产KPC的肺炎克雷伯菌临床血培养分离株对头孢他啶/阿维巴坦、美罗培南/瓦博巴坦、亚胺培南/瑞来巴坦耐药的体外活性及基因组特征：一项意大利全国多中心观察性研究（2022 - 23年）
In vitro activity and genomic characterization of KPC-producing Klebsiella pneumoniae clinical blood culture isolates resistant to ceftazidime/avibactam, meropenem/vaborbactam, imipenem/relebactam: an Italian nationwide multicentre observational study (2022-23).
作者信息
Bianco Gabriele, Boattini Matteo, Lupo Laura, Ambretti Simone, Greco Rita, Degl'Innocenti Linda, Chiatamone Ranieri Sofia, Fasciana Teresa, Mazzariol Annarita, Gibellini Davide, Antonelli Guido, Sacco Federica, Quirino Angela, Farina Claudio, Paglietti Bianca, Comini Sara, Fiamma Maura, Broccolo Francesco, Cavallo Rossana, Costa Cristina, Gaibani Paolo
机构信息
Department of Experimental Medicine, University of Salento, Lecce, Italy.
Microbiology and Virology Unit, University Hospital Città della Salute e della Scienza di Torino, Turin, Italy.
出版信息
J Antimicrob Chemother. 2025 Feb 3;80(2):583-592. doi: 10.1093/jac/dkae450.
OBJECTIVES
To evaluate the in vitro activity of ceftazidime/avibactam, meropenem/vaborbactam, imipenem/relebactam and comparators against KPC-producing Klebsiella pneumoniae (KPC-Kp) clinical isolates collected from a multicentre study in Italy (2022-23) and genomic characterization of the molecular mechanisms causing resistance.
METHODS
Consecutive KPC-Kp isolates from blood cultures (n = 264) were collected from 14 hospital centres in the period 2022-23. Antimicrobial susceptibility testing was performed using broth microdilution. WGS was used to investigate KPC-Kp strains resistant to the new approved β-lactam/β-lactam inhibitor combinations (BLICs).
RESULTS
Overall, meropenem/vaborbactam (95.1% susceptible by EUCAST and 93.9% susceptible by CLSI; MIC50 = 0.5 mg/L; MIC90 = 4 mg/L) and imipenem/relebactam (97% susceptible by EUCAST and 92.8% susceptible by CLSI; MIC50 = 0.25 mg/L; MIC90 = 0.5 mg/L) showed similar activity, followed by ceftazidime/avibactam (93.9% susceptible by both EUCAST and CLSI; MIC50 = 2 mg/L; MIC90 = 8 mg/L). Ten out of 13 (76.9%) KPC-Kp resistant to ceftazidime/avibactam carried a blaKPC variant including blaKPC-31, blaKPC-205, blaKPC-203 and blaKPC-93. Among KPC-Kp resistant to meropenem/vaborbactam and imipenem/relebactam, 90.9% (10/11) and 80% (4/5) harboured a WT carbapenemase (i.e. blaKPC-2 or blaKPC-3), respectively. All strains resistant to meropenem/vaborbactam and/or imipenem/relebactam carried truncated OmpK35 and/or mutated (ins135GD) OmpK36.
CONCLUSIONS
New BLICs were shown to be the most widely active therapeutic option against KPC-Kp clinical isolates collected in Italy. Ceftazidime/avibactam resistance is mainly driven by the expression of KPC variants, whereas the loss of function of the OmpK35 and OmpK36 porins appears to play a key but not exclusive role in the development of meropenem/vaborbactam and/or imipenem/relebactam resistance.
目的
评估头孢他啶/阿维巴坦、美罗培南/法硼巴坦、亚胺培南/瑞来巴坦及对照药物对从意大利一项多中心研究（2022 - 2023年）中收集的产KPC肺炎克雷伯菌（KPC - Kp）临床分离株的体外活性，以及对导致耐药的分子机制进行基因组特征分析。
方法
在2022 - 2023年期间，从14家医院中心收集连续的血培养KPC - Kp分离株（n = 264）。采用肉汤微量稀释法进行药敏试验。全基因组测序（WGS）用于研究对新批准的β - 内酰胺/β - 内酰胺酶抑制剂复方制剂（BLICs）耐药的KPC - Kp菌株。
结果
总体而言，美罗培南/法硼巴坦（根据欧盟CAST标准95.1%敏感，根据CLSI标准93.9%敏感；MIC50 = 0.5 mg/L；MIC90 = 4 mg/L）和亚胺培南/瑞来巴坦（根据欧盟CAST标准97%敏感，根据CLSI标准92.8%敏感；MIC50 = 0.25 mg/L；MIC90 = 0.5 mg/L）表现出相似的活性，其次是头孢他啶/阿维巴坦（根据欧盟CAST和CLSI标准均为93.9%敏感；MIC50 = 2 mg/L；MIC90 = 8 mg/L）。13株对头孢他啶/阿维巴坦耐药的KPC - Kp中有10株（76.9%）携带blaKPC变体，包括blaKPC - 31、blaKPC - 205、blaKPC - 203和blaKPC - 93。在对美罗培南/法硼巴坦和亚胺培南/瑞来巴坦耐药的KPC - Kp中，分别有90.9%（10/11）和80%（4/5）携带野生型碳青霉烯酶（即blaKPC - 2或blaKPC - 3）。所有对美罗培南/法硼巴坦和/或亚胺培南/瑞来巴坦耐药的菌株均携带截短的OmpK35和/或突变的（ins135GD）OmpK36。
结论
新的BLICs被证明是针对在意大利收集的KPC - Kp临床分离株最具广泛活性的治疗选择。头孢他啶/阿维巴坦耐药主要由KPC变体的表达驱动，而OmpK35和OmpK36孔蛋白功能丧失似乎在美罗培南/法硼巴坦和/或亚胺培南/瑞来巴坦耐药的发生中起关键但非唯一作用。
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