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https://hdl.handle.net/2183/47690 Molecular mechanisms driving the in vivo development of OXA-10-mediated resistance to ceftolozane/tazobactam and ceftazidime/avibactam during treatment of XDR Pseudomonas aeruginosa infections
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Arca-Suárez, Jorge
Lasarte-Monterrubio, Cristina
Rodiño-Janeiro, Bruno Kotska
Cabot, Gabriel
Vázquez-Ucha, Juan Carlos
Rodríguez-Iglesias, Manuel
Galán-Sánchez, Fátima
Beceiro Casas, Alejandro
González-Bello, Concepción
Oliver, Antonio
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Arca-Suárez J, Lasarte-Monterrubio C, Rodiño-Janeiro BK, Cabot G, Vázquez-Ucha JC, Rodríguez-Iglesias M, Galán-Sánchez F, Beceiro A, González-Bello C, Oliver A, Bou G. Molecular mechanisms driving the in vivo development of OXA-10-mediated resistance to ceftolozane/tazobactam and ceftazidime/avibactam during treatment of XDR Pseudomonas aeruginosa infections. J Antimicrob Chemother. 2021 Jan 1;76(1):91-100.
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Abstract
[Abstract] Background: The development of resistance to ceftolozane/tazobactam and ceftazidime/avibactam during treatment of Pseudomonas aeruginosa infections is concerning.
Objectives: Characterization of the mechanisms leading to the development of OXA-10-mediated resistance to ceftolozane/tazobactam and ceftazidime/avibactam during treatment of XDR P. aeruginosa infections.
Methods: Four paired ceftolozane/tazobactam- and ceftazidime/avibactam-susceptible/resistant isolates were evaluated. MICs were determined by broth microdilution. STs, resistance mechanisms and genetic context of β-lactamases were determined by genotypic methods, including WGS. The OXA-10 variants were cloned in PAO1 to assess their impact on resistance. Models for the OXA-10 derivatives were constructed to evaluate the structural impact of the amino acid changes.
Results: The same XDR ST253 P. aeruginosa clone was detected in all four cases evaluated. All initial isolates showed OprD deficiency, produced an OXA-10 enzyme and were susceptible to ceftazidime, ceftolozane/tazobactam, ceftazidime/avibactam and colistin. During treatment, the isolates developed resistance to all cephalosporins. Comparative genomic analysis revealed that the evolved resistant isolates had acquired mutations in the OXA-10 enzyme: OXA-14 (Gly157Asp), OXA-794 (Trp154Cys), OXA-795 (ΔPhe153-Trp154) and OXA-824 (Asn143Lys). PAO1 transformants producing the evolved OXA-10 derivatives showed enhanced ceftolozane/tazobactam and ceftazidime/avibactam resistance but decreased meropenem MICs in a PAO1 background. Imipenem/relebactam retained activity against all strains. Homology models revealed important changes in regions adjacent to the active site of the OXA-10 enzyme. The blaOXA-10 gene was plasmid borne and acquired due to transposition of Tn6746 in the pHUPM plasmid scaffold.
Conclusions: Modification of OXA-10 is a mechanism involved in the in vivo acquisition of resistance to cephalosporin/β-lactamase inhibitor combinations in P. aeruginosa.
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This is a pre-copyedited, author-produced version of an article accepted for publication in The Journal of antimicrobial chemotherapy following peer review. The version of record is available online at Oxford Academic web.