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Purpose <p>To prospectively monitor the evolution of the resistome of OXA-48-producing <i>Klebsiella</i> species in a patient with long-term colonization, with a particular focus into the plasmid dynamics and the evolution of ceftazidime/avibactam resistance.</p> Methods <p>All OXA-48-producing <i>Klebsiella</i> spp. isolates from a single patient admitted to a hospital during seven months were prospectively collected. MICs were determined through reference broth microdilution. Multilocus sequence types, SNPs analysis, resistance mechanisms, genetic context of β-lactamases and plasmid dynamics were determined by WGS and bioinformatic analysis. The impact of β-lactamase variant obtained after ceftazidime/avibactam exposure was determined via cloning experiments.</p> Results <p>Four isolates, two before (one OXA-48-producing <i>K. pneumoniae</i> and one CTX-M-15-like-producing <i>K. pneumoniae</i>) and two after treatment with ceftazidime/avibactam (one OXA-48- and CTX-M-15-like-producing <i>K. pneumoniae</i> and one OXA-48- and CTX-M-15-like-producing <i>K. aerogenes</i>) were collected. The plasmid dynamics analysis demonstrated that the IncL and IncFIIK plasmids, in which <i>bla</i><sub>OXA-48</sub> and <i>bla</i><sub>CTX-M-15-like</sub> genes were located, respectively, exhibited a high degree of conservation indicating a potential for both intra- and interspecies transmission. The <i>K. pneumoniae</i> isolate obtained after treatment, which differed from the previous isolate by just six SNPs, exhibited resistance to ceftazidime/avibactam through P167S substitution in CTX-M-15, which is now designated CTX-M-273. Cloning experiments demonstrated enhanced resistance to ceftazidime/avibactam.</p> Conclusion <p>The transfer of plasmid-borne β-lactamase resistance genes between intra- and interspecies bacterial populations enables the rapid diversification of the bacterial genome. The emergence of ceftazidime/avibactam resistance through the modification of CTX-M-enzymes represents a mechanism by which OXA-48-producing Enterobacterales may evolve toward ceftazidime/avibactam resistance in vivo.</p>

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Evolution of ceftazidime/avibactam resistance and plasmid dynamics in OXA-48-producing Klebsiella spp. during long-term patient colonization

  • 期刊论文

  • 发表日期：

    2025年1月21日

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  • Salud Rodríguez-Pallares,
  • María Alejandra Mateo-Vargas,
  • Manuel Antonio Rodríguez-Iglesias,
  • Jorge Arca-Suárez,
  • Fátima Galán-Sánchez

摘要

Purpose

To prospectively monitor the evolution of the resistome of OXA-48-producing Klebsiella species in a patient with long-term colonization, with a particular focus into the plasmid dynamics and the evolution of ceftazidime/avibactam resistance.

Methods

All OXA-48-producing Klebsiella spp. isolates from a single patient admitted to a hospital during seven months were prospectively collected. MICs were determined through reference broth microdilution. Multilocus sequence types, SNPs analysis, resistance mechanisms, genetic context of β-lactamases and plasmid dynamics were determined by WGS and bioinformatic analysis. The impact of β-lactamase variant obtained after ceftazidime/avibactam exposure was determined via cloning experiments.

Results

Four isolates, two before (one OXA-48-producing K. pneumoniae and one CTX-M-15-like-producing K. pneumoniae) and two after treatment with ceftazidime/avibactam (one OXA-48- and CTX-M-15-like-producing K. pneumoniae and one OXA-48- and CTX-M-15-like-producing K. aerogenes) were collected. The plasmid dynamics analysis demonstrated that the IncL and IncFIIK plasmids, in which blaOXA-48 and blaCTX-M-15-like genes were located, respectively, exhibited a high degree of conservation indicating a potential for both intra- and interspecies transmission. The K. pneumoniae isolate obtained after treatment, which differed from the previous isolate by just six SNPs, exhibited resistance to ceftazidime/avibactam through P167S substitution in CTX-M-15, which is now designated CTX-M-273. Cloning experiments demonstrated enhanced resistance to ceftazidime/avibactam.

Conclusion

The transfer of plasmid-borne β-lactamase resistance genes between intra- and interspecies bacterial populations enables the rapid diversification of the bacterial genome. The emergence of ceftazidime/avibactam resistance through the modification of CTX-M-enzymes represents a mechanism by which OXA-48-producing Enterobacterales may evolve toward ceftazidime/avibactam resistance in vivo.