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605. Identification of a Novel CMY-Variant Enzyme in a Clinical Escherichia coli Strain with Treatment-Emergent Ceftazidime–Avibactam Resistance

BACKGROUND: Ceftazidime–avibactam (CZA) is a novel β-lactam / β-lactamase inhibitor with in vitro activity against multidrug-resistant Gram-negatives, including those harboring CMY-2 enzymes. Treatment-emergent resistance to CZA has been described in KPC-producing Klebsiella pneumoniae but has not b...

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Autores principales: Aitken, Samuel L, Endres, Bradley T, Khan, Ayesha, Shropshire, William C, Borjan, Jovan, Bhatti, Micah M, Sahasrabhojane, Pranoti V, Doi, Yohei, Shields, Ryan K, Shelburne, Samuel A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811110/
http://dx.doi.org/10.1093/ofid/ofz360.674
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author Aitken, Samuel L
Aitken, Samuel L
Endres, Bradley T
Khan, Ayesha
Shropshire, William C
Borjan, Jovan
Bhatti, Micah M
Sahasrabhojane, Pranoti V
Doi, Yohei
Shields, Ryan K
Shelburne, Samuel A
Shelburne, Samuel A
author_facet Aitken, Samuel L
Aitken, Samuel L
Endres, Bradley T
Khan, Ayesha
Shropshire, William C
Borjan, Jovan
Bhatti, Micah M
Sahasrabhojane, Pranoti V
Doi, Yohei
Shields, Ryan K
Shelburne, Samuel A
Shelburne, Samuel A
author_sort Aitken, Samuel L
collection PubMed
description BACKGROUND: Ceftazidime–avibactam (CZA) is a novel β-lactam / β-lactamase inhibitor with in vitro activity against multidrug-resistant Gram-negatives, including those harboring CMY-2 enzymes. Treatment-emergent resistance to CZA has been described in KPC-producing Klebsiella pneumoniae but has not been described in non-carbapenemase-producing, carbapenem-resistant Enterobacteriaceae (CRE). METHODS: A patient with an intra-abdominal infection due to a carbapenem-resistant E. coli (ertapenem MIC 16 µg/mL; meropenem MIC 2 µg/mL; CZA MIC 2 µg/mL; carbapenemase negative) was treated with CZA. On day 48 of therapy, a CZA resistant, carbapenem-sensitive E. coli was identified from abdominal drainage (CZA MIC ≥256 µg/mL; meropenem MIC 0.19 µg/mL). Illumina MiSeq whole-genome sequencing (WGS) was performed on both isolates to identify potential resistance mechanisms. The ResFinder database was used to identify known β-lactamase enzymes, and in silico modeling of β-lactamase structure was assessed. RESULTS: WGS revealed that both isolates were ST410 E. coli, with the sole difference in β-lactam resistance determinants between the two being a novel CMY β-lactamase harbored on an Inc1-type conjugative plasmid in the second isolate. The novel CMY has 4 amino acid substitutions relative to CMY-2: A134E, Q140K, V231S, and N366Y. The V231S substitution is found in CMY-42 and has previously been associated with increased ceftazidime hydrolysis. The remaining three substitutions have not previously been identified. Previous studies have identified that substitutions at position 366 influence the rate of ceftazidime hydrolysis rate. Preliminary protein structure analysis suggests that positions 140 and 366 are in the active site. No other differences in β-lactam resistance determinants were identified between the first and second isolates. CONCLUSION: To our knowledge, we have identified the first case of CMY-associated CZA resistance. Given the widespread and transferrable nature of CMY enzymes, this finding raises concern for additional cases of resistance with increasing usage of CZA. Further analysis is needed to identify the mechanism by which this enzyme confers CZA resistance. DISCLOSURES: Samuel L. Aitken, PharmD, Melinta Therapeutics: Grant/Research Support, Research Grant; Merck, Sharpe, and Dohme: Advisory Board; Shionogi: Advisory Board.
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spelling pubmed-68111102019-10-28 605. Identification of a Novel CMY-Variant Enzyme in a Clinical Escherichia coli Strain with Treatment-Emergent Ceftazidime–Avibactam Resistance Aitken, Samuel L Aitken, Samuel L Endres, Bradley T Khan, Ayesha Shropshire, William C Borjan, Jovan Bhatti, Micah M Sahasrabhojane, Pranoti V Doi, Yohei Shields, Ryan K Shelburne, Samuel A Shelburne, Samuel A Open Forum Infect Dis Abstracts BACKGROUND: Ceftazidime–avibactam (CZA) is a novel β-lactam / β-lactamase inhibitor with in vitro activity against multidrug-resistant Gram-negatives, including those harboring CMY-2 enzymes. Treatment-emergent resistance to CZA has been described in KPC-producing Klebsiella pneumoniae but has not been described in non-carbapenemase-producing, carbapenem-resistant Enterobacteriaceae (CRE). METHODS: A patient with an intra-abdominal infection due to a carbapenem-resistant E. coli (ertapenem MIC 16 µg/mL; meropenem MIC 2 µg/mL; CZA MIC 2 µg/mL; carbapenemase negative) was treated with CZA. On day 48 of therapy, a CZA resistant, carbapenem-sensitive E. coli was identified from abdominal drainage (CZA MIC ≥256 µg/mL; meropenem MIC 0.19 µg/mL). Illumina MiSeq whole-genome sequencing (WGS) was performed on both isolates to identify potential resistance mechanisms. The ResFinder database was used to identify known β-lactamase enzymes, and in silico modeling of β-lactamase structure was assessed. RESULTS: WGS revealed that both isolates were ST410 E. coli, with the sole difference in β-lactam resistance determinants between the two being a novel CMY β-lactamase harbored on an Inc1-type conjugative plasmid in the second isolate. The novel CMY has 4 amino acid substitutions relative to CMY-2: A134E, Q140K, V231S, and N366Y. The V231S substitution is found in CMY-42 and has previously been associated with increased ceftazidime hydrolysis. The remaining three substitutions have not previously been identified. Previous studies have identified that substitutions at position 366 influence the rate of ceftazidime hydrolysis rate. Preliminary protein structure analysis suggests that positions 140 and 366 are in the active site. No other differences in β-lactam resistance determinants were identified between the first and second isolates. CONCLUSION: To our knowledge, we have identified the first case of CMY-associated CZA resistance. Given the widespread and transferrable nature of CMY enzymes, this finding raises concern for additional cases of resistance with increasing usage of CZA. Further analysis is needed to identify the mechanism by which this enzyme confers CZA resistance. DISCLOSURES: Samuel L. Aitken, PharmD, Melinta Therapeutics: Grant/Research Support, Research Grant; Merck, Sharpe, and Dohme: Advisory Board; Shionogi: Advisory Board. Oxford University Press 2019-10-23 /pmc/articles/PMC6811110/ http://dx.doi.org/10.1093/ofid/ofz360.674 Text en © The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Abstracts
Aitken, Samuel L
Aitken, Samuel L
Endres, Bradley T
Khan, Ayesha
Shropshire, William C
Borjan, Jovan
Bhatti, Micah M
Sahasrabhojane, Pranoti V
Doi, Yohei
Shields, Ryan K
Shelburne, Samuel A
Shelburne, Samuel A
605. Identification of a Novel CMY-Variant Enzyme in a Clinical Escherichia coli Strain with Treatment-Emergent Ceftazidime–Avibactam Resistance
title 605. Identification of a Novel CMY-Variant Enzyme in a Clinical Escherichia coli Strain with Treatment-Emergent Ceftazidime–Avibactam Resistance
title_full 605. Identification of a Novel CMY-Variant Enzyme in a Clinical Escherichia coli Strain with Treatment-Emergent Ceftazidime–Avibactam Resistance
title_fullStr 605. Identification of a Novel CMY-Variant Enzyme in a Clinical Escherichia coli Strain with Treatment-Emergent Ceftazidime–Avibactam Resistance
title_full_unstemmed 605. Identification of a Novel CMY-Variant Enzyme in a Clinical Escherichia coli Strain with Treatment-Emergent Ceftazidime–Avibactam Resistance
title_short 605. Identification of a Novel CMY-Variant Enzyme in a Clinical Escherichia coli Strain with Treatment-Emergent Ceftazidime–Avibactam Resistance
title_sort 605. identification of a novel cmy-variant enzyme in a clinical escherichia coli strain with treatment-emergent ceftazidime–avibactam resistance
topic Abstracts
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811110/
http://dx.doi.org/10.1093/ofid/ofz360.674
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