Emergence of a KPC-90 Variant that Confers Resistance to Ceftazidime-Avibactam in an ST463 Carbapenem-Resistant Pseudomonas aeruginosa Strain
ABSTRACT Carbapenem-resistant Pseudomonas aeruginosa (CRPA) has become a serious challenge in the clinic. Recently, the prevalence of CRPA isolates carrying the blaKPC-2 gene has been increasing in China. Ceftazidime-avibactam (CZA) has shown good efficacy against large portions of KPC-2-producing C...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-02-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.01869-21 |
| _version_ | 1819279633814650880 |
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| author | Yuexing Tu Dairong Wang Yiwei Zhu Jiayan Li Yan Jiang Wenhao Wu Xi Li Hua Zhou |
| author_facet | Yuexing Tu Dairong Wang Yiwei Zhu Jiayan Li Yan Jiang Wenhao Wu Xi Li Hua Zhou |
| author_sort | Yuexing Tu |
| collection | DOAJ |
| description | ABSTRACT Carbapenem-resistant Pseudomonas aeruginosa (CRPA) has become a serious challenge in the clinic. Recently, the prevalence of CRPA isolates carrying the blaKPC-2 gene has been increasing in China. Ceftazidime-avibactam (CZA) has shown good efficacy against large portions of KPC-2-producing CRPA strains. However, with the increasing usage of this drug, CZA resistance in CRPA strains has been reported. Here, we reported for the first time that resistance of the ST463 CRPA strain to CZA was caused by a novel variant in the KPC gene that arose after CZA exposure. The CRPA strain PA2207 is a carbapenem- and CZA-resistant strain that harbors a mutated blaKPC gene, named blaKPC-90. Cloning and expression of blaKPC-90 in Escherichia coli DH5α revealed that KPC-90 led to a 64-fold increase in the MIC value of CZA. Conjugation experiments further confirmed that blaKPC-90 was located on a conjugative plasmid. Whole-genome sequencing analysis showed that this plasmid had high sequence similarity to a previously reported novel blaKPC-2-harboring plasmid in a clinical P. aeruginosa strain isolated in China. In addition, overexpression of an efflux pump (MexXY-OprM) might be associated with the CZA resistance phenotype, as determined by reverse transcription-quantitative PCR and efflux pump inhibition experiments. For the first time, we reported a KPC variant, KPC-90, in a clinical ST463 CRPA strain with CZA resistance that was mediated by a 2 amino acid insertion outside the KPC omega-loop region. Our study further highlights that diverse KPC variants that mediate CZA resistance have emerged in the CRPA strain. Furthermore, KPC-90 mutation combined with efflux pump overexpression resulted in a high level of resistance to CZA in the PA2207 isolate. Effective surveillance should be conducted to prevent CZA resistance from spreading in the CRPA strain. IMPORTANCE For the first time, we reported a KPC variant, KPC-90, in a clinical ST463 CRPA strain with CZA resistance. CZA resistance was mediated by a 2 amino acid insertion outside the KPC omega-loop region in CRPA. Our study further emphasized that CZA resistance caused by blaKPC gene mutation could be selected in CRPA after CZA therapy. Considering the widespread presence of the ST463 CRPA strain in China, clinicians should pay attention to the risk of the development of CZA resistance in CRPA strains under treatment pressure. |
| first_indexed | 2024-12-24T00:31:01Z |
| format | Article |
| id | doaj.art-df86cc28bcd244909dfe73a5988bc671 |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-12-24T00:31:01Z |
| publishDate | 2022-02-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-df86cc28bcd244909dfe73a5988bc6712022-12-21T17:24:16ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972022-02-0110110.1128/spectrum.01869-21Emergence of a KPC-90 Variant that Confers Resistance to Ceftazidime-Avibactam in an ST463 Carbapenem-Resistant Pseudomonas aeruginosa StrainYuexing Tu0Dairong Wang1Yiwei Zhu2Jiayan Li3Yan Jiang4Wenhao Wu5Xi Li6Hua Zhou7Department of Rehabilitation Medicine, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, ChinaBlood Center of Zhejiang Province, Hangzhou, Zhejiang, ChinaDepartment of Critical Care Medicine, Renji Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Rehabilitation Medicine, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, ChinaDepartment of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaCentre of Laboratory Medicine, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, ChinaCentre of Laboratory Medicine, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, ChinaDepartment of Respiratory and Critical Care Medicine, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, ChinaABSTRACT Carbapenem-resistant Pseudomonas aeruginosa (CRPA) has become a serious challenge in the clinic. Recently, the prevalence of CRPA isolates carrying the blaKPC-2 gene has been increasing in China. Ceftazidime-avibactam (CZA) has shown good efficacy against large portions of KPC-2-producing CRPA strains. However, with the increasing usage of this drug, CZA resistance in CRPA strains has been reported. Here, we reported for the first time that resistance of the ST463 CRPA strain to CZA was caused by a novel variant in the KPC gene that arose after CZA exposure. The CRPA strain PA2207 is a carbapenem- and CZA-resistant strain that harbors a mutated blaKPC gene, named blaKPC-90. Cloning and expression of blaKPC-90 in Escherichia coli DH5α revealed that KPC-90 led to a 64-fold increase in the MIC value of CZA. Conjugation experiments further confirmed that blaKPC-90 was located on a conjugative plasmid. Whole-genome sequencing analysis showed that this plasmid had high sequence similarity to a previously reported novel blaKPC-2-harboring plasmid in a clinical P. aeruginosa strain isolated in China. In addition, overexpression of an efflux pump (MexXY-OprM) might be associated with the CZA resistance phenotype, as determined by reverse transcription-quantitative PCR and efflux pump inhibition experiments. For the first time, we reported a KPC variant, KPC-90, in a clinical ST463 CRPA strain with CZA resistance that was mediated by a 2 amino acid insertion outside the KPC omega-loop region. Our study further highlights that diverse KPC variants that mediate CZA resistance have emerged in the CRPA strain. Furthermore, KPC-90 mutation combined with efflux pump overexpression resulted in a high level of resistance to CZA in the PA2207 isolate. Effective surveillance should be conducted to prevent CZA resistance from spreading in the CRPA strain. IMPORTANCE For the first time, we reported a KPC variant, KPC-90, in a clinical ST463 CRPA strain with CZA resistance. CZA resistance was mediated by a 2 amino acid insertion outside the KPC omega-loop region in CRPA. Our study further emphasized that CZA resistance caused by blaKPC gene mutation could be selected in CRPA after CZA therapy. Considering the widespread presence of the ST463 CRPA strain in China, clinicians should pay attention to the risk of the development of CZA resistance in CRPA strains under treatment pressure.https://journals.asm.org/doi/10.1128/spectrum.01869-21ceftazidime-avibactamresistanceCRPAKPC-90ST463 |
| spellingShingle | Yuexing Tu Dairong Wang Yiwei Zhu Jiayan Li Yan Jiang Wenhao Wu Xi Li Hua Zhou Emergence of a KPC-90 Variant that Confers Resistance to Ceftazidime-Avibactam in an ST463 Carbapenem-Resistant Pseudomonas aeruginosa Strain Microbiology Spectrum ceftazidime-avibactam resistance CRPA KPC-90 ST463 |
| title | Emergence of a KPC-90 Variant that Confers Resistance to Ceftazidime-Avibactam in an ST463 Carbapenem-Resistant Pseudomonas aeruginosa Strain |
| title_full | Emergence of a KPC-90 Variant that Confers Resistance to Ceftazidime-Avibactam in an ST463 Carbapenem-Resistant Pseudomonas aeruginosa Strain |
| title_fullStr | Emergence of a KPC-90 Variant that Confers Resistance to Ceftazidime-Avibactam in an ST463 Carbapenem-Resistant Pseudomonas aeruginosa Strain |
| title_full_unstemmed | Emergence of a KPC-90 Variant that Confers Resistance to Ceftazidime-Avibactam in an ST463 Carbapenem-Resistant Pseudomonas aeruginosa Strain |
| title_short | Emergence of a KPC-90 Variant that Confers Resistance to Ceftazidime-Avibactam in an ST463 Carbapenem-Resistant Pseudomonas aeruginosa Strain |
| title_sort | emergence of a kpc 90 variant that confers resistance to ceftazidime avibactam in an st463 carbapenem resistant pseudomonas aeruginosa strain |
| topic | ceftazidime-avibactam resistance CRPA KPC-90 ST463 |
| url | https://journals.asm.org/doi/10.1128/spectrum.01869-21 |
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