Mechanisms of Reduced Susceptibility to Cefiderocol Among Isolates from the CREDIBLE-CR and APEKS-NP Clinical Trials.
Mechanisms of Reduced Susceptibility to Cefiderocol Among Isolates from the CREDIBLE-CR and APEKS-NP Clinical Trials.
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DOI：
10.1089/mdr.2021.0180
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发表时间：
2022-04
影响因子：
2.6
通讯作者：
Yamano, Yoshinori
中科院分区：
文献类型：
--
作者：
Nordmann, Patrice;Shields, Ryan K.;Doi, Yohei;Takemura, Miki;Echols, Roger;Matsunaga, Yuko;Yamano, Yoshinori
本研究的目的是在3期APEKS-NP和CREDIBLE-CR研究中，对接受头孢地罗可治疗院内获得性肺炎或碳青霉烯类耐药感染的患者中头孢地罗可敏感性降低的分离株进行表征。在中心实验室进行分离株的药敏试验，并根据头孢地罗可的可用折点评价治疗后变化。对分离株进行全基因组测序和多位点序列分型，以确认其来源和鉴定突变。与遗传相关基线分离株相比，5株（APEKS-NP）和9株（CREDIBLE-CR）分离株的最小抑菌浓度（MIC）增加≥ 4倍;尽管MIC增加≥4倍，但大多数分离株仍对头孢地罗可敏感。在4/14株分离株中鉴定出β-内酰胺酶或青霉素结合蛋白（PBP）突变：1株阴沟肠杆菌（ACT-17中的氨基酸[AA]取代[A313 P]）;两株鲍曼不动杆菌（一个PBP 3 AA取代[H370 Y]，一个具有OXA-23取代[N85 I和P225 S]）;和一个铜绿假单胞菌（PDC-30 [4AA缺失“TPMA”位置316-319]）。使用含有野生型和那些突变型头孢菌素酶的同基因大肠杆菌菌株的克隆实验表明，突变型酶可能有助于降低对头孢地罗的敏感性。有9名患者的药代动力学数据可用，这些患者的头孢地罗暴露超过100%fT> 4 × MIC。未观察到突变与MIC增加的发展或程度之间的明确模式。在恢复的革兰氏阴性分离株中，未发现与铁转运相关的基因突变，包括fiu、cirA、piuA/C和pirA。 APEKS-NP：NCT 03032380; CREDIBLE-CR：NCT 02714595。
The objective of this study was to characterize isolates with reduced susceptibility to cefiderocol in patients receiving cefiderocol for nosocomial pneumonia or carbapenem-resistant infections in the Phase 3 APEKS-NP and CREDIBLE-CR studies. Susceptibility testing of isolates was conducted at a central laboratory, and post-treatment changes were evaluated according to available breakpoints for cefiderocol. Whole-genome sequencing and multilocus sequence typing were performed for isolates to confirm their origin and identify mutations. Five (APEKS-NP) and nine (CREDIBLE-CR) isolates demonstrated a ≥ 4-fold minimum inhibitory concentration (MIC) increase compared with genetically related baseline isolates; most remained susceptible to cefiderocol despite the ≥4-fold MIC increase. Mutations in β-lactamases or penicillin-binding protein (PBP) were identified in 4/14 isolates: one Enterobacter cloacae (amino acid [AA] substitution [A313P] in ACT-17); two Acinetobacter baumannii (one PBP3 AA substitution [H370Y], one with OXA-23 substitutions [N85I and P225S]); and one Pseudomonas aeruginosa (PDC-30 [4AA deletion “TPMA” position 316–319]). Cloning experiments using isogenic Escherichia coli strains containing wild-type and those mutant cephalosporinase enzymes show that the mutant enzymes may contribute to decreased susceptibility to cefiderocol. Pharmacokinetic data were available for nine patients, for whom cefiderocol exposures exceeded 100% fT > 4 × MIC. No clear pattern between mutations and development or extent of MIC increases was observed. No mutations were identified in genes related to iron transport, including fiu, cirA, piuA/C, and pirA, among recovered Gram-negative isolates. APEKS-NP: NCT03032380; CREDIBLE-CR: NCT02714595.
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