Innate Aminoglycoside Resistance of Achromobacter xylosoxidans Is Due to AxyXY-OprZ, an RND-Type Multidrug Efflux Pump

Bador, Julien; Amoureux, Lucie; Blanc, Emmanuel; Neuwirth, Catherine

doi:10.1128/aac.01243-12

Cited by 84 publications

(89 citation statements)

References 19 publications

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“…It is an opportunistic pathogen that can cause a wide variety of infections in immunocompromised patients (7)(8)(9)(10) but is mainly recovered from CF patients' airways. As previously reported, this species is innately resistant to cephalothin, cefoxitin, cefotaxime, aztreonam, and aminoglycosides (11,12). Acquired resistance to carbapenems, ceftazidime, and ciprofloxacin is frequent, dramatically limiting therapeutic choices (13,14).…”

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confidence: 83%

Detection of Achromobacter xylosoxidans in Hospital, Domestic, and Outdoor Environmental Samples and Comparison with Human Clinical Isolates

Amoureux

Bador

Fardeheb

et al. 2013

Appl Environ Microbiol

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Achromobacter xylosoxidans is an aerobic nonfermentative Gram-negative rod considered an important emerging pathogen among cystic fibrosis (CF) patients worldwide and among immunocompromised patients. This increased prevalence remains unexplained, and to date no environmental reservoir has been identified. The aim of this study was to identify potential reservoirs of A. xylosoxidans in hospital, domestic, and outdoor environments and to compare the isolates with clinical ones. From 2011 to 2012, 339 samples were collected in Dijon's university hospital, in healthy volunteers' homes in the Dijon area, and in the outdoor environment in Burgundy (soil, water, mud, and plants). We designed a protocol to detect A. xylosoxidans in environmental samples based on a selective medium: MCXVAA (MacConkey agar supplemented with xylose, vancomycin, aztreonam, and amphotericin B). Susceptibility testing, genotypic analysis by pulsed-field gel electrophoresis, and bla OXA-114 sequencing were performed on the isolates. A total of 50 strains of A. xylosoxidans were detected in hospital (33 isolates), domestic (9 isolates), and outdoor (8 isolates) samples, mainly in hand washing sinks, showers, and water. Most of them were resistant to ciprofloxacin (49 strains). Genotypic analysis and bla OXA-114 sequencing revealed a wide diversity among the isolates, with 35 pulsotypes and 18 variants of oxacillinases. Interestingly, 10 isolates from hospital environment were clonally related to clinical isolates previously recovered from hospitalized patients, and one domestic isolate was identical to one recovered from a CF patient. These results indicate that A. xylosoxidans is commonly distributed in various environments and therefore that CF patients or immunocompromised patients are surrounded by these reservoirs.

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Detection of Achromobacter xylosoxidans in Hospital, Domestic, and Outdoor Environmental Samples and Comparison with Human Clinical Isolates

Amoureux

Bador

Fardeheb

et al. 2013

Appl Environ Microbiol

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“…Molecular characterization based on MLST and nrdA 765 sequencing identified 6 different species or genogroups and 13 different sequence types (STs) among 15 Achromobacter isolates from 14 patients: 10 (71.4%) A. xylosoxidans (ST3, ST20, ST27, ST153, ST154, ST156, ST158, ST160), and one (7.1%) each of Achromobacter genogroup 2a (ST144), Achromobacter genogroup 2b (ST150), Achromobacter genogroup 7 (ST152), Achromobacter genogroup 14 (ST162), and Achromobacter genogroup 17 (ST149) ( Table 2) (18). Similar diversity of species was also observed in a recent study that included 341 isolates from 86 CF centers in the United States.…”

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Molecular Characterization of Achromobacter Isolates from Cystic Fibrosis and Non-Cystic Fibrosis Patients in Madrid, Spain

et al. 2013

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bMultilocus sequence typing and nrdA sequence analysis identified 6 different species or genogroups and 13 sequence types (STs) among 15 Achromobacter isolates from cystic fibrosis (CF) patients and 7 species or genogroups and 11 STs among 11 isolates from non-CF patients. Achromobacter xylosoxidans was the most frequently isolated species among CF patients.A chromobacter spp. are nonfermenting, Gram-negative rods that are widely distributed in nature, some of which are associated with opportunistic infection of humans (1). Because phenotypic methods for identification are inadequate, multilocus sequence typing (MLST) (2) and nrdA 765 DNA sequencing (3) have recently been developed to elucidate the taxonomy and epidemiology of Achromobacter isolates. In addition to seven previously named Achromobacter species, 14 new taxa have now been described, some of which are associated with infections in cystic fibrosis (CF) patients (2-5). The recent changes in the knowledge of the biodiversity of Achromobacter infections and the novel taxonomy mean that there are few published data on the clinical impact of different Achromobacter species. The aims of this study were to determine the prevalence and clinical importance of Achromobacter infection in CF patients in Spain and to understand the distribution of this genus among CF and non-CF patients.We undertook a retrospective study of all CF patients who were colonized or infected with Achromobacter and who were treated at the CF reference center of the Hospital Universitario 12 de Octubre (Madrid) between 2002 and 2012. Patients were considered chronically colonized if at least three positive cultures were obtained in 1 year and sporadically colonized if there were less than three positive cultures. Clinical records were reviewed to collect demographic, clinical, and microbiology data. Sputum samples were inoculated onto different culture media (Columbia 5% blood agar, MacConkey agar, mannitol-salt agar, chocolate agar, and Burkholderia cepacia selective agar [BCSA] medium). Phenotypic identification was performed using the Wider system (Francisco Soria-Melguizo, Spain) and API 20 NE (bioMérieux, Marcy l=Etoile, France). Antimicrobial susceptibility was determined by broth microdilution and the ε-test method and interpreted according to CLSI guidelines (6). Sequence analysis of 16S rRNA was used to confirm the phenotypic identification of Achromobacter spp., and MLST (2) and nrdA 765 DNA sequencing (3) were performed on all isolates. We tested for the presence of the bla OXA-114 -like gene by PCR for the identification of A. xylosoxidans (7). Taxonomic status was obtained by comparison of results to those in the GenBank (http://www.ncbi.nlm.nih.gov/BLAST) and MLST (http://pubmlst.org/achromobacter/) databases. Achromobacter isolates were also genotyped by pulsed-field gel electrophoresis (PFGE) (8). Univariate analysis was performed using the t test for continuous variables and the 2 or Fisher's exact test for categorical variables.Over the study period, 5.6% (14/250) of C...

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“…AXX-A has been used in previous studies to characterize AxyABM and AxyXY-OprZ RND-type efflux systems (21,22). It was used in the present work to examine the role of axyZ in the expression of axyXY-oprZ by gene deletion.…”

Section: Methodsmentioning

confidence: 99%

“…scribed to date in Achromobacter and contribute to its intrinsic antibiotic resistance: AxyABM and AxyXY-OprZ (21,22). The latter system is encoded by three chromosomal genes: axyX, axyY, and oprZ.…”

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Role of AxyZ Transcriptional Regulator in Overproduction of AxyXY-OprZ Multidrug Efflux System in Achromobacter Species Mutants Selected by Tobramycin

Bador

Neuwirth

Grangier

et al. 2017

Antimicrob Agents Chemother

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AxyXY-OprZ is an RND-type efflux system that confers innate aminoglycoside resistance to Achromobacter spp. We investigated here a putative TetR family transcriptional regulator encoded by the axyZ gene located upstream of axyXY-oprZ. An in-frame axyZ gene deletion assay led to increased MICs of antibiotic substrates of the efflux system, including aminoglycosides, cefepime, fluoroquinolones, tetracyclines, and erythromycin, indicating that the product of axyZ negatively regulates expression of axyXY-oprZ. Moreover, we identified an amino acid substitution at position 29 of AxyZ (V29G) in a clinical Achromobacter strain that occurred during the course of chronic respiratory tract colonization in a cystic fibrosis (CF) patient. This substitution, also detected in three other strains exposed in vitro to tobramycin, led to an increase in the axyY transcription level (5-to 17-fold) together with an increase in antibiotic resistance level. This overproduction of AxyXY-OprZ is the first description of antibiotic resistance acquisition due to modification of a chromosomally encoded mechanism in Achromobacter and might have an impact on the management of infected CF patients. Indeed, tobramycin is widely used for aerosol therapy within this population, and we have demonstrated that it easily selects mutants with increased MICs of not only aminoglycosides but also fluoroquinolones, cefepime, and tetracyclines.

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Innate Aminoglycoside Resistance of Achromobacter xylosoxidans Is Due to AxyXY-OprZ, an RND-Type Multidrug Efflux Pump

Cited by 84 publications

References 19 publications

Detection of Achromobacter xylosoxidans in Hospital, Domestic, and Outdoor Environmental Samples and Comparison with Human Clinical Isolates

Detection of Achromobacter xylosoxidans in Hospital, Domestic, and Outdoor Environmental Samples and Comparison with Human Clinical Isolates

Molecular Characterization of Achromobacter Isolates from Cystic Fibrosis and Non-Cystic Fibrosis Patients in Madrid, Spain

Role of AxyZ Transcriptional Regulator in Overproduction of AxyXY-OprZ Multidrug Efflux System in Achromobacter Species Mutants Selected by Tobramycin

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