In vitro mimicry of in vivo KPC mutations by ceftazidime-avibactam: phenotypes, mechanisms, genetic structure and kinetics of enzymatic hydrolysis
Ceftazidime-avibactam (CZA) is employed for the treatment of infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-KP). Resistance to CZA is frequently linked to point mutations in the blaKPC. We conducted in vitro simulations of in vivo blaKPC mutations using CZA. Fo...
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Taylor & Francis Group
2024-12-01
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| Series: | Emerging Microbes and Infections |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/22221751.2024.2356146 |
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| author | Siquan Shen Chengkang Tang Weiwei Yang Li Ding Renru Han Qingyu Shi Yan Guo Dandan Yin Fupin Hu |
| author_facet | Siquan Shen Chengkang Tang Weiwei Yang Li Ding Renru Han Qingyu Shi Yan Guo Dandan Yin Fupin Hu |
| author_sort | Siquan Shen |
| collection | DOAJ |
| description | Ceftazidime-avibactam (CZA) is employed for the treatment of infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-KP). Resistance to CZA is frequently linked to point mutations in the blaKPC. We conducted in vitro simulations of in vivo blaKPC mutations using CZA. Four pre-therapy KPC-KP isolates (K1, K2, K3, and K4) were evaluated, all initially exhibited susceptibility to CZA and produced KPC-2. The crucial distinction was that following CZA treatment, the blaKPC-2 mutated in K1, K2, and K3, rendering them resistant to CZA, while K4 achieved microbiological clearance, and blaKPC-2 remained unaltered. The induction assay identified various blaKPC-2 variants, including blaKPC-25, blaKPC-127, blaKPC-100, blaKPC-128, blaKPC-137, blaKPC-138, blaKPC-144 and blaKPC-180. Our findings suggest that the resistance of KPC-KP to CZA primarily results from the emergence of KPC variants, complemented by increased blaKPC expression. A close correlation exists between avibactam concentration and the rate of increased CZA minimum Inhibitory concentration, as well as blaKPC mutation. Inadequate avibactam concentration is more likely to induce resistance in strains against CZA, there is also a higher likelihood of mutation in the blaKPC-2 and the optimal avibactam ratio remains to be determined. Simultaneously, we selected a blaKPC-33-producing K. pneumoniae strain (mutated from blaKPC-2) and induced it with imipenem and meropenem, respectively. The blaKPC-2 was detected during the process, indicating that the mutation is reversible. Clinical use of carbapenems to treat KPC variant strains increases the risk of infection, as the gene can mutate back to blaKPC-2, rendering the strain even more cross-resistant to carbapenems and CZA. |
| format | Article |
| id | doaj-art-e3e101210cdd45f1b52cd05f7cad48e5 |
| institution | Kabale University |
| issn | 2222-1751 |
| language | English |
| publishDate | 2024-12-01 |
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| series | Emerging Microbes and Infections |
| spelling | doaj-art-e3e101210cdd45f1b52cd05f7cad48e52024-12-07T04:40:17ZengTaylor & Francis GroupEmerging Microbes and Infections2222-17512024-12-0113110.1080/22221751.2024.2356146In vitro mimicry of in vivo KPC mutations by ceftazidime-avibactam: phenotypes, mechanisms, genetic structure and kinetics of enzymatic hydrolysisSiquan Shen0Chengkang Tang1Weiwei Yang2Li Ding3Renru Han4Qingyu Shi5Yan Guo6Dandan Yin7Fupin Hu8Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of ChinaInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of ChinaCeftazidime-avibactam (CZA) is employed for the treatment of infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-KP). Resistance to CZA is frequently linked to point mutations in the blaKPC. We conducted in vitro simulations of in vivo blaKPC mutations using CZA. Four pre-therapy KPC-KP isolates (K1, K2, K3, and K4) were evaluated, all initially exhibited susceptibility to CZA and produced KPC-2. The crucial distinction was that following CZA treatment, the blaKPC-2 mutated in K1, K2, and K3, rendering them resistant to CZA, while K4 achieved microbiological clearance, and blaKPC-2 remained unaltered. The induction assay identified various blaKPC-2 variants, including blaKPC-25, blaKPC-127, blaKPC-100, blaKPC-128, blaKPC-137, blaKPC-138, blaKPC-144 and blaKPC-180. Our findings suggest that the resistance of KPC-KP to CZA primarily results from the emergence of KPC variants, complemented by increased blaKPC expression. A close correlation exists between avibactam concentration and the rate of increased CZA minimum Inhibitory concentration, as well as blaKPC mutation. Inadequate avibactam concentration is more likely to induce resistance in strains against CZA, there is also a higher likelihood of mutation in the blaKPC-2 and the optimal avibactam ratio remains to be determined. Simultaneously, we selected a blaKPC-33-producing K. pneumoniae strain (mutated from blaKPC-2) and induced it with imipenem and meropenem, respectively. The blaKPC-2 was detected during the process, indicating that the mutation is reversible. Clinical use of carbapenems to treat KPC variant strains increases the risk of infection, as the gene can mutate back to blaKPC-2, rendering the strain even more cross-resistant to carbapenems and CZA.https://www.tandfonline.com/doi/10.1080/22221751.2024.2356146Ceftazidime-avibactamKlebsiella pneumoniaeKPC variantsinductionin vitro mimicry |
| spellingShingle | Siquan Shen Chengkang Tang Weiwei Yang Li Ding Renru Han Qingyu Shi Yan Guo Dandan Yin Fupin Hu In vitro mimicry of in vivo KPC mutations by ceftazidime-avibactam: phenotypes, mechanisms, genetic structure and kinetics of enzymatic hydrolysis Emerging Microbes and Infections Ceftazidime-avibactam Klebsiella pneumoniae KPC variants induction in vitro mimicry |
| title | In vitro mimicry of in vivo KPC mutations by ceftazidime-avibactam: phenotypes, mechanisms, genetic structure and kinetics of enzymatic hydrolysis |
| title_full | In vitro mimicry of in vivo KPC mutations by ceftazidime-avibactam: phenotypes, mechanisms, genetic structure and kinetics of enzymatic hydrolysis |
| title_fullStr | In vitro mimicry of in vivo KPC mutations by ceftazidime-avibactam: phenotypes, mechanisms, genetic structure and kinetics of enzymatic hydrolysis |
| title_full_unstemmed | In vitro mimicry of in vivo KPC mutations by ceftazidime-avibactam: phenotypes, mechanisms, genetic structure and kinetics of enzymatic hydrolysis |
| title_short | In vitro mimicry of in vivo KPC mutations by ceftazidime-avibactam: phenotypes, mechanisms, genetic structure and kinetics of enzymatic hydrolysis |
| title_sort | in vitro mimicry of in vivo kpc mutations by ceftazidime avibactam phenotypes mechanisms genetic structure and kinetics of enzymatic hydrolysis |
| topic | Ceftazidime-avibactam Klebsiella pneumoniae KPC variants induction in vitro mimicry |
| url | https://www.tandfonline.com/doi/10.1080/22221751.2024.2356146 |
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