Abstract：
OBJECTIVE: Despite the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, Pseudomonas aeruginosa is still a major pathogen in people with cystic fibrosis (pwCF). We determine the activity of cefiderocol and comparators in a collection of 154 P. aeruginosa isolates recovered from pwCF during three multicentre studies performed in 17 Spanish hospitals in 2013, 2017 and 2021.
METHODS: ISO broth microdilution was performed and MICs were interpreted with CLSI and EUCAST criteria. Mutation frequency and WGS were also performed.
RESULTS: Overall, 21.4% were MDR, 20.8% XDR and 1.3% pandrug-resistant (PDR). Up to 17% of the isolates showed a hypermutator phenotype. Cefiderocol demonstrated excellent activity; only 13 isolates (8.4%) were cefiderocol resistant by EUCAST (none using CLSI). A high proportion of the isolates resistant to ceftolozane/tazobactam (71.4%), meropenem/vaborbactam (70.0%), imipenem/relebactam (68.0%) and ceftazidime/avibactam (55.6%) were susceptible to cefiderocol. Nine out of 13 cefiderocol-resistant isolates were hypermutators (P < 0.001). Eighty-three STs were detected, with ST98 being the most frequent. Only one isolate belonging to the ST175 high-risk clone carried blaVIM-2. Exclusive mutations affecting genes involved in membrane permeability, AmpC overexpression (L320P-AmpC) and efflux pump up-regulation were found in cefiderocol-resistant isolates (MIC = 4-8 mg/L). Cefiderocol resistance could also be associated with mutations in genes related to iron uptake (tonB-dependent receptors and pyochelin/pyoverdine biosynthesis).
CONCLUSIONS: Our results position cefiderocol as a therapeutic option in pwCF infected with P. aeruginosa resistant to most recent β-lactam/β-lactamase inhibitor combinations.
METHODS: ISO broth microdilution was performed and MICs were interpreted with CLSI and EUCAST criteria. Mutation frequency and WGS were also performed.
RESULTS: Overall, 21.4% were MDR, 20.8% XDR and 1.3% pandrug-resistant (PDR). Up to 17% of the isolates showed a hypermutator phenotype. Cefiderocol demonstrated excellent activity; only 13 isolates (8.4%) were cefiderocol resistant by EUCAST (none using CLSI). A high proportion of the isolates resistant to ceftolozane/tazobactam (71.4%), meropenem/vaborbactam (70.0%), imipenem/relebactam (68.0%) and ceftazidime/avibactam (55.6%) were susceptible to cefiderocol. Nine out of 13 cefiderocol-resistant isolates were hypermutators (P < 0.001). Eighty-three STs were detected, with ST98 being the most frequent. Only one isolate belonging to the ST175 high-risk clone carried blaVIM-2. Exclusive mutations affecting genes involved in membrane permeability, AmpC overexpression (L320P-AmpC) and efflux pump up-regulation were found in cefiderocol-resistant isolates (MIC = 4-8 mg/L). Cefiderocol resistance could also be associated with mutations in genes related to iron uptake (tonB-dependent receptors and pyochelin/pyoverdine biosynthesis).
CONCLUSIONS: Our results position cefiderocol as a therapeutic option in pwCF infected with P. aeruginosa resistant to most recent β-lactam/β-lactamase inhibitor combinations.
摘要：
目的：尽管引入了囊性纤维化跨膜传导调节因子（CFTR），铜绿假单胞菌仍然是囊性纤维化（pwCF）患者的主要病原体。在2013年，2017年和2021年在17家西班牙医院进行的三项多中心研究中，我们确定了154个从pwCF中回收的铜绿假单胞菌分离株中头孢地洛和比较物的活性。
方法：进行ISO肉汤微量稀释，并使用CLSI和EUCAST标准解释MIC。还进行了突变频率和WGS。
结果：总体而言，21.4%为MDR，20.8%的XDR和1.3%的pandrug抗性(PDR)。多达17％的分离株显示出超突变表型。头孢地洛表现出优异的活性；只有13个分离株（8.4％）对EUCAST具有头孢地洛抗性（没有使用CLSI）。对头孢洛赞/他唑巴坦耐药的分离株比例很高（71.4%），美罗培南/伐巴坦（70.0%），亚胺培南/来巴坦（68.0％）和头孢他啶/阿维巴坦（55.6％）对头孢地洛敏感。13株对头孢地洛耐药的分离株中有9株是高突变株（P<0.001）。检测到83个STs，ST98是最常见的。只有一个属于ST175高风险克隆的分离株携带blaVIM-2。影响膜通透性基因的排他性突变，在头孢地醇抗性分离株中发现AmpC过表达（L320P-AmpC）和外排泵上调（MIC=4-8mg/L）。头孢地醇抗性也可能与与铁摄取相关的基因（tonB依赖性受体和pytochelin/pyoverdine生物合成）的突变有关。
结论：我们的结果将头孢地洛定位为对最近的β-内酰胺/β-内酰胺酶抑制剂组合耐药的铜绿假单胞菌感染的pwCF的治疗选择。
方法：进行ISO肉汤微量稀释，并使用CLSI和EUCAST标准解释MIC。还进行了突变频率和WGS。
结果：总体而言，21.4%为MDR，20.8%的XDR和1.3%的pandrug抗性(PDR)。多达17％的分离株显示出超突变表型。头孢地洛表现出优异的活性；只有13个分离株（8.4％）对EUCAST具有头孢地洛抗性（没有使用CLSI）。对头孢洛赞/他唑巴坦耐药的分离株比例很高（71.4%），美罗培南/伐巴坦（70.0%），亚胺培南/来巴坦（68.0％）和头孢他啶/阿维巴坦（55.6％）对头孢地洛敏感。13株对头孢地洛耐药的分离株中有9株是高突变株（P<0.001）。检测到83个STs，ST98是最常见的。只有一个属于ST175高风险克隆的分离株携带blaVIM-2。影响膜通透性基因的排他性突变，在头孢地醇抗性分离株中发现AmpC过表达（L320P-AmpC）和外排泵上调（MIC=4-8mg/L）。头孢地醇抗性也可能与与铁摄取相关的基因（tonB依赖性受体和pytochelin/pyoverdine生物合成）的突变有关。
结论：我们的结果将头孢地洛定位为对最近的β-内酰胺/β-内酰胺酶抑制剂组合耐药的铜绿假单胞菌感染的pwCF的治疗选择。
