TY - JOUR
T1 - Extensively Drug-Resistant Pseudomonas aeruginosa ST309 Harboring Tandem Guiana Extended Spectrum β-Lactamase Enzymes
T2 - A Newly Emerging Threat in the United States
AU - Khan, Ayesha
AU - Tran, Truc T.
AU - Rios, Rafael
AU - Hanson, Blake
AU - Shropshire, William C.
AU - Sun, Zhizeng
AU - Diaz, Lorena
AU - Dinh, An Q.
AU - Wanger, Audrey
AU - Ostrosky-Zeichner, Luis
AU - Palzkill, Timothy
AU - Arias, Cesar A.
AU - Miller, William R.
N1 - Funding Information:
Financial support. This work was funded by the National Institutes of Health (NIH) Grants R01 AI134637, R21 AI143229, and K24 AI121296 (to C. A. A.); UTHealth Presidential Award (to C. A. A.); University of Texas System STARS Award (to C. A. A.); NIH Grant K08 AI113317 (to T. T. T.); NIH Grant K08 AI135093 (to W. R. M.); NIH Grant R01 AI32956 (to T. P.); and UTHealth Center for Antimicrobial Resistance and Microbial Genomics (CARMiG) seed funds (to W. R. M.).
Funding Information:
Potential conflicts of interest. C. A. A. has received grants from Merck, MeMed Diagnostics, and Entasis Pharmaceuticals. L. O.-Z. has received grants and/or speaking and consulting honoraria from Merck, Astellas, Pfizer, Gilead, The Medicines Company, Cidara, Scynexis, Aradigm, and Bayer. W. R. M. has received grants and/or honoraria from Merck, Entasis, Achaogen, and Shionogi. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Publisher Copyright:
© 2019 The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2019/7/1
Y1 - 2019/7/1
N2 - Background: Treatment of serious infections due to multidrug-resistant (MDR) Pseudomonas aeruginosa remains a challenge, despite the introduction of novel therapeutics. In this study, we report 2 extensively drug-resistant clinical isolates of sequence type (ST) 309 P aeruginosa resistant to all β-lactams, including the novel combinations ceftolozane/tazobactam, ceftazidime/avibactam, and meropenem/vaborbactam. Methods: Isolates were sequenced using both short-read (Illumina) and long-read technology to identify resistance determinants, polymorphisms (compared with P aeruginosa PAO1), and reconstruct a phylogenetic tree. A pair of β-lactamases, Guiana extended spectrum β-lactamase (GES)-19 and GES-26, were cloned and expressed in a laboratory strain of Escherichia coli to examine their relative impact on resistance. Using cell lysates from E coli expressing the GES genes individually and in tandem, we determined relative rates of hydrolysis for nitrocefin and ceftazidime. Results: Two ST309 P aeruginosa clinical isolates were found to harbor the extended spectrum β-lactamases GES-19 and GES-26 clustered in tandem on a chromosomal class 1 integron. The presence of both enzymes in E coli was associated with significantly elevated minimum inhibitory concentrations to aztreonam, cefepime, meropenem, ceftazidime/avibactam, and ceftolozane/tazobactam, compared with those expressed individually. The combination of ceftazidime/avibactam plus aztreonam was active in vitro and used to achieve cure in one patient. Phylogenetic analysis revealed ST309 P aeruginosa are closely related to MDR strains from Mexico also carrying tandem GES. Conclusions: The presence of tandem GES-19 and GES-26 is associated with resistance to all β-lactams, including ceftolozane/tazobactam. Phylogenetic analysis suggests that ST309 P aeruginosa may be an emerging threat in the United States.
AB - Background: Treatment of serious infections due to multidrug-resistant (MDR) Pseudomonas aeruginosa remains a challenge, despite the introduction of novel therapeutics. In this study, we report 2 extensively drug-resistant clinical isolates of sequence type (ST) 309 P aeruginosa resistant to all β-lactams, including the novel combinations ceftolozane/tazobactam, ceftazidime/avibactam, and meropenem/vaborbactam. Methods: Isolates were sequenced using both short-read (Illumina) and long-read technology to identify resistance determinants, polymorphisms (compared with P aeruginosa PAO1), and reconstruct a phylogenetic tree. A pair of β-lactamases, Guiana extended spectrum β-lactamase (GES)-19 and GES-26, were cloned and expressed in a laboratory strain of Escherichia coli to examine their relative impact on resistance. Using cell lysates from E coli expressing the GES genes individually and in tandem, we determined relative rates of hydrolysis for nitrocefin and ceftazidime. Results: Two ST309 P aeruginosa clinical isolates were found to harbor the extended spectrum β-lactamases GES-19 and GES-26 clustered in tandem on a chromosomal class 1 integron. The presence of both enzymes in E coli was associated with significantly elevated minimum inhibitory concentrations to aztreonam, cefepime, meropenem, ceftazidime/avibactam, and ceftolozane/tazobactam, compared with those expressed individually. The combination of ceftazidime/avibactam plus aztreonam was active in vitro and used to achieve cure in one patient. Phylogenetic analysis revealed ST309 P aeruginosa are closely related to MDR strains from Mexico also carrying tandem GES. Conclusions: The presence of tandem GES-19 and GES-26 is associated with resistance to all β-lactams, including ceftolozane/tazobactam. Phylogenetic analysis suggests that ST309 P aeruginosa may be an emerging threat in the United States.
KW - GES beta-lactamase
KW - carbapenem-resistant Pseudomonas aeruginosa
KW - ceftolozane/tazobactam
KW - combination therapy
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U2 - 10.1093/ofid/ofz273
DO - 10.1093/ofid/ofz273
M3 - Article
AN - SCOPUS:85075409290
VL - 6
JO - Open Forum Infectious Diseases
JF - Open Forum Infectious Diseases
SN - 2328-8957
IS - 7
M1 - ofz273
ER -