Ceftazidime-avibactam (CZA) is currently one of the last resorts used to treat infections caused by carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa. However, KPC variants have become the main mechanism mediating CZA resistance in KPC-producing gram-negative bacteria after increasing the application of CZA. Our previous study revealed that CZA-resistant KPC-33 had emerged in carbapenem-resistant P. aeruginosa (CRPA) and had resulted in death due to hypervirulence and extensive drug resistance; however, the evolutionary path of KPC-33-producing CRPA has not been investigated. Here, we observed the emergence of blaKPC-33 in CRPA under drug pressure, leading to resistance to CZA. We further elucidated the pathway of resistance development due to blaKPC mutations in P. aeruginosa. Three KPC-producing P. aeruginosa (KPC-PA) strains (including one blaKPC-33-positive strain and two blaKPC-2-positive strains) were successively isolated from a hospitalized patient. The blaKPC-33-positive CZA-resistant strain SRPA0656 (CZA MIC >128 μg/mL, imipenem MIC = 32 μg/mL) was isolated after the blaKPC-2-positive P. aeruginosa SRP2863 (CZA MIC = 1 μg/mL, imipenem MIC >128 μg/mL) was treated with CZA. The subsequent use of carbapenems to treat the infection led to the re-emergence of the KPC-2-producing strain SRPA3703. Additionally, we collected four other KPC-33-producing P. aeruginosa strains. Antimicrobial susceptibility testing revealed that all the KPC-33-bearing P. aeruginosa strains in this study were multidrug-resistant but susceptible to colistin and amikacin. Whole-genome sequencing indicated that blaKPC-33 was located on two Tn4401-like transposons contained in the plasmids and that most of these plasmids could be transferred into P. aeruginosa PAO1Rif isolates. Growth rate determination demonstrated that the relative growth rate of P. aeruginosa harboring blaKPC-33 was faster than that of P. aeruginosa harboring blaKPC-2 in the logarithmic phase. Global phylogenetic analysis revealed that most KPC-PA strains were isolated from China and the USA. MLST revealed that the most common ST in KPC-PA was ST463, which was detected only in China, and that all the strains carried blaKPC-2 or its derivatives. These results indicated that the use of CZA for the treatment of KPC-2-producing P. aeruginosa may have contributed to the evolution of KPC-33. The widespread dissemination of KPC-PA (especially the ST463) and Tn4401 transposons may increase the spread of CRPA isolates carrying blaKPC-33. Close attention to the development of resistance to CZA during clinical treatment of CRPA infection and monitoring CZA-resistant strains is necessary to prevent further spread.

Global phylogeography and genetic characterization of carbapenem and ceftazidime-avibactam resistant KPC-33-producing Pseudomonas aeruginosa

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2025年1月7日

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Longjie Zhou,
Jiayao Yao,
Ying Zhang,
Xiaofan Zhang,
Yueyue Hu,
Haiyang Liu,
Jintao He,
Yunsong Yu,
Minhua Chen,
Yuexing Tu,
Xi Li

摘要

Ceftazidime-avibactam (CZA) is currently one of the last resorts used to treat infections caused by carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa. However, KPC variants have become the main mechanism mediating CZA resistance in KPC-producing gram-negative bacteria after increasing the application of CZA. Our previous study revealed that CZA-resistant KPC-33 had emerged in carbapenem-resistant P. aeruginosa (CRPA) and had resulted in death due to hypervirulence and extensive drug resistance; however, the evolutionary path of KPC-33-producing CRPA has not been investigated. Here, we observed the emergence of bla_KPC-33 in CRPA under drug pressure, leading to resistance to CZA. We further elucidated the pathway of resistance development due to bla_KPC mutations in P. aeruginosa. Three KPC-producing P. aeruginosa (KPC-PA) strains (including one bla_KPC-33-positive strain and two bla_KPC-2-positive strains) were successively isolated from a hospitalized patient. The bla_KPC-33-positive CZA-resistant strain SRPA0656 (CZA MIC >128 μg/mL, imipenem MIC = 32 μg/mL) was isolated after the bla_KPC-2-positive P. aeruginosa SRP2863 (CZA MIC = 1 μg/mL, imipenem MIC >128 μg/mL) was treated with CZA. The subsequent use of carbapenems to treat the infection led to the re-emergence of the KPC-2-producing strain SRPA3703. Additionally, we collected four other KPC-33-producing P. aeruginosa strains. Antimicrobial susceptibility testing revealed that all the KPC-33-bearing P. aeruginosa strains in this study were multidrug-resistant but susceptible to colistin and amikacin. Whole-genome sequencing indicated that bla_KPC-33 was located on two Tn4401-like transposons contained in the plasmids and that most of these plasmids could be transferred into P. aeruginosa PAO1^Rif isolates. Growth rate determination demonstrated that the relative growth rate of P. aeruginosa harboring bla_KPC-33 was faster than that of P. aeruginosa harboring bla_KPC-2 in the logarithmic phase. Global phylogenetic analysis revealed that most KPC-PA strains were isolated from China and the USA. MLST revealed that the most common ST in KPC-PA was ST463, which was detected only in China, and that all the strains carried bla_KPC-2 or its derivatives. These results indicated that the use of CZA for the treatment of KPC-2-producing P. aeruginosa may have contributed to the evolution of KPC-33. The widespread dissemination of KPC-PA (especially the ST463) and Tn4401 transposons may increase the spread of CRPA isolates carrying bla_KPC-33. Close attention to the development of resistance to CZA during clinical treatment of CRPA infection and monitoring CZA-resistant strains is necessary to prevent further spread.