西菲德罗考

**西菲德罗考**
临床资料
商品名（英语：Drug nomenclature）	Fetroja，Fetcroja
其他名称	RSC-649266
AHFS/Drugs.com	Monograph
MedlinePlus	a620008
核准状况	欧 EMA: yes; 美 DailyMed: Cefiderocol_sulfate_tosylate;
给药途径	静脉注射
药物类别（英语：Drug class）	铁螯合头孢菌素
ATC码	J01DI04 (WHO) ;
法律规范状态
法律规范	欧：Rx-only; 美：处方药（℞-only）; 处方药（℞-only）;
药物动力学数据
血浆蛋白结合率	56–58%
生物半衰期	2.8小时
排泄途径	主要为肾脏 (60–70%维持原形排除)
识别信息
	IUPAC命名法 (6R,7R)-7-[[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-(2-carboxypropan-2-yloxyimino)acetyl]amino]-3-[[1-[2-[(2-chloro-3,4-dihydroxybenzoyl)amino]ethyl]pyrrolidin-1-ium-1-yl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate; ;
CAS号	1225208-94-5
PubChem CID	77843966;
DrugBank	DB14879;
ChemSpider	52084902;
UNII	SZ34OMG6E8;
KEGG	D11013; D11302;
ChEBI	CHEBI:140376;
ChEMBL	ChEMBL3989974;
CompTox Dashboard（英语：CompTox Chemicals Dashboard） (EPA)	DTXSID401098052 ;
化学信息
化学式	C30H34ClN7O10S2
摩尔质量	752.21 g·mol−1
3D模型（JSmol（英语：JSmol））	交互式图像;
	SMILES CC(C)(C(=O)O)ON=C(C1=CSC(=N1)N)C(=O)NC2C3N(C2=O)C(=C(CS3)C[N+]4(CCCC4)CCNC(=O)C5=C(C(=C(C=C5)O)O)Cl)C(=O)[O-];
	InChI InChI=1S/C30H34ClN7O10S2/c1-30(2,28(46)47)48-36-19(16-13-50-29(32)34-16)24(42)35-20-25(43)37-21(27(44)45)14(12-49-26(20)37)11-38(8-3-4-9-38)10-7-33-23(41)15-5-6-17(39)22(40)18(15)31/h5-6,13,20,26H,3-4,7-12H2,1-2H3,(H7-,32,33,34,35,36,39,40,41,42,44,45,46,47)/t20-,26-/m1/s1; Key:DBPPRLRVDVJOCL-FQRUVTKNSA-N;

西菲德罗考（英语：Cefiderocol）以Fetroja等品牌于市面销售，是一种抗生素，在没其他治疗选项的情况下可用此药物来治疗复杂的泌尿道感染。^[5]适用于治疗包括绿脓杆菌在内的多重抗生素抗药性革兰氏阴性菌。^[6]^[7]^[8]此药物透过静脉注射给药。^[1]

使用后常见的副作用有腹泻、注射部位反应、便秘和皮疹。^[9]

西菲德罗考属于头孢菌素类药物，^[5]^[10]于2019年11月获得美国食品药物管理局（FDA）核准用于医疗用途，并于2020年4月经欧盟核准用于医疗用途。^[5]^[11]^[2]Fetroja于2020年9月^[12]经由补充新药申请（英语：New Drug Application）(sNDA)，获得FDA核准用于治疗对其他抗生素产生抗药性的革兰氏阴性菌引起的院内感染细菌性肺炎（英语：Hospital-acquired pneumonia）和呼吸器相关肺炎（英语：Ventilator-associated pneumonia）。它已被列入世界卫生组织基本药物标准清单之中。^[13]

医疗用途[编辑]

西菲德罗考用于治疗患有复杂泌尿道感染的成人，包括由易感革兰氏阴性微生物引起的肾脏感染，而患者并无其他替代治疗选项，或是其他选项不足。^[5]^[10]

在美国，西菲德罗考适用于治疗复杂性泌尿道感染 (cUTI) ，而替代治疗选项有限或无替代治疗选项的18岁或以上成人患者，包括由以下易感革兰氏阴性微生物引起的肾盂肾炎（英语：pyelonephritis）：大肠杆菌、肺炎克雷伯氏菌、奇异变形杆菌（英语：Proteus mirabilis）、绿脓杆菌及阴沟肠杆菌（英语：Enterobacter cloacae）复合体。^[1]

用于治疗重症肺炎（院内感染细菌性肺炎和呼吸器相关肺炎），适用于18岁及以上的患者，其肺炎对其他更常用的抗生素没反应，并且被证实是由以下革兰氏阴性菌之一所引起:

鲍氏不动杆菌复合体
大肠杆菌
阴沟肠杆菌复合体
肺炎克雷伯氏菌
绿脓杆菌
黏质沙雷氏菌

这类适应症得到一项研究的支持，其中西菲德罗考在治疗革兰氏阴性菌引起的院内感染肺炎的作用与美罗培南相当。研究的主要终点是第14天因任何原因导致的死亡率，两种抗生素被证明同样有效。^[14]

截至2020年，西菲德罗考可在欧盟用于治疗因选项有限的成人需氧革兰氏阴性菌感染。^[2]

不良影响[编辑]

西菲德罗考可能会引起严重且危及生命的过敏反应、艰难梭菌引起的严重腹泻和癫痫发作。^[9]

在针对多重抗药性革兰氏阴性细菌感染的病危患者进行的一项单独临床试验中，使用西菲德罗考治疗与使用其他抗生素治疗相比，患者死亡率增加。^[5]^[9]在接受院内感染/呼吸器相关性肺炎、菌血症或败血症治疗的群体中观察到较高的死亡率。死亡原因尚未确定，但有些死亡是由于感染恶化或并发症，或潜在的合并症所致。^[5]西菲德罗考治疗这类感染的安全性和有效性尚未确定。因此此药物标签包含有关较高全因死亡率的黑框警告。^[5]

于2021年，出现第一例对此药物抗药性的报告，^[15]截至2022年，据报某些族群中抗药性的比例高达50%。2022年9月，德国罗伯特·科赫研究所（RKI）通报几起俄乌战争伤者的伤口感染病例（肺炎克雷伯氏菌和鲍氏不动杆菌），这些患者曾在德国接受过治疗。^[16]

药理学[编辑]

此药物结构与头孢哌米（英语：cefepime）和头孢他啶类似，但C-3侧链末端的氯儿茶酚基团进一步增强其β-内酰胺酶稳定性，使其成为铁载体（英语：siderophore）。^[17]

这表示它透过与铁结合，铁被主动转运到细菌细胞，药物随之进入。^[1]^[18]^[19]^[20]^[21]此药物是FDA批准的第一种铁载体抗生素。^[22]它利用细菌自身的铁转运系统进行转运，而绕过细菌孔蛋白通道。^[23]西菲德罗考一旦进入周质空间就会与铁分离并与青霉素结合蛋白（英语：Penicillin-binding proteins）结合，抑制细菌肽聚糖细胞壁的合成。^[24]

西菲德罗考对β-内酰胺酶表现出高稳定性，对所有类别的碳青霉烯酶具有广谱活性，包括丝氨酸碳青霉烯酶和金属-β-内酰胺酶。^[25]

历史[编辑]

西菲德罗考已获得FDA的合格传染病产品核准，并取得优先审查的资格。^[5]FDA于2019年11月批准Shionogi & Co.生产的西菲德罗考作为抗菌药物，用于治疗18岁或以上患有复杂性泌尿道感染(cUTI) 的成人，包括由易感革兰氏阴性微生物引起的肾脏感染，这些患者的替代治疗选项有限或无替代治疗选项。^[5]^[11]^[1]

一项针对448名cUTI参与者的研究（NCT02321800），证明西菲德罗考的安全性和有效性。^[5]^[9]在接受西菲德罗考治疗的参与者中，72.6%的人在完成疗程后约7天症状得到缓解并已消除细菌，而接受替代抗生素（亚胺培南/西司他丁）的参与者中的此种比例为54.6%。^[5]两个治疗组的临床反应率相似。^[5]该试验中包括来自欧洲、美国和墨西哥的参与者。^[9]

参见[编辑]

^ ^1.0 ^1.1 ^1.2 ^1.3 ^1.4 Fetroja- cefiderocol sulfate tosylate injection, powder, for solution. DailyMed. 2019-11-19 [2020-04-29].
^ ^2.0 ^2.1 ^2.2 Fetcroja EPAR. European Medicines Agency (EMA). 2020-02-24 [2020-04-29]. 本文含有此来源中属于公有领域的内容。
^ Fetcroja Product information. Union Register of medicinal products. [2023-03-03].
^ Katsube T, Echols R, Arjona Ferreira JC, Krenz HK, Berg JK, Galloway C. Cefiderocol, a Siderophore Cephalosporin for Gram-Negative Bacterial Infections: Pharmacokinetics and Safety in Subjects With Renal Impairment. Journal of Clinical Pharmacology. May 2017, 57 (5): 584–591. PMC 5412848 . PMID 27874971. doi:10.1002/jcph.841.
^ ^5.00 ^5.01 ^5.02 ^5.03 ^5.04 ^5.05 ^5.06 ^5.07 ^5.08 ^5.09 ^5.10 ^5.11 FDA approves new antibacterial drug to treat complicated urinary tract infections as part of ongoing efforts to address antimicrobial resistance. U.S. Food and Drug Administration (FDA) (新闻稿). 2019-11-14 [2019-11-15]. （原始内容存档于2019-11-16）. 本文含有此来源中属于公有领域的内容。
^ Choi JJ, McCarthy MW. Cefiderocol: a novel siderophore cephalosporin. Expert Opinion on Investigational Drugs. February 2018, 27 (2): 193–197. PMID 29318906. S2CID 205768562. doi:10.1080/13543784.2018.1426745.
^ Aoki T, Yoshizawa H, Yamawaki K, Yokoo K, Sato J, Hisakawa S, et al. Cefiderocol (S-649266), A new siderophore cephalosporin exhibiting potent activities against Pseudomonas aeruginosa and other gram-negative pathogens including multi-drug resistant bacteria: Structure activity relationship. European Journal of Medicinal Chemistry. July 2018, 155: 847–868. PMID 29960205. S2CID 49682995. doi:10.1016/j.ejmech.2018.06.014.
^ Portsmouth S, van Veenhuyzen D, Echols R, Machida M, Ferreira JC, Ariyasu M, et al. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial. The Lancet. Infectious Diseases. December 2018, 18 (12): 1319–1328. PMID 30509675. S2CID 54552812. doi:10.1016/S1473-3099(18)30554-1.
^ ^9.0 ^9.1 ^9.2 ^9.3 ^9.4 Drug Trials Snapshot: Fetroja. U.S. Food and Drug Administration (FDA). 2019-11-14 [2020-04-29]. 本文含有此来源中属于公有领域的内容。
^ ^10.0 ^10.1 Zhanel GG, Golden AR, Zelenitsky S, Wiebe K, Lawrence CK, Adam HJ, et al. Cefiderocol: A Siderophore Cephalosporin with Activity Against Carbapenem-Resistant and Multidrug-Resistant Gram-Negative Bacilli. Drugs. February 2019, 79 (3): 271–289. PMID 30712199. S2CID 59541210. doi:10.1007/s40265-019-1055-2.
^ ^11.0 ^11.1 Drug Approval Package: Fetroja (cefiderocol). U.S. Food and Drug Administration (FDA). 2019-12-19 [29 April 2020-04-29].
^ FDA Approves Fetroja (cefiderocol) for the Treatment of Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia. Drugs.com. [2020-09-29] （英语）.
^ World Health Organization. World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. 2021. hdl:10665/345533 . WHO/MHP/HPS/EML/2021.02.
^ Matsunaga Y, Echols R, Katsube T, Yamano Y, Ariyasu M, Nagata TD. Cefiderocol (S-649266) for Nosocomial Pneumonia Caused by Gram-Negative Pathogens: Study Design of APEKS-NP, a Phase 3 Double-Blind Parallel-Group Randomized Clinical Trial. American Journal of Respiratory and Critical Care Medicine (Abstract). May 2018 [20 September 2020]. doi:10.1164/ajrccm-conference.2018.197.1_MeetingAbstracts.A3290 (不活跃 2024-01-31). 已忽略未知参数|article-number= (帮助)
^ Choby JE, Ozturk T, Satola SW, et al. Widespread cefiderocol heteroresistance in carbapenem- resistant Gram-negative pathogens. Lancet Infect Dis 2021; 21: 597-598
^ Infektionsmedizinische und chirurgische Herausforderungen durch Carbapenem-resistente bakterielle Erreger bei der Versorgung Kriegsverletzter aus der Ukraine (PDF). Epidemiologisches Bulletin 36/2022. 2022-09-08.
^ Karakonstantis S, Rousaki M, Kritsotakis EI. Cefiderocol: Systematic Review of Mechanisms of Resistance, Heteroresistance and In Vivo Emergence of Resistance. Antibiotics. May 2022, 11 (6): 723. PMC 9220290 . PMID 35740130. doi:10.3390/antibiotics11060723 .
^ Sato T, Yamawaki K. Cefiderocol: Discovery, Chemistry, and In Vivo Profiles of a Novel Siderophore Cephalosporin. Clinical Infectious Diseases. November 2019, 69 (Suppl 7): S538–S543. PMC 6853759 . PMID 31724047. doi:10.1093/cid/ciz826.
^ Matthews-King A. Antibiotic 'Trojan horse' could defeat superbugs causing global medical crisis, trial finds. The Independent. 2018-10-26 [2018-10-26].
^ Newey S. New 'Trojan horse' drug proves effective against antibiotic resistant bacteria. The Telegraph. 2018-10-26 [2018-10-26]. ISSN 0307-1235.
^ Simpson DH, Scott P. Antimicrobial Metallodrugs. Lo KK (编). Inorganic and Organometallic Transition Metal Complexes with Biological Molecules and Living Cells. Elsevier. 2017. ISBN 978-0-12-803887-1.
^ Saisho Y, Katsube T, White S, Fukase H, Shimada J. Pharmacokinetics, Safety, and Tolerability of Cefiderocol, a Novel Siderophore Cephalosporin for Gram-Negative Bacteria, in Healthy Subjects. Antimicrobial Agents and Chemotherapy. March 2018, 62 (3): 1–12. PMC 5826143 . PMID 29311072. doi:10.1128/AAC.02163-17.
^ Ito A, Nishikawa T, Matsumoto S, Yoshizawa H, Sato T, Nakamura R, et al. Siderophore Cephalosporin Cefiderocol Utilizes Ferric Iron Transporter Systems for Antibacterial Activity against Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy. December 2016, 60 (12): 7396–7401. PMC 5119021 . PMID 27736756. doi:10.1128/AAC.01405-16.
^ Principe L, Lupia T, Andriani L, Campanile F, Carcione D, Corcione S, et al. Microbiological, Clinical, and PK/PD Features of the New Anti-Gram-Negative Antibiotics: β-Lactam/β-Lactamase Inhibitors in Combination and Cefiderocol-An All-Inclusive Guide for Clinicians. Pharmaceuticals. April 2022, 15 (4): 463. PMC 9028825 . PMID 35455461. doi:10.3390/ph15040463 .
^ El-Lababidi RM, Rizk JG. Cefiderocol: A Siderophore Cephalosporin. The Annals of Pharmacotherapy. December 2020, 54 (12): 1215–1231. PMID 32522005. S2CID 219586396. doi:10.1177/1060028020929988.

延伸阅读[编辑]

Committee for Medicinal Products for Human Use. Fetcroja: EPAR - Public assessment report (PDF). European Medicines Agency (EMA). 2020-02-27. EMA/136096/2020.

外部链接[编辑]

Cefiderocol. Drug Information Portal. U.S. National Library of Medicine.
Cefiderocol sulfate tosylate. Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT02321800 for "A Study of Efficacy and Safety of Intravenous Cefiderocol (S-649266) Versus Imipenem/Cilastatin in Complicated Urinary Tract Infections (APEKS-cUTI)" at ClinicalTrials.gov

[Fetroja_FDA_label-1] 1.0 ^1.1 ^1.2 ^1.3 ^1.4 Fetroja- cefiderocol sulfate tosylate injection, powder, for solution. DailyMed. 2019-11-19 [2020-04-29].

[Fetcroja_EPAR-2] 2.0 ^2.1 ^2.2 Fetcroja EPAR. European Medicines Agency (EMA). 2020-02-24 [2020-04-29]. 本文含有此来源中属于公有领域的内容。

[3] Fetcroja Product information. Union Register of medicinal products. [2023-03-03].

[4] Katsube T, Echols R, Arjona Ferreira JC, Krenz HK, Berg JK, Galloway C. Cefiderocol, a Siderophore Cephalosporin for Gram-Negative Bacterial Infections: Pharmacokinetics and Safety in Subjects With Renal Impairment. Journal of Clinical Pharmacology. May 2017, 57 (5): 584–591. PMC 5412848 . PMID 27874971. doi:10.1002/jcph.841.

[FDA2019-5] 5.00 ^5.01 ^5.02 ^5.03 ^5.04 ^5.05 ^5.06 ^5.07 ^5.08 ^5.09 ^5.10 ^5.11 FDA approves new antibacterial drug to treat complicated urinary tract infections as part of ongoing efforts to address antimicrobial resistance. U.S. Food and Drug Administration (FDA) (新闻稿). 2019-11-14 [2019-11-15]. （原始内容存档于2019-11-16）. 本文含有此来源中属于公有领域的内容。

[pmid29318906ReviewArticle-6] Choi JJ, McCarthy MW. Cefiderocol: a novel siderophore cephalosporin. Expert Opinion on Investigational Drugs. February 2018, 27 (2): 193–197. PMID 29318906. S2CID 205768562. doi:10.1080/13543784.2018.1426745.

[7] Aoki T, Yoshizawa H, Yamawaki K, Yokoo K, Sato J, Hisakawa S, et al. Cefiderocol (S-649266), A new siderophore cephalosporin exhibiting potent activities against Pseudomonas aeruginosa and other gram-negative pathogens including multi-drug resistant bacteria: Structure activity relationship. European Journal of Medicinal Chemistry. July 2018, 155: 847–868. PMID 29960205. S2CID 49682995. doi:10.1016/j.ejmech.2018.06.014.

[Portsmouth2018-8] Portsmouth S, van Veenhuyzen D, Echols R, Machida M, Ferreira JC, Ariyasu M, et al. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial. The Lancet. Infectious Diseases. December 2018, 18 (12): 1319–1328. PMID 30509675. S2CID 54552812. doi:10.1016/S1473-3099(18)30554-1.

[FDA_snapshot-9] 9.0 ^9.1 ^9.2 ^9.3 ^9.4 Drug Trials Snapshot: Fetroja. U.S. Food and Drug Administration (FDA). 2019-11-14 [2020-04-29]. 本文含有此来源中属于公有领域的内容。

[pmid30712199-10] 10.0 ^10.1 Zhanel GG, Golden AR, Zelenitsky S, Wiebe K, Lawrence CK, Adam HJ, et al. Cefiderocol: A Siderophore Cephalosporin with Activity Against Carbapenem-Resistant and Multidrug-Resistant Gram-Negative Bacilli. Drugs. February 2019, 79 (3): 271–289. PMID 30712199. S2CID 59541210. doi:10.1007/s40265-019-1055-2.

[FDA_Approval-11] 11.0 ^11.1 Drug Approval Package: Fetroja (cefiderocol). U.S. Food and Drug Administration (FDA). 2019-12-19 [29 April 2020-04-29].

[12] FDA Approves Fetroja (cefiderocol) for the Treatment of Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia. Drugs.com. [2020-09-29] （英语）.

[WHO22nd-13] World Health Organization. World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. 2021. hdl:10665/345533 . WHO/MHP/HPS/EML/2021.02.

[14] Matsunaga Y, Echols R, Katsube T, Yamano Y, Ariyasu M, Nagata TD. Cefiderocol (S-649266) for Nosocomial Pneumonia Caused by Gram-Negative Pathogens: Study Design of APEKS-NP, a Phase 3 Double-Blind Parallel-Group Randomized Clinical Trial. American Journal of Respiratory and Critical Care Medicine (Abstract). May 2018 [20 September 2020]. doi:10.1164/ajrccm-conference.2018.197.1_MeetingAbstracts.A3290 (不活跃 2024-01-31). 已忽略未知参数|article-number= (帮助)

[15] Choby JE, Ozturk T, Satola SW, et al. Widespread cefiderocol heteroresistance in carbapenem- resistant Gram-negative pathogens. Lancet Infect Dis 2021; 21: 597-598

[16] Infektionsmedizinische und chirurgische Herausforderungen durch Carbapenem-resistente bakterielle Erreger bei der Versorgung Kriegsverletzter aus der Ukraine (PDF). Epidemiologisches Bulletin 36/2022. 2022-09-08.

[Karakonastantis-17] Karakonstantis S, Rousaki M, Kritsotakis EI. Cefiderocol: Systematic Review of Mechanisms of Resistance, Heteroresistance and In Vivo Emergence of Resistance. Antibiotics. May 2022, 11 (6): 723. PMC 9220290 . PMID 35740130. doi:10.3390/antibiotics11060723 .

[18] Sato T, Yamawaki K. Cefiderocol: Discovery, Chemistry, and In Vivo Profiles of a Novel Siderophore Cephalosporin. Clinical Infectious Diseases. November 2019, 69 (Suppl 7): S538–S543. PMC 6853759 . PMID 31724047. doi:10.1093/cid/ciz826.

[indy-19] Matthews-King A. Antibiotic 'Trojan horse' could defeat superbugs causing global medical crisis, trial finds. The Independent. 2018-10-26 [2018-10-26].

[20] Newey S. New 'Trojan horse' drug proves effective against antibiotic resistant bacteria. The Telegraph. 2018-10-26 [2018-10-26]. ISSN 0307-1235.

[21] Simpson DH, Scott P. Antimicrobial Metallodrugs. Lo KK (编). Inorganic and Organometallic Transition Metal Complexes with Biological Molecules and Living Cells. Elsevier. 2017. ISBN 978-0-12-803887-1.

[22] Saisho Y, Katsube T, White S, Fukase H, Shimada J. Pharmacokinetics, Safety, and Tolerability of Cefiderocol, a Novel Siderophore Cephalosporin for Gram-Negative Bacteria, in Healthy Subjects. Antimicrobial Agents and Chemotherapy. March 2018, 62 (3): 1–12. PMC 5826143 . PMID 29311072. doi:10.1128/AAC.02163-17.

[pmid27736756-23] Ito A, Nishikawa T, Matsumoto S, Yoshizawa H, Sato T, Nakamura R, et al. Siderophore Cephalosporin Cefiderocol Utilizes Ferric Iron Transporter Systems for Antibacterial Activity against Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy. December 2016, 60 (12): 7396–7401. PMC 5119021 . PMID 27736756. doi:10.1128/AAC.01405-16.

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