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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
aEA7361 Structure, dynamic, function and expression of broad spectrum β-lactamases, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, France
bFaculty of Medicine, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, France
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Agnès B. Jousset
aEA7361 Structure, dynamic, function and expression of broad spectrum β-lactamases, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, France
bFaculty of Medicine, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, France
cDepartment of Bacteriology-Hygiene, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France
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Rémy A. Bonnin
aEA7361 Structure, dynamic, function and expression of broad spectrum β-lactamases, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, France
bFaculty of Medicine, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, France
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Aurélie Barrail-Tran
dDepartment of Pharmacy, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France
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Adrien Borgel
aEA7361 Structure, dynamic, function and expression of broad spectrum β-lactamases, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, France
bFaculty of Medicine, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, France
cDepartment of Bacteriology-Hygiene, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France
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Saoussen Oueslati
aEA7361 Structure, dynamic, function and expression of broad spectrum β-lactamases, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, France
bFaculty of Medicine, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, France
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Thierry Naas
aEA7361 Structure, dynamic, function and expression of broad spectrum β-lactamases, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, France
bFaculty of Medicine, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, France
cDepartment of Bacteriology-Hygiene, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France
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Laurent Dortet
aEA7361 Structure, dynamic, function and expression of broad spectrum β-lactamases, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, France
bFaculty of Medicine, Paris-Sud University, Paris Saclay University, Le Kremlin-Bicêtre, France
cDepartment 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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    FIG 1

    (A) Time schedule of the 27 clinical P. aeruginosa isolates that were selected for whole-genome sequencing. Ceftolozane-tazobactam treatment is indicated with an orange arrow over the time schedule. Ceftolozane-tazobactam-resistant isolates (17, 18, and 26) are highlighted in yellow. Types of clinical samples are indicated by different colored shapes (yellow triangle, bile; brown star, stool; green hexagon, wound; red circle, blood; blue square, pulmonary sample). (B) Phylogenetic relationship of the 27 clinical P. aeruginosa isolates (all ST-111). The tables next to phylogenetic tree correspond to (i) MICs to ceftazidime (CAZ), piperacillin-tazobactam (TZP), ceftolozane-tazobactam (C-T), imipenem (IMP), meropenem (MEM), and ceftazidime-avibactam (CZA), the background corresponds to the susceptibility categorization according to EUCAST breakpoints (black for resistant, gray for intermediate, and white for susceptible), (ii) the status of the intrinsic cephalosporinase (AmpC), wild type (WT) or G183D mutant (MUT), and (iii) the matrix of SNP numbers.

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    FIG 2

    (A) Phylogenetic relationships and sequence types of the 27 clinical P. aeruginosa isolates with P. aeruginosa genomes from the GenBank database. (B) Evolution rates of the ST-111 P. aeruginosa clone (27 clinical P. aeruginosa isolates). Each point corresponds to one P. aeruginosa clinical isolate. The first isolate was used as a reference. The numbers correspond to the isolate number indicated in Fig. 1. Ceftolozane-tazobactam-resistant isolates are indicated in orange. The red curve corresponds to the tendency curve. The evolution rate (indicated in red) corresponds to the slope of the tendency curve.

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    FIG 3

    (A to E) Comparison of three-dimensional (3D) structures of the wild-type (A and D) and G183D mutant (B, C, and E) PDC β-lactamase. The wild-type PDC corresponds to the 6I30 PDB crystal structure of the AmpC from Pseudomonas aeruginosa in complex with bicyclic boronate, as described by Cahill et al. (24). (C) The clashes between D183 and N179 in the mutated PDC are indicated in red. (D and E) Surface charges of the wild-type (D) and G183D mutant (E) PDC β-lactamase. The 3D structure of G183D mutant PDC was modeled using the Phyre2 software (http://www.sbg.bio.ic.ac.uk/~phyre2/html/page.cgi?id=index). Both 3D structure visualizations were performed using the EzMol 2.1 software (http://www.sbg.bio.ic.ac.uk/).

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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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