Acquisition of resistance to ceftazidime-avibactam during infection treatment in Pseudomonas aeruginosa through D179Y mutation in one of two blaKPC-2 gene copies without losing carbapenem resistance

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dc.article.number981792
dc.catalogadoraba
dc.contributor.authorGarcía, P.
dc.contributor.authorBrito, B.
dc.contributor.authorAlcalde-Rico, M.
dc.contributor.authorMunita, J.M.
dc.contributor.authorMartínez, J.R.W.
dc.contributor.authorOlivares-Pacheco, J.
dc.contributor.authorQuiroz, V.
dc.contributor.authorWozniak, A.
dc.date.accessioned2024-03-04T15:19:39Z
dc.date.available2024-03-04T15:19:39Z
dc.date.issued2022
dc.description.abstractCeftazidime/Avibactam (CAZ/AVI) is frequently used to treat KPC-producing Pseudomonas aeruginosa (KPC-PA) and Enterobacterales. CAZ/AVI resistance is driven by several mechanisms. In P. aeruginosa this mainly occurs through alteration of AmpC, porins, and/or efflux pump overexpression, whereas in Enterobacterales it frequently occurs through D179Y substitution in the active site of KPC enzyme. This aminoacid change abolishes AVI binding to the KPC active site, hence inhibition is impaired. However, this substitution also decreases KPC-mediated resistance to carbapenems (“see-saw” effect). The goal of this work was to characterize the in vivo acquisition of CAZ/AVI resistance through D179Y substitution in a KPC-PA isolated from a hospitalized patient after CAZ/AVI treatment. Two KPC-PA isolates were obtained. The first isolate, PA-1, was obtained before CAZ/AVI treatment and was susceptible to CAZ/AVI. The second isolate, PA-2, was obtained after CAZ/AVI treatment and exhibited high-level CAZ/AVI resistance. Characterization of isolates PA-1 and PA-2 was performed through short and long-read whole genome sequencing analysis. The hybrid assembly showed that PA-1 and PA-2A had a single plasmid of 54,030 bp, named pPA-1 and pPA-2 respectively. Each plasmid harbored two copies of the blaKPC-containing Tn4401b transposon. However, while pPA-1 carried two copies of blaKPC-2, pPA-2 had one copy of blaKPC-2 and one copy of blaKPC-33, the allele with the D179Y substitution. Interestingly, isolate PA-2 did not exhibit the “see-saw” effect. The blaKPC-33 allele was detected only through hybrid assembly using a long-read-first approach. The present work describes a KPC-PA isolate harboring a plasmid-borne CAZ/AVI resistance mechanism based on two copies of blaKPC-2-Tn4401b and D179Y mutation in one of them, that is not associated with loss of resistance to carbapenems. These findings highlight the usefulness of a fine-tuned combined analysis of short and long-read data to detect similar emerging resistance mechanisms.
dc.fechaingreso.objetodigital2024-05-23
dc.format.extent11 páginas
dc.fuente.origenORCID
dc.identifier.doi10.3389/fcimb.2022.981792
dc.identifier.eissn2235-2988
dc.identifier.urihttps://doi.org/10.3389/fcimb.2022.981792
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/82448
dc.information.autorucEscuela de Medicina; Wozniak Banchero, Aniela; 0000-0001-9559-7660; 1008612
dc.language.isoen
dc.nota.accesoContenido completo
dc.pagina.final11
dc.pagina.inicio1
dc.revistaFrontiers in Cellular and Infection Microbiology
dc.rightsacceso abierto
dc.rights.licenseCC BY 4.0 DEED Attribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectCeftazidime/avibactam resistance
dc.subjectPseudomonas aeruginosa
dc.subjectD179Y substitution
dc.subjectBlaKPC-2 gene
dc.subjectTn4401b transposon
dc.subject.ddc570
dc.subject.deweyBiologíaes_ES
dc.titleAcquisition of resistance to ceftazidime-avibactam during infection treatment in Pseudomonas aeruginosa through D179Y mutation in one of two blaKPC-2 gene copies without losing carbapenem resistance
dc.typeartículo
dc.volumen12
sipa.codpersvinculados1008612
sipa.trazabilidadORCID;2024-01-15
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