Zhou Longjie, Yao Jiayao, Zhang Ying, Zhang Xiaofan, Hu Yueyue, Liu Haiyang, He Jintao, Yu Yunsong, Chen Minhua, Tu Yuexing, Li Xi
Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China.
Center for General Practice Medicine, Department of Infectious Diseases, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China.
NPJ Antimicrob Resist. 2025 Jan 7;3(1):3. doi: 10.1038/s44259-024-00073-0.
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 in CRPA under drug pressure, leading to resistance to CZA. We further elucidated the pathway of resistance development due to bla mutations in P. aeruginosa. Three KPC-producing P. aeruginosa (KPC-PA) strains (including one bla-positive strain and two bla-positive strains) were successively isolated from a hospitalized patient. The bla-positive CZA-resistant strain SRPA0656 (CZA MIC >128 μg/mL, imipenem MIC = 32 μg/mL) was isolated after the bla-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 was located on two Tn4401-like transposons contained in the plasmids and that most of these plasmids could be transferred into P. aeruginosa PAO1 isolates. Growth rate determination demonstrated that the relative growth rate of P. aeruginosa harboring bla was faster than that of P. aeruginosa harboring bla 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 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. 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.
头孢他啶-阿维巴坦（CZA）目前是用于治疗耐碳青霉烯类肠杆菌科细菌和铜绿假单胞菌所致感染的最后手段之一。然而，随着CZA应用的增加，KPC变异体已成为产KPC革兰阴性菌中介导CZA耐药的主要机制。我们之前的研究显示，耐碳青霉烯类铜绿假单胞菌（CRPA）中已出现耐CZA的KPC-33，且因其高毒力和广泛耐药导致了死亡；然而，产KPC-33的CRPA的进化路径尚未得到研究。在此，我们观察到在药物压力下CRPA中bla的出现，导致对CZA耐药。我们进一步阐明了铜绿假单胞菌中由于bla突变导致的耐药发展途径。从一名住院患者中先后分离出3株产KPC的铜绿假单胞菌（KPC-PA）菌株（包括1株bla阳性菌株和2株bla阳性菌株）。在用CZA处理bla阳性的铜绿假单胞菌SRP2863（CZA MIC = 1μg/mL，亚胺培南MIC>128μg/mL）后，分离出bla阳性的耐CZA菌株SRPA0656（CZA MIC>128μg/mL，亚胺培南MIC = 32μg/mL）。随后使用碳青霉烯类药物治疗感染导致产KPC-2的菌株SRPA3703再次出现。此外，我们还收集了另外4株产KPC-33的铜绿假单胞菌菌株。药敏试验显示，本研究中所有携带KPC-33的铜绿假单胞菌菌株均对多种药物耐药，但对黏菌素和阿米卡星敏感。全基因组测序表明，bla位于质粒中所含的两个Tn4401样转座子上，且这些质粒中的大多数可转移至铜绿假单胞菌PAO1分离株中。生长速率测定表明，携带bla的铜绿假单胞菌在对数期的相对生长速率快于携带bla的铜绿假单胞菌。全球系统发育分析显示，大多数KPC-PA菌株分离自中国和美国。多位点序列分型显示，KPC-PA中最常见的序列型为ST463，仅在中国检测到，且所有菌株均携带bla或其衍生物。这些结果表明，使用CZA治疗产KPC-2的铜绿假单胞菌可能促成了KPC-33的进化。KPC-PA（尤其是ST463）和Tn4401转座子的广泛传播可能会增加携带bla的CRPA分离株的传播。在CRPA感染的临床治疗过程中密切关注对CZA的耐药发展并监测耐CZA菌株对于防止进一步传播是必要的。
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