KPC-2 allelic variants in Klebsiella pneumoniae isolates resistant to ceftazidime-avibactam from Argentina: bla KPC-80 , bla KPC-81 , bla KPC-96 and bla KPC-97

作者：María Belén Sanz, Fernando Pasterán, Juan Manuel de Mendieta, Florencia Brunetti, Ezequiel Albornoz, Melina Rapoport, Celeste Lucero, Laura Errecalde, Maria Rosa Nuñez, Renata Monge, Magdalena Pennini, P.P. Power, Alejandra Corso, Sonia Gómez · 发表于：Microbiology Spectrum · 年份：2024 · DOI：10.1128/spectrum.04111-23 · 被引用次数：11 · 研究领域：Antibiotic Resistance in Bacteria、Antibiotics Pharmacokinetics and Efficacy、Infections and bacterial resistance

ABSTRACT Ceftazidime-avibactam (CZA) therapy has significantly improved survival rates for patients infected by carbapenem-resistant bacteria, including KPC producers. However, resistance to CZA is a growing concern, attributed to multiple mechanisms. In this study, we characterized four clinical CZA-resistant Klebsiella pneumoniae isolates obtained between July 2019 and December 2020. These isolates expressed novel allelic variants of bla KPC-2 resulting from changes in hotspots of the mature protein, particularly in loops surrounding the active site of KPC. Notably, KPC-80 had an K269_D270insPNK mutation near the Lys270-loop, KPC-81 had a del_I173 mutation within the Ω-loop, KPC-96 showed a Y241N substitution within the Val240-loop and KPC-97 had an V277_I278insNSEAV mutation within the Lys270-loop. Three of the four isolates exhibited low-level resistance to imipenem (4 µg/mL), while all remained susceptible to meropenem. Avibactam and relebactam effectively restored carbapenem susceptibility in resistant isolates. Cloning mutant bla KPC genes into pMBLe increased imipenem MICs in recipient Escherichia coli TOP10 for bla KPC-80 , bla KPC-96 , and bla KPC-97 by two dilutions; again, these MICs were restored by avibactam and relebactam. Frameshift mutations disrupted omp K35 in three isolates. Additional resistance genes, including bla TEM-1 , bla OXA-18 and bla OXA-1 , were also identified. Interestingly, three isolates belonged to clonal complex 11 (ST258 and ST11) and one...