#ESBLs and #resistance to #ceftazidime / #avibactam and #ceftolozane / #tazobactam combinations in #Escherichia coli and #Pseudomonas aeruginosa (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

ESBLs and resistance to ceftazidime/avibactam and ceftolozane/tazobactam combinations in Escherichia coli and Pseudomonas aeruginosa

José-Manuel Ortiz de la Rosa, Patrice Nordmann, Laurent Poirel

Journal of Antimicrobial Chemotherapy, dkz149, https://doi.org/10.1093/jac/dkz149

Published: 23 April 2019

 

Abstract

Objectives

To evaluate the efficacy of the recently launched β-lactam/β-lactamase inhibitor combinations ceftazidime/avibactam and ceftolozane/tazobactam against ESBL-producing Escherichia coli and Pseudomonas aeruginosa strains.

Methods

A series of ESBL-encoding genes (blaTEM, blaSHV, blaCTX-M, blaVEB, blaPER, blaGES and blaBEL) was cloned and expressed in E. coli or P. aeruginosa recipient strains. Cultures of E. coli TOP10 harbouring recombinant plasmids and therefore producing the different ESBLs tested were grown in order to perform measurements of catalytic activities, using benzylpenicillin, ceftazidime and ceftolozane as substrates. IC50s were additionally determined for clavulanic acid, tazobactam and avibactam.

Results

We showed here an overall better activity of ceftazidime/avibactam compared with ceftolozane/tazobactam toward ESBL-producing E. coli and P. aeruginosa. Several ESBLs of the GES, PER and BEL types conferred resistance to ceftolozane/tazobactam in E. coli and P. aeruginosa. For GES-6 and PER-1 producers, resistance to ceftolozane/tazobactam could be explained by a high hydrolysis of ceftolozane and a low activity of tazobactam as an inhibitor. On the other hand, PER-producing P. aeruginosa also exhibited resistance to ceftazidime/avibactam.

Conclusions

Altogether, the results show that the ESBL PER-1, which is widespread worldwide, may be a source of resistance to both ceftolozane/tazobactam and ceftazidime/avibactam. Excellent activity of ceftazidime/avibactam was highlighted for both ESBL-producing E. coli and ESBL-producing P. aeruginosa.

Issue Section: ORIGINAL RESEARCH

© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Antibiotics; Drugs Resistance; E. Coli; Pseudomonas aeruginosa; Ceftazidime; Avibactam; Ceftolozane; Tazobactam.

——

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#Spanish nationwide #survey on #Pseudomonas aeruginosa #antimicrobial #resistance mechanisms and #epidemiology (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Spanish nationwide survey on Pseudomonas aeruginosa antimicrobial resistance mechanisms and epidemiology

Ester del Barrio-Tofiño, Laura Zamorano, Sara Cortes-Lara, Carla López-Causapé, Irina Sánchez-Diener, Gabriel Cabot, Germán Bou, Luis Martínez-Martínez, Antonio Oliver

Journal of Antimicrobial Chemotherapy, dkz147, https://doi.org/10.1093/jac/dkz147

Published: 15 April 2019

 

Abstract

Objectives

To undertake a Spanish nationwide survey on Pseudomonas aeruginosamolecular epidemiology and antimicrobial resistance.

Methods

Up to 30 consecutive healthcare-associated P. aeruginosa isolates collected in 2017 from each of 51 hospitals were studied. MICs of 13 antipseudomonal agents were determined by broth microdilution. Horizontally acquired β-lactamases were detected by phenotypic methods and PCR. Clonal epidemiology was evaluated through PFGE and MLST; at least one XDR isolate from each clone and hospital (n = 185) was sequenced.

Results

The most active antipseudomonals against the 1445 isolates studied were colistin and ceftolozane/tazobactam (both 94.6% susceptible, MIC50/90 = 1/2 mg/L) followed by ceftazidime/avibactam (94.2% susceptible, MIC50/90 = 2/8 mg/L). Up to 252 (17.3%) of the isolates were XDR. Carbapenemases/ESBLs were detected in 3.1% of the isolates, including VIM, IMP, GES, PER and OXA enzymes. The most frequent clone among the XDR isolates was ST175 (40.9%), followed by CC235 (10.7%), ST308 (5.2%) and CC111 (4.0%). Carbapenemase production varied geographically and involved diverse clones, including 16.5% of ST175 XDR isolates. Additionally, 56% of the sequenced XDR isolates showed horizontally acquired aminoglycoside-modifying enzymes, which correlated with tobramycin resistance. Two XDR isolates produced QnrVC1, but fluoroquinolone resistance was mostly caused by QRDR mutations. Beyond frequent mutations (>60%) in OprD and AmpC regulators, four isolates showed AmpC mutations associated with resistance to ceftolozane/tazobactam and ceftazidime/avibactam.

Conclusions

ST175 is the most frequent XDR high-risk clone in Spanish hospitals, but this nationwide survey also indicates a complex scenario in which major differences in local epidemiology, including carbapenemase production, need to be acknowledged in order to guide antimicrobial therapy.

Topic: phenotype – polymerase chain reaction – pseudomonas aeruginosa – mutation – colistin – epidemiology – ceftazidime – clone cells – drug resistance, microbial – electrophoresis, gel, pulsed-field – epidemiology, molecular – fluoroquinolones – spain – enzymes – tobramycin – aminoglycosides – antimicrobials – tazobactam – extended-spectrum beta lactamases – malnutrition-inflammation-cachexia syndrome – ceftolozane – avibactam

Issue Section: ORIGINAL RESEARCH

© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Antibiotics; Drugs Resistance; Pseudomonas aeruginosa; Spain; Colistin; Ceftazidime; Fluoroquinolones; Tobramycin; Aminoglycosides; Tazobactam; Avibactam.

——-

High #incidence of #MDR and #XDR #Pseudomonas aeruginosa isolates obtained from #patients with #ventilator-associated #pneumonia in #Greece, #Italy and #Spain as part of the MagicBullet clinical trial (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

High incidence of MDR and XDR Pseudomonas aeruginosa isolates obtained from patients with ventilator-associated pneumonia in Greece, Italy and Spain as part of the MagicBullet clinical trial

Astrid Pérez, Eva Gato, José Pérez-Llarena, Felipe Fernández-Cuenca, María José Gude, Marina Oviaño, María Eugenia Pachón, José Garnacho, Verónica González, Álvaro Pascual, José Miguel Cisneros, Germán Bou

Journal of Antimicrobial Chemotherapy, dkz030, https://doi.org/10.1093/jac/dkz030

Published: 08 February 2019

 

Abstract

Objectives

To characterize the antimicrobial susceptibility, molecular epidemiology and carbapenem resistance mechanisms in Pseudomonas aeruginosa isolates recovered from respiratory tract samples from patients with ventilator-associated pneumonia enrolled in the MagicBullet clinical trial.

Methods

Isolates were collected from 53 patients from 12 hospitals in Spain, Italy and Greece. Susceptibility was determined using broth microdilution and Etest. MALDI-TOF MS was used to detect carbapenemase activity and carbapenemases were identified by PCR and sequencing. Molecular epidemiology was investigated using PFGE and MLST.

Results

Of the 53 isolates, 2 (3.8%) were considered pandrug resistant (PDR), 19 (35.8%) were XDR and 16 (30.2%) were MDR. Most (88.9%) of the isolates from Greece were MDR, XDR or PDR, whereas fewer of the isolates from Spain (33.3%) and Italy (43.5%) showed antibiotic resistance. Three Greek isolates were resistant to colistin. Overall, the rates of resistance of P. aeruginosa isolates to imipenem, ciprofloxacin, ceftolozane/tazobactam and ceftazidime/avibactam were 64.1%, 54.7%, 22.6% and 24.5%, respectively. All isolates resistant to ceftolozane/tazobactam and ceftazidime/avibactam (Greece, n = 10; and Italy, n = 2) carried blaVIM-2. Spanish isolates were susceptible to the new drug combinations. Forty-eight restriction patterns and 27 STs were documented. Sixty percent of isolates belonged to six STs, including the high-risk clones ST-111, ST-175 and ST-235.

Conclusions

MDR/XDR isolates were highly prevalent, particularly in Greece. The most effective antibiotic against P. aeruginosa was colistin, followed by ceftolozane/tazobactam and ceftazidime/avibactam. blaVIM-2 is associated with resistance to ceftolozane/tazobactam and ceftazidime/avibactam, and related to highly resistant phenotypes. ST-111 was the most frequent and disseminated clone and the clonal diversity was lower in XDR and PDR strains.

Topic: antibiotics – phenotype – polymerase chain reaction – pseudomonas aeruginosa – antibiotic resistance, bacterial – colistin – ciprofloxacin – ceftazidime – clone cells – drug combinations – electrophoresis, gel, pulsed-field – epidemiology, molecular – greece – ichthyosis, x-linked – imipenem – italy – respiratory system – sequence tagged sites – spain – spectrometry, mass, matrix-assisted laser desorption-ionization – sodium thiosulfate – antimicrobial susceptibility – tazobactam – ventilator-associated pneumonia – ceftolozane – avibactam – carbapenem resistance

Issue Section:

ORIGINAL RESEARCH

© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Antibiotics; Drugs Resistance; Pseudomonas aeruginosa; Pneumonia; Italy; Spain; Greece; Colistin; Ciprofloxacin; Ceftazidime; Iminpenem; Tazobactam; Ceftolozane; Avibactam.

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Mechanisms of high-level #ceftolozane/tazobactam #resistance in #Pseudomonas aeruginosa from a severely #neutropenic patient and treatment success from synergy with #tobramycin (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Mechanisms of high-level ceftolozane/tazobactam resistance in Pseudomonas aeruginosa from a severely neutropenic patient and treatment success from synergy with tobramycin

Wonhee So, James Shurko, Ralph Galega, Rod Quilitz, John N Greene, Grace C Lee

Journal of Antimicrobial Chemotherapy, dky393, https://doi.org/10.1093/jac/dky393

Published: 08 October 2018

___

Sir,

We read the article by Fraile-Ribot et al.1 with great interest and herein report another case of ceftolozane/tazobactam-resistant Pseudomonas aeruginosabacteraemia that developed after 5 weeks of exposure to ceftolozane/tazobactam. A retrospective review of the medical records of a single patient case does not mandate review by the University of South Florida College of Medicine Institutional Review Board (IRB), thus informed consent was not required.

… The patient had AML and was induced with cladribine, cytarabine, filgrastim plus mitoxantrone on days 1–6 then reinduced with 5 days of cladribine plus cytarabine on days 15–19. The patient had a long history of hidradenitis…

___

Topic: pseudomonas aeruginosa – neutropenia – tobramycin – tazobactam – ceftolozane

Issue Section: Research letter

© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Antibiotics; Drugs Resistance; Pseudomonas aeruginosa; Ceftolozane; Tazobactam; Tobramycin.

—–

Effect of #Piperacillin – #Tazobactam vs #Meropenem on 30-Day #Mortality for Patients With #Ecoli or #Klebsiella pneumoniae #Bloodstream Infection and Ceftriaxone Resistance – A RCT (JAMA, abstract)

[Source: JAMA, full page: (LINK). Abstract, edited.]

Original Investigation / September 11, 2018

Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone ResistanceA Randomized Clinical Trial

Patrick N. A. Harris, MBBS1,2,3; Paul A. Tambyah, MD4; David C. Lye, MBBS5,6,7; et al Yin Mo, MBBS4; Tau H. Lee, MBBS5,6,7; Mesut Yilmaz, MD8; Thamer H. Alenazi, MD9; Yaseen Arabi, MD9; Marco Falcone, MD10; Matteo Bassetti, MD, PhD11; Elda Righi, MD, PhD11; Benjamin A. Rogers, MBBS, PhD12,13; Souha Kanj, MD14; Hasan Bhally, MBBS15; Jon Iredell, MBBS, PhD16,17; Marc Mendelson, MBBS, PhD18; Tom H. Boyles, MD18; David Looke, MBBS3,19; Spiros Miyakis, MD, PhD20,21,22; Genevieve Walls, MB, ChB23; Mohammed Al Khamis, MD24; Ahmed Zikri, PharmD24; Amy Crowe, MBBS25,26; Paul Ingram, MBBS27,28,29; Nick Daneman, MD30; Paul Griffin, MBBS19,31,32; Eugene Athan, MBBS, MPH, PhD33; Penelope Lorenc, RN1; Peter Baker, PhD34; Leah Roberts, BSc35; Scott A. Beatson, PhD35; Anton Y. Peleg, MBBS, PhD36,37,38; Tiffany Harris-Brown, RN, MPH1; David L. Paterson, MBBS, PhD1,39; for the MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN)

Author Affiliations: 1 University of Queensland, UQ Centre for Clinical Research, Brisbane, Queensland, Australia; 2 Department of Microbiology, Pathology Queensland, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia; 3 Infection Management Services, Princess Alexandra Hospital, Brisbane, Queensland, Australia; 4 Department of Infectious Diseases, National University Hospital, Singapore; 5 Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 6 Department of Infectious Diseases, Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, Singapore; 7 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; 8 Department of Infectious Diseases and Clinical Microbiology, School of Medicine, Istanbul Medipol University, Istanbul, Turkey; 9 King Saud Bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Riyadh, Saudi Arabia; 10 Department of Public Health and Infectious Diseases, “Sapienza” University of Rome, Italy; 11 Infectious Diseases Clinic, Department of Medicine University of Udine and Santa Maria Misericordia Hospital, Udine, Italy; 12 Monash University, Centre for Inflammatory Diseases, Melbourne, Victoria, Australia; 13 Monash Infectious Diseases, Monash Health, Melbourne, Victoria, Australia; 14 Division of Infectious Diseases, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon; 15 Department of Medicine and Infectious Diseases, North Shore Hospital, Auckland, New Zealand; 16 Marie Bashir Institute for Infectious Disease and Biosecurity, University of Sydney, Sydney, New South Wales, Australia; 17 Centre for Infectious Diseases and Microbiology, Westmead Hospital, Westmead, New South Wales, Australia; 18 Division of Infectious Diseases & HIV Medicine, Department of Medicine, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa; 19 University of Queensland, Brisbane, Queensland, Australia; 20 School of Medicine, University of Wollongong, Wollongong, New South Wales, Australia; 21 Illawarra Health and Medical Research Institute, Wollongong, New South Wales, Australia; 22 Department of Infectious Diseases, Wollongong Hospital, Wollongong, New South Wales, Australia; 23 Department of Infectious Diseases, Middlemore Hospital, Auckland, New Zealand; 24 King Fahad Specialist Hospital, Dammam, Saudi Arabia; 25 Department of Infectious Diseases, St Vincent’s Hospital, Melbourne, Victoria, Australia; 26 Department of Microbiology, St Vincent’s Hospital, Melbourne, Victoria, Australia; 27 School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, Australia; 28 Department of Infectious Diseases, Fiona Stanley Hospital, Murdoch, Australia; 29 Department of Microbiology, PathWest Laboratory Medicine, Perth, Western Australia; 30 Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada; 31 Department of Medicine and Infectious Diseases, Mater Hospital and Mater Medical Research Institute, Brisbane, Queensland, Australia; 32 QIMR Berghofer, Brisbane, Queensland, Australia; 33 Department of Infectious Diseases, Barwon Health and Deakin University, Geelong, Victoria, Australia; 34 School of Public Health, University of Queensland, Brisbane, Queensland, Australia; 35 Australian Centre for Ecogenomics, School of Chemistry and Molecular Biosciences, The University of Queensland, Queensland, Australia; 36 Infection & Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, Australia; 37 Department of Microbiology, Monash University, Clayton, Australia; 38 Department of Infectious Diseases, Alfred Hospital and Central Clinical School, Monash University, Melbourne, Victoria, Australia; 39 Department of Infectious Diseases, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia

JAMA. 2018;320(10):984-994. doi:10.1001/jama.2018.12163

 

Key Points

  • Question  – Can piperacillin-tazobactam be used as carbapenem-sparing therapy in patients with bloodstream infections caused by ceftriaxone-resistant Escherichia coli or Klebsiella pneumoniae?
  • Findings   – In this noninferiority randomized clinical trial that included 391 patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, the 30-day mortality rate for patients treated with piperacillin-tazobactam compared with meropenem was 12.3% vs 3.7%, respectively. The difference did not meet the noninferiority margin of 5%.
  • Meaning  – These findings do not support piperacillin-tazobactam compared with meropenem for these infections.

 

Abstract

Importance 

Extended-spectrum β-lactamases mediate resistance to third-generation cephalosporins (eg, ceftriaxone) in Escherichia coli and Klebsiella pneumoniae. Significant infections caused by these strains are usually treated with carbapenems, potentially selecting for carbapenem resistance. Piperacillin-tazobactam may be an effective “carbapenem-sparing” option to treat extended-spectrum β-lactamase producers.

Objectives 

To determine whether definitive therapy with piperacillin-tazobactam is noninferior to meropenem (a carbapenem) in patients with bloodstream infection caused by ceftriaxone-nonsusceptible E coli or K pneumoniae.

Design, Setting, and Participants 

Noninferiority, parallel group, randomized clinical trial included hospitalized patients enrolled from 26 sites in 9 countries from February 2014 to July 2017. Adult patients were eligible if they had at least 1 positive blood culture with E coli or Klebsiella spp testing nonsusceptible to ceftriaxone but susceptible to piperacillin-tazobactam. Of 1646 patients screened, 391 were included in the study.

Interventions 

Patients were randomly assigned 1:1 to intravenous piperacillin-tazobactam, 4.5 g, every 6 hours (n = 188 participants) or meropenem, 1 g, every 8 hours (n = 191 participants) for a minimum of 4 days, up to a maximum of 14 days, with the total duration determined by the treating clinician.

Main Outcomes and Measures 

The primary outcome was all-cause mortality at 30 days after randomization. A noninferiority margin of 5% was used.

Results 

Among 379 patients (mean age, 66.5 years; 47.8% women) who were randomized appropriately, received at least 1 dose of study drug, and were included in the primary analysis population, 378 (99.7%) completed the trial and were assessed for the primary outcome. A total of 23 of 187 patients (12.3%) randomized to piperacillin-tazobactam met the primary outcome of mortality at 30 days compared with 7 of 191 (3.7%) randomized to meropenem (risk difference, 8.6% [1-sided 97.5% CI, −∞ to 14.5%]; P = .90 for noninferiority). Effects were consistent in an analysis of the per-protocol population. Nonfatal serious adverse events occurred in 5 of 188 patients (2.7%) in the piperacillin-tazobactam group and 3 of 191 (1.6%) in the meropenem group.

Conclusions and relevance 

Among patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, definitive treatment with piperacillin-tazobactam compared with meropenem did not result in a noninferior 30-day mortality. These findings do not support use of piperacillin-tazobactam in this setting.

Trial Registration  anzctr.org.au Identifiers: ACTRN12613000532707 and ACTRN12615000403538 and ClinicalTrials.gov Identifier: NCT02176122

Keywords: Antibiotics; Drugs Resistance; Beta-lactams; Ceftriaxone; Piperacillin; Tazobactam; E. Coli; K. Pneumoniae; Bacteremia.

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#Antibacterial activity of #ceftolozane / #tazobactam alone and in combination with other antimicrobial agents against #MDR #Pseudomonas aeruginosa (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Antibacterial activity of ceftolozane/tazobactam alone and in combination with other antimicrobial agents against MDR Pseudomonas aeruginosa

Marguerite L Monogue, David P Nicolau

Journal of Antimicrobial Chemotherapy, dkx483, https://doi.org/10.1093/jac/dkx483

Published:  18 December 2017

 

Abstract

Objectives

Broad-spectrum antimicrobial resistance in Pseudomonas aeruginosa (PSA) isolates is a growing concern as our therapeutic options have become significantly limited. Although ceftolozane/tazobactam (C/T) has been shown to be highly active against MDR PSA pathogens, combination regimens are often employed in real-world settings. To assist the clinical decision-making process regarding the selection of combination antibiotics and dosages for this pathogen, we performed time–kill studies assessing clinical free peak and trough C/T concentrations alone and in combination with eight anti-pseudomonal agents against four clinical MDR PSA isolates.

Methods

Time–kill analyses were performed over 24 h in duplicate using C/T concentrations reflective of the free peak concentrations of a 3 g dose every 8 h (q8h; 120/25.2 mg/L) and the peak and trough of a 1.5 g q8h dose (60/12.6 and 7.5/1.6 mg/L) in humans. The activity of C/T 120, 60 and 7.5 mg/L alone and C/T 7.5 mg/L in combination with free peak and trough concentrations of clinical doses for cefepime, ciprofloxacin, colistin, aztreonam, meropenem, piperacillin/tazobactam, fosfomycin and amikacin was tested for all isolates.

Results

C/T 3 and 1.5 g q8h peak concentrations demonstrated killing against the MDR PSA. Colistin and fosfomycin were synergistic with C/T as dual therapy and triple therapy regimens.

Conclusions

As a result of escalating resistance, PSA is an increasingly challenging pathogen in the clinical setting. Our findings aid in the identification of novel treatment options using achievable drug exposures for the treatment of MDR PSA.

Issue Section: ORIGINAL RESEARCH

Keywords: Antibiotics; Drugs Resistance; Pseudomonas aeruginosa; Colistin; Ceftolozane; Tazobactam.

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