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Editor's Pick Mechanisms of Resistance

A 2.5-Year Within-Patient Evolution of Pseudomonas aeruginosa Isolates with In Vivo Acquisition of Ceftolozane-Tazobactam and Ceftazidime-Avibactam Resistance upon Treatment

Thibaud Boulant, Agnès B. Jousset, Rémy A. Bonnin, Aurélie Barrail-Tran, Adrien Borgel, Saoussen Oueslati, Thierry Naas, Laurent Dortet
Thibaud Boulant
EA7361 Structure, dynamic, function and expression of broad spectrum β-lactamases, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, FranceFaculty of Medicine, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, France
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Agnès B. Jousset
EA7361 Structure, dynamic, function and expression of broad spectrum β-lactamases, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, FranceFaculty of Medicine, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, FranceDepartment of Bacteriology-Hygiene, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France
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Rémy A. Bonnin
EA7361 Structure, dynamic, function and expression of broad spectrum β-lactamases, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, FranceFaculty of Medicine, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, France
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Aurélie Barrail-Tran
Department of Pharmacy, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France
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Adrien Borgel
EA7361 Structure, dynamic, function and expression of broad spectrum β-lactamases, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, FranceFaculty of Medicine, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, FranceDepartment of Bacteriology-Hygiene, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France
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Saoussen Oueslati
EA7361 Structure, dynamic, function and expression of broad spectrum β-lactamases, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, FranceFaculty of Medicine, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, France
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Thierry Naas
EA7361 Structure, dynamic, function and expression of broad spectrum β-lactamases, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, FranceFaculty of Medicine, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, FranceDepartment of Bacteriology-Hygiene, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France
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Laurent Dortet
EA7361 Structure, dynamic, function and expression of broad spectrum β-lactamases, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, FranceFaculty of Medicine, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, FranceDepartment of Bacteriology-Hygiene, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France
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DOI: 10.1128/AAC.01637-19
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ABSTRACT

Ceftolozane-tazobactam is considered to be a last-resort treatment for infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa. Although resistance to this antimicrobial has been described in vitro, the development of resistance in vivo has rarely been reported. Here, we describe the evolution of resistance to ceftolozane-tazobactam of P. aeruginosa isolates recovered from the same patient during recurrent infections over 2.5 years. Antimicrobial susceptibility testing results showed that 24 of the 27 P. aeruginosa isolates recovered from blood (n = 18), wound (n = 2), pulmonary (n = 1), bile (n = 2), and stool (n = 4) samples from the same patient were susceptible to ceftolozane-tazobactam and ceftazidime-avibactam but resistant to ceftazidime, piperacillin-tazobactam, imipenem, and meropenem. Three clinical isolates acquired resistance to ceftolozane-tazobactam and ceftazidime-avibactam along with a partial restoration of piperacillin-tazobactam and carbapenem susceptibilities. Whole-genome sequencing analysis reveals that all isolates were clonally related (sequence type 111 [ST-111]), with a median of 24.9 single nucleotide polymorphisms (SNPs) (range, 8 to 48 SNPs). The ceftolozane-tazobactam and ceftazidime-avibactam resistance was likely linked to the same G183D substitution in the chromosome-encoded cephalosporinase. Our results suggest that resistance to ceftolozane-tazobactam in P. aeruginosa might occur in vivo upon treatment through an amino acid substitution in the intrinsic AmpC leading to ceftolozane-tazobactam and ceftazidime-avibactam resistance, accompanied by resensitization to piperacillin-tazobactam and carbapenems.

FOOTNOTES

    • Received 13 August 2019.
    • Returned for modification 30 August 2019.
    • Accepted 25 September 2019.
    • Accepted manuscript posted online 21 October 2019.
  • Supplemental material for this article may be found at https://doi.org/10.1128/AAC.01637-19.

  • Copyright © 2019 American Society for Microbiology.

All Rights Reserved.

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A 2.5-Year Within-Patient Evolution of Pseudomonas aeruginosa Isolates with In Vivo Acquisition of Ceftolozane-Tazobactam and Ceftazidime-Avibactam Resistance upon Treatment
Thibaud Boulant, Agnès B. Jousset, Rémy A. Bonnin, Aurélie Barrail-Tran, Adrien Borgel, Saoussen Oueslati, Thierry Naas, Laurent Dortet
Antimicrobial Agents and Chemotherapy Nov 2019, 63 (12) e01637-19; DOI: 10.1128/AAC.01637-19

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A 2.5-Year Within-Patient Evolution of Pseudomonas aeruginosa Isolates with In Vivo Acquisition of Ceftolozane-Tazobactam and Ceftazidime-Avibactam Resistance upon Treatment
Thibaud Boulant, Agnès B. Jousset, Rémy A. Bonnin, Aurélie Barrail-Tran, Adrien Borgel, Saoussen Oueslati, Thierry Naas, Laurent Dortet
Antimicrobial Agents and Chemotherapy Nov 2019, 63 (12) e01637-19; DOI: 10.1128/AAC.01637-19
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KEYWORDS

AmpC
G183D
Pseudomonas aeruginosa
ceftolozane-tazobactam
ceftazidime-avibactam

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