Abstract：
Carbapenem-resistant Enterobacterales represent a major health threat and have few approved therapeutic options. Enterobacterales isolates were collected from hospitalized inpatients from 49 sites in six European countries (1 January-31 December 2020) and underwent susceptibility testing to cefiderocol and β-lactam/β-lactamase inhibitor combinations. Meropenem-resistant (MIC >8 mg/L) and cefiderocol-susceptible isolates were analyzed by PCR, and cefiderocol-resistant isolates by whole-genome sequencing, to identify resistance mechanisms. Overall, 1,909 isolates (including 970 Klebsiella spp., 382 Escherichia coli, and 244 Enterobacter spp.) were collected, commonly from bloodstream infections (43.6%). Cefiderocol susceptibility was higher than approved β-lactam/β-lactamase inhibitor combinations and largely comparable to cefepime-taniborbactam and aztreonam-avibactam against all Enterobacterales (98.1% vs 78.1%-97.4% and 98.7%-99.1%, respectively) and Enterobacterales resistant to meropenem (n = 148, including 125 Klebsiella spp.; 87.8% vs 0%-71.6% and 93.2%-98.6%, respectively), β-lactam/β-lactamase inhibitor combinations (66.7%-92.1% vs 0%-88.1% and 66.7%-97.9%, respectively), and to both meropenem and β-lactam/β-lactamase inhibitor combinations (61.9%-65.9% vs 0%-20.5% and 76.2%-97.7%, respectively). Susceptibilities to approved and developmental β-lactam/β-lactamase inhibitor combinations against cefiderocol-resistant Enterobacterales (n = 37) were 10.8%-56.8% and 78.4%-94.6%, respectively. Most meropenem-resistant Enterobacterales harbored Klebsiella pneumoniae carbapenemase (110/148) genes, although metallo-β-lactamase (35/148) and oxacillinase (OXA) carbapenemase (6/148) genes were less common; cefiderocol susceptibility was retained in β-lactamase producers, other than NDM, AmpC, and non-carbapenemase OXA producers. Most cefiderocol-resistant Enterobacterales had multiple resistance mechanisms, including ≥1 iron uptake-related mutation (37/37), carbapenemase gene (33/37), and ftsI mutation (24/37). The susceptibility to cefiderocol was higher than approved β-lactam/β-lactamase inhibitor combinations against European Enterobacterales, including meropenem- and β-lactam/β-lactamase inhibitor combination-resistant isolates.
OBJECTIVE: This study collected a notably large number of Enterobacterales isolates from Europe, including meropenem- and β-lactam/β-lactamase inhibitor combination-resistant isolates against which the in vitro activities of cefiderocol and developmental β-lactam/β-lactamase inhibitor combinations were directly compared for the first time. The MIC breakpoint for high-dose meropenem was used to define meropenem resistance, so isolates that would remain meropenem resistant with doses clinically available to patients were included in the data. Susceptibility to cefiderocol, as a single active compound, was high against Enterobacterales and was higher than or comparable to available β-lactam/β-lactamase inhibitor combinations. These results provide insights into the treatment options for infections due to Enterobacterales with resistant phenotypes. Early susceptibility testing of cefiderocol in parallel with β-lactam/β-lactamase inhibitor combinations will allow patients to receive the most appropriate treatment option(s) available in a timely manner. This is particularly important when options are more limited, such as against metallo-β-lactamase-producing Enterobacterales.
OBJECTIVE: This study collected a notably large number of Enterobacterales isolates from Europe, including meropenem- and β-lactam/β-lactamase inhibitor combination-resistant isolates against which the in vitro activities of cefiderocol and developmental β-lactam/β-lactamase inhibitor combinations were directly compared for the first time. The MIC breakpoint for high-dose meropenem was used to define meropenem resistance, so isolates that would remain meropenem resistant with doses clinically available to patients were included in the data. Susceptibility to cefiderocol, as a single active compound, was high against Enterobacterales and was higher than or comparable to available β-lactam/β-lactamase inhibitor combinations. These results provide insights into the treatment options for infections due to Enterobacterales with resistant phenotypes. Early susceptibility testing of cefiderocol in parallel with β-lactam/β-lactamase inhibitor combinations will allow patients to receive the most appropriate treatment option(s) available in a timely manner. This is particularly important when options are more limited, such as against metallo-β-lactamase-producing Enterobacterales.
摘要：
耐碳青霉烯的肠杆菌代表了主要的健康威胁，几乎没有批准的治疗选择。从六个欧洲国家（2020年1月1日至12月31日）的49个地点的住院患者中收集肠杆菌分离株，并对头孢地洛和β-内酰胺/β-内酰胺酶抑制剂组合进行了敏感性测试。通过PCR分析了耐美罗培南（MIC>8mg/L）和对头孢地洛敏感的分离株，通过全基因组测序和抗头孢霉素分离株，确定抗性机制。总的来说,1,909株（包括970个克雷伯菌属。,382大肠杆菌，和244种肠杆菌属。)被收集，通常来自血液感染（43.6％）。头孢地醇对所有肠杆菌的敏感性高于批准的β-内酰胺/β-内酰胺酶抑制剂组合，并且与头孢吡肟-坦尼巴坦和氨曲南-阿维巴坦相当（98.1％vs78.1％-97.4％和98.7％-99.1％，分别）和对美罗培南耐药的肠杆菌（n=148，包括125种克雷伯菌。；87.8%vs0%-71.6%和93.2%-98.6%，分别)，β-内酰胺/β-内酰胺酶抑制剂组合（66.7%-92.1%vs0%-88.1%和66.7%-97.9%，分别)，美罗培南和β-内酰胺/β-内酰胺酶抑制剂组合(61.9%-65.9%vs0%-20.5%和76.2%-97.7%，分别)。批准和开发的β-内酰胺/β-内酰胺酶抑制剂组合对头孢地洛耐药肠杆菌（n=37）的敏感性分别为10.8％-56.8％和78.4％-94.6％，分别。大多数耐美罗培南的肠杆菌含有肺炎克雷伯菌碳青霉烯酶（110/148）基因，尽管金属-β-内酰胺酶（35/148）和氧嘧啶酶（OXA）碳青霉烯酶（6/148）基因较不常见；头孢地洛敏感性保留在β-内酰胺酶生产者中，除了NDM，AMPC,和非碳青霉烯酶OXA生产者。大多数头孢地洛耐药肠杆菌具有多种耐药机制，包括≥1个铁摄取相关突变（37/37），碳青霉烯酶基因（33/37），和FTSI突变（24/37）。对头孢地洛的敏感性高于批准的β-lac+tam/β-内酰胺酶抑制剂组合对欧洲肠杆菌的敏感性，包括美罗培南和β-内酰胺/β-内酰胺酶抑制剂组合耐药的分离株。
目的：这项研究收集了大量来自欧洲的肠杆菌分离株，首次直接比较了头孢地洛和发育型β-内酰胺/β-内酰胺酶抑制剂组合的体外活性。高剂量美罗培南的MIC断点用于定义美罗培南耐药性，因此，在临床上可用于患者的剂量下，仍对美罗培南耐药的分离株被包括在数据中。对头孢地洛的易感性，作为单一的活性化合物，对肠杆菌的抵抗力较高，并且高于或与可用的β-内酰胺/β-内酰胺酶抑制剂组合相当。这些结果提供了对由于具有抗性表型的肠杆菌引起的感染的治疗选择的见解。头孢地洛与β-内酰胺/β-内酰胺酶抑制剂组合平行的早期敏感性测试将允许患者及时接受最合适的治疗选择。当选项更有限时，这一点尤其重要，例如针对产生金属-β-内酰胺酶的肠杆菌。
目的：这项研究收集了大量来自欧洲的肠杆菌分离株，首次直接比较了头孢地洛和发育型β-内酰胺/β-内酰胺酶抑制剂组合的体外活性。高剂量美罗培南的MIC断点用于定义美罗培南耐药性，因此，在临床上可用于患者的剂量下，仍对美罗培南耐药的分离株被包括在数据中。对头孢地洛的易感性，作为单一的活性化合物，对肠杆菌的抵抗力较高，并且高于或与可用的β-内酰胺/β-内酰胺酶抑制剂组合相当。这些结果提供了对由于具有抗性表型的肠杆菌引起的感染的治疗选择的见解。头孢地洛与β-内酰胺/β-内酰胺酶抑制剂组合平行的早期敏感性测试将允许患者及时接受最合适的治疗选择。当选项更有限时，这一点尤其重要，例如针对产生金属-β-内酰胺酶的肠杆菌。
