loss of permeability and derepression of its intrinsic ampC.https://www.frontiersin.org/articles/10.3389/fcimb.2023.1098944/fullPseudomonas aeruginosaceftazidime-avibactam (CZA)molecular resistance mechanismsimipenemwhole genome sequencing (WGS) |
| spellingShingle | Baharak Babouee Flury Baharak Babouee Flury Baharak Babouee Flury Anja Bösch Anja Bösch Valentin Gisler Valentin Gisler Adrian Egli Salome N. Seiffert Oliver Nolte Jacqueline Findlay Multifactorial resistance mechanisms associated with resistance to ceftazidime-avibactam in clinical Pseudomonas aeruginosa isolates from Switzerland Frontiers in Cellular and Infection Microbiology Pseudomonas aeruginosa ceftazidime-avibactam (CZA) molecular resistance mechanisms imipenem whole genome sequencing (WGS) |
| title | Multifactorial resistance mechanisms associated with resistance to ceftazidime-avibactam in clinical Pseudomonas aeruginosa isolates from Switzerland |
| title_full | Multifactorial resistance mechanisms associated with resistance to ceftazidime-avibactam in clinical Pseudomonas aeruginosa isolates from Switzerland |
| title_fullStr | Multifactorial resistance mechanisms associated with resistance to ceftazidime-avibactam in clinical Pseudomonas aeruginosa isolates from Switzerland |
| title_full_unstemmed | Multifactorial resistance mechanisms associated with resistance to ceftazidime-avibactam in clinical Pseudomonas aeruginosa isolates from Switzerland |
| title_short | Multifactorial resistance mechanisms associated with resistance to ceftazidime-avibactam in clinical Pseudomonas aeruginosa isolates from Switzerland |
| title_sort | multifactorial resistance mechanisms associated with resistance to ceftazidime avibactam in clinical pseudomonas aeruginosa isolates from switzerland |
| topic | Pseudomonas aeruginosa ceftazidime-avibactam (CZA) molecular resistance mechanisms imipenem whole genome sequencing (WGS) |
| url | https://www.frontiersin.org/articles/10.3389/fcimb.2023.1098944/full |
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