Cefiderocol   中文名称: 头孢地尔

β-lactam

Cefiderocol (S-649266) 是一种与儿茶酚部分缀合的新型肠外铁载体头孢菌素。它对多种需氧革兰氏阴性菌具有很强的抗菌活性，包括铜绿假单胞菌、鲍曼不动杆菌等非发酵菌以及肠杆菌科碳青霉烯类耐药菌株。头孢地考主要与非发酵细菌结合，例如肠杆菌科的 GR20263 和 PBP3。当铜绿假单胞菌中的铁转运蛋白 PiuA 或大肠杆菌中的 CirA 和 Fiu 缺陷时，头孢地罗可的 MIC 可以升高 16 倍，表明这些铁转运蛋白有助于头孢地罗考穿过外膜。铜绿假单胞菌中的外排泵 MexA-MexB-OprM 或肺炎克雷伯菌中的 OmpK35/36 缺陷[1]。

除必须测定特定情况下的 MIC 的情况外，制备贫铁阳离子调节的 Mueller-Hinton 肉汤 (ID-CAMHB) 是为了测定头孢地罗科尔 MIC。头孢菌素对大肠杆菌 ATCC 25922 和铜绿假单胞菌 ATCC 27853 的质量控制最低抑菌浓度 (MIC) 范围为 0.06 至 0.5 μg/mL。补充有血红素、维生素 K1 和湖羊血的布鲁塞氏菌琼脂用于厌氧菌[1]。

Absorption, Distribution and Excretion
A single intravenous dose of 2 g of cefiderocol in healthy patients produces a Cmax of 89.7 mg/L and an AUC of 386 mg\*h/L. In patients with complicated urinary tract infections and a creatinine clearance of at least 60 mL/min, doses of 2 g cefiderocol every 8 hours produced an AUC of 394.7 mg*h/L and a Cmax of 138 mg/L. However the infusion rate for this chronic dosing was 3 times the recommended rate. Cmax and AUC are known to increase proportionally with dosage.
98.6% of cefiderocol is eliminated in the urine with 90.6% as the unchanged parent drug. The remaining 8% is eliminated as metabolites. 2.8% is eliminated in the feces. Less than 10% of cefiderocol is metabolized.
Cefiderocol has a mean volume of distribution of 18 L.
Cefiderocol has a mean clearance of 5.18 L/h.

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Metabolism / Metabolites
Cefiderocol undergoes a small degree of metabolism to a cefiderocol epimer at the 7 position, cefiderocol catechol-3-methoxy and -4-methoxy, and a pyrrolidine chlorobenzamide product (PCBA). PCBA undergoes further metabolism to sulfated, methylated, and glucuronidated metabolites. The enzymes involved in these reactions have yet to be identified and cefiderocol has not been shown to interfere in the metabolism of other agents.

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Biological Half-Life
The terminal elimination half-life of cefiderocol is 2-3 h.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Although no information is available on the use of cefiderocol during breastfeeding, cephalosporins are generally not expected to cause adverse effects in breastfed infants. Occasionally disruption of the infant's gastrointestinal flora, resulting in diarrhea or thrush have been reported with cephalosporins, but these effects have not been adequately evaluated. Cefiderocol is acceptable to use in nursing mothers.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Cefiderocol is 40-60% bound to plasma proteins, predominantly to albumin.

[1]. Antimicrob Agents Chemother. 2017 Dec 21;62(1).

[2]. Clin Infect Dis. 2019 Nov 13;69(Supplement_7):S544-S551.

Cefiderocol is a cephalosporin antibacterial drug and exerts a mechanism of action similar to other β-lactam antibiotics. Unlike other agents in this category, cefiderocol is a siderophore able to undergo active transport into the bacterial cell through iron channels. It represents a significant addition to antibacterial treatment option as it has proven to be effective *in vitro* against multidrug resistant strains including extended spectrum β-lactamase producers and carbapenemase producing bacteria. Cefiderocol was granted designation as a Qualified Infectious Disease Product and granted priority review status by the FDA on November 14, 2019. It is indicated for use in complicated urinary tract infections in patients with limited or no alternative treatments available. This indication was supported by a positive clinical trial composed of 448 patients with complicated urinary tract infections which demonstrated a 72.6% rate of symptom resolution and bacterial eradication with cefiderocol compared to 54.6% with the comparator, imipenem/cilastatin. A concern noted in the trial was a 0.3% higher rate of all cause mortality, the cause of which has not been determined.
Cefiderocol is a Cephalosporin Antibacterial.
See also: Cefiderocol Sulfate Tosylate (active moiety of).

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Drug Indication
Cefiderocol is indicated for the treatment of complicated urinary tract infections with or without pyelonephritis.
FDA Label
Fetcroja is indicated for the treatment of infections   due to aerobic Gram-negative organisms in adults with limited treatment options (see sections 4. 2, 4. 4 and 5. 1). Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Treatment of infections due to aerobic Gram-negative bacteria

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Mechanism of Action
Cefiderocol acts by binding to and inhibiting penicillin-binding proteins (PBPs), preventing cell wall synthesis and ultimately causing death of the bacterial cell. Like other β-lactam antibiotics cefiderocol is able to enter bacterial cells via passive diffusion through porins. Unlike other β-lactams, cefiderocol contains a chlorocatechol group which allows it to chelate iron. Once bound to ferric iron cefiderocol is able to undergo active transport into bacterial cells through iron channels in the outer cell membrane such as those encoded by the *cirA* and *fiu* genes in *E. coli* or the *PiuA* gene in *P. aeruginosa*. Once inside the cell, cefiderocol binds to and inhibits PBP3 with high affinity thereby preventing the linking of peptodoglycan layers via the pentapeptide bridge. PBP1a, 1b, 2,and 4 are also bound and inhibited by cefiderocol but with a lesser potency than PBP3 and are therefore expected to contribute less to its antibacterial effect.

C30H34CLN7O10S2

752.21

751.149

C, 47.90; H, 4.56; Cl, 4.71; N, 13.03; O, 21.27; S, 8.52

1225208-94-5

1883830-01-0 (ditosylate hydrate);1225208-94-5;2009350-94-9 (sulfate tosylate 3:1:4);2135543-94-9 (sulfate tosylate hydrate 3:1:4:1);

77843966

White to off-white solid powder

-1.02

310

6

15

12

50

1440

2

ClC1C(=C(C([H])=C([H])C=1C(N([H])C([H])([H])C([H])([H])[N+]1(C([H])([H])C2C([H])([H])S[C@]3([H])[C@@]([H])(C(N3C=2C(=O)[O-])=O)N([H])C(/C(/C2=C([H])SC(N([H])[H])=N2)=N\OC(C(=O)O[H])(C([H])([H])[H])C([H])([H])[H])=O)C([H])([H])C([H])([H])C([H])([H])C1([H])[H])=O)O[H])O[H]

DBPPRLRVDVJOCL-FQRUVTKNSA-N

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

(6R,7R)-7-[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetamido]-3-({1-[2-(2-chloro-3,4-dihydroxybenzamido)ethyl]pyrrolidin-1-ium-1-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

S-649266; S 649266; S649266; GSK2696266D; GSK-2696266D; GSK 2696266D; S-649266D; S 649266D; S649266D; Cefiderocol; Fetroja.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： (1). 请将本产品存放在密封且受保护的环境中（例如氮气保护），避免吸湿/受潮。  (2). 该产品在溶液状态不稳定，请现配现用。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 125 mg/mL (~166.18 mM)
H2O : ~1.06 mg/mL (~1.41 mM)
Ethanol : < 1 mg/mL

配方 1 中的溶解度: ≥ 2.75 mg/mL (3.66 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 27.5 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.75 mg/mL (3.66 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 27.5mg/mL澄清的DMSO储备液加入到900μL 20％SBE-β-CD生理盐水中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.75 mg/mL (3.66 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 27.5 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.75 mg/mL (3.66 mM)

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。