Cefiderocol (S-649266)
(Synonyms: 头孢地尔; S-649266) 目录号 : GC32079
Cefiderocol is a new type of iron carrier cephalosporin with strong in vitro activity against Gram-negative bacteria and non-fermented Gram-negative bacteria[1-3].
Cas No.:1225208-94-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >97.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
|
Cell lines |
Peripheral blood mononuclear cells (PBMCs) |
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Preparation Method |
Cells were stimulated with 100 ng/mL LPS with or without cefiderocol (10 mg/L, 40 mg/L, 70 mg/L) for 3 days |
|
Reaction Conditions |
10/40/70 mg/L;3 days |
|
Applications |
Higher concentrations of cefiderocol inhibit the production of lipopolysaccharide-stimulated proinflammatory cytokines. |
| Animal experiment [2]: | |
|
Animal models |
Pathogen-free male Sprague-Dawley rats |
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Preparation Method |
Inoculants of 0.1 ml(Pseudomonas aeruginosa) or 0.2 ml(Pseudomonas baumannii or Klebsiella pneumoniae) were injected into the lungs of rats to induce respiratory infection, The infected rats were given cefiderocol subcutaneously. |
|
Dosage form |
2 g every 8 h as a 3-h infusion for 4 days |
|
Applications |
Administering cefiderocol 2 g every 8 h as a 3-h infusion for 4 days achieved a greater than 3 log10 reduction in cells of carbapenem-resistant isolates of P. aeruginosa, A. baumannii, and K. pneumoniae in rat lung infection. |
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References: [1]. Hildebrand D, BÖhringer J, et,al. Cefiderocol Protects against Cytokine- and Endotoxin-Induced Disruption of Vascular Endothelial Cell Integrity in an In Vitro Experimental Model. Antibiotics (Basel). 2022 Apr 26;11(5):581. doi: 10.3390/antibiotics11050581. PMID: 35625225; PMCID: PMC9137736. |
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Cefiderocol is a new type of iron carrier cephalosporin with strong in vitro activity against Gram-negative bacteria and non-fermented Gram-negative bacteria[1-3].
Cefiderocol(10/40/70 mg/L;3 days) dampens LPS-stimulated production of pro-inflammatory cytokines[4]. The absence of iron transporters PiuA in Pseudomonas aeruginosa or CirA and Fiu in Escherichia coli resulted in a 16-fold increase in cefiderocol MIC, suggesting that these iron transporters contribute to cefiderocol penetration through the outer membrane[5].
Administering cefiderocol 2 g every 8 h as a 3-h infusion for 4 days achieved a greater than 3 log10 reduction in cells of carbapenem-resistant isolates of P. aeruginosa, A. baumannii, and K. pneumoniae in rat lung infection[6]. The pharmacodynamics of cefiderocol in the thigh infection model of neutropenia mice showed a sigmoid dose-response curve, and the bactericidal effect was better with the increase of dose[7].
References:
[1]. Choi JJ, McCarthy MW. Cefiderocol: a novel siderophore cephalosporin. Expert Opin Investig Drugs. 2018 Feb;27(2):193-197. doi: 10.1080/13543784.2018.1426745. Epub 2018 Jan 24. PMID: 29318906.
[2]. Soriano MC, Montufar J,et,al. Cefiderocol. Rev Esp Quimioter. 2022 Apr;35 Suppl 1(Suppl 1):31-34. doi: 10.37201/req/s01.07.2022. Epub 2022 Apr 22. PMID: 35488822; PMCID: PMC9106201.
[3]. GijÓn Cordero D, Castillo-Polo JA, et,al. Antibacterial spectrum of cefiderocol. Rev Esp Quimioter. 2022 Sep;35 Suppl 2(Suppl 2):20-27. doi: 10.37201/req/s02.03.2022. Epub 2022 Oct 4. PMID: 36193981; PMCID: PMC9632062.
[4]. Hildebrand D, BÖhringer J, et,al. Cefiderocol Protects against Cytokine- and Endotoxin-Induced Disruption of Vascular Endothelial Cell Integrity in an In Vitro Experimental Model. Antibiotics (Basel). 2022 Apr 26;11(5):581. doi: 10.3390/antibiotics11050581. PMID: 35625225; PMCID: PMC9137736.
[5]. Ito A, Sato T, et,al. In Vitro Antibacterial Properties of Cefiderocol, a Novel Siderophore Cephalosporin, against Gram-Negative Bacteria. Antimicrob Agents Chemother. 2017 Dec 21;62(1):e01454-17. doi: 10.1128/AAC.01454-17. PMID: 29061741; PMCID: PMC5740388.
[6]. Matsumoto S, Singley CM, et,al. Efficacy of Cefiderocol against Carbapenem-Resistant Gram-Negative Bacilli in Immunocompetent-Rat Respiratory Tract Infection Models Recreating Human Plasma Pharmacokinetics. Antimicrob Agents Chemother. 2017 Aug 24;61(9):e00700-17. doi: 10.1128/AAC.00700-17. PMID: 28630178; PMCID: PMC5571323.
[7]. Ghazi IM, Monogue ML, et,al. Pharmacodynamics of cefiderocol, a novel siderophore cephalosporin, in a Pseudomonas aeruginosa neutropenic murine thigh model. Int J Antimicrob Agents. 2018 Feb;51(2):206-212. doi: 10.1016/j.ijantimicag.2017.10.008. Epub 2017 Oct 27. PMID: 29111435.
Cefiderocol是一种新型铁载体头孢菌素，对革兰氏阴性菌和非发酵革兰氏阴性菌具有较强的体外活性[1-3]。
Cefiderocol(10/40/70 mg/L；3 天）抑制 LPS 刺激的促炎细胞因子的产生[4]。铜绿假单胞菌中铁转运体 PiuA 或大肠杆菌中 CirA 和 Fiu 的缺失导致头孢地尔考 MIC 增加 16 倍，表明这些铁转运体有助于头孢地尔考穿过外膜[5]。
<p >每 8 小时给予 2 克头孢地尔考 3 小时输注 4 天，使大鼠肺部感染的铜绿假单胞菌、鲍曼不动杆菌和肺炎克雷伯菌的碳青霉烯类耐药菌株的细胞减少了 3 log10 以上[6 ].头孢地尔考在白细胞减少小鼠大腿感染模型中的药效学呈S型剂量-反应曲线，随着剂量的增加杀菌效果更好[7]。
| Cas No. | 1225208-94-5 | SDF | |
| 别名 | 头孢地尔; S-649266 | ||
| Canonical SMILES | O=C(C(N12)=C(C[N+]3(CCNC(C4=CC=C(O)C(O)=C4Cl)=O)CCCC3)CS[C@]2([H])[C@H](NC(/C(C5=CSC(N)=N5)=N\OC(C)(C(O)=O)C)=O)C1=O)[O-] | ||
| 分子式 | C30H34ClN7O10S2 | 分子量 | 752.21 |
| 溶解度 | DMSO : 50 mg/mL (66.47 mM) | 储存条件 | Store at -20°C, stored under nitrogen,unstable in solution, ready to use. |
| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 1.3294 mL | 6.6471 mL | 13.2942 mL |
| 5 mM | 0.2659 mL | 1.3294 mL | 2.6588 mL |
| 10 mM | 0.1329 mL | 0.6647 mL | 1.3294 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
New Perspectives on Antimicrobial Agents: Cefiderocol
Antimicrob Agents Chemother 2021 Jul 16;65(8):e0217120.PMID:34031052DOI:10.1128/AAC.02171-20.
Bacterial resistance to carbapenem agents has reached alarming levels. Accordingly, collaborative efforts between national and international organizations and the pharmaceutical industry have led to an impressive expansion of commercially available β-lactam agents in recent years. No available agent comes close to the broad range of activity afforded by Cefiderocol, a novel siderophore-cephalosporin conjugate. The novelty of and need for Cefiderocol are clear, but available clinical data are conflicting, leaving infectious diseases specialists puzzled as to when to prescribe this agent in clinical practice. After a brief overview of Cefiderocol pharmacokinetics and pharmacodynamics, safety data, Cefiderocol susceptibility testing, and putative mechanisms of Cefiderocol resistance, this review focuses on determining Cefiderocol's role in the management of specific pathogens, including carbapenem-resistant Acinetobacter baumannii complex, carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Enterobacterales, and less commonly identified glucose-nonfermenting organisms such as Stenotrophomonas maltophilia, Burkholderia species, and Achromobacter species. Available preclinical, clinical trial, and postmarketing data are summarized for each organism, and each section concludes with our opinions on where to position Cefiderocol as a clinical therapeutic.
Cefiderocol: A Siderophore Cephalosporin
Ann Pharmacother 2020 Dec;54(12):1215-1231.PMID:32522005DOI:10.1177/1060028020929988.
Objective: This article reviews the available data on the chemistry, spectrum of activity, pharmacokinetic and pharmacodynamic properties, clinical efficacy, and potential place in therapy of Cefiderocol. Data sources: A literature search through PubMed, Google Scholar, and ClinicalTrials.gov was conducted (2009 to March 2020) using the search terms Cefiderocol and S-649266. Abstracts presented at recent conferences, prescribing information, and information from the US Food and Drug Administration (FDA) and the manufacturer's website were reviewed. Study selection and data extraction: All relevant published articles, package inserts, and unpublished meeting abstracts on Cefiderocol were reviewed. Data synthesis: Cefiderocol is the first siderophore antibiotic to be approved by the FDA. It was shown to be active against a wide range of resistant Gram-negative pathogens, including multidrug-resistant (MDR) Pseudomonas aeruginosa, Acinetobacter baumannii, Enterobacteriaceae, and Stenotrophomonas maltophilia. Cefiderocol was studied in the treatment of adult patients with complicated urinary tract infections (cUTIs) and nosocomial pneumonia and was well tolerated. In a recently completed prospective study, higher mortality was observed with Cefiderocol in the treatment of serious infections caused by carbapenem-resistant (CR) Gram-negative pathogens. Relevance to patient care and clinical practice: The approval of Cefiderocol provides a new option in the treatment of cUTIs and potentially treatment of nosocomial pneumonia caused by resistant Gram-negative pathogens. Given the higher mortality observed with Cefiderocol, its use in the treatment of CR Gram-negative infections should be carefully considered. Conclusion: Cefiderocol shows promising activity against MDR Gram-negative pathogens. Its use in the treatment of serious infections caused by CR Gram-negative bacteria needs further evaluation in phase III clinical studies.
Efficacy and safety of Cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial
Lancet Infect Dis 2021 Feb;21(2):226-240.PMID:33058795DOI:10.1016/S1473-3099(20)30796-9.
Background: New antibiotics are needed for the treatment of patients with life-threatening carbapenem-resistant Gram-negative infections. We assessed the efficacy and safety of Cefiderocol versus best available therapy in adults with serious carbapenem-resistant Gram-negative infections. Methods: We did a randomised, open-label, multicentre, parallel-group, pathogen-focused, descriptive, phase 3 study in 95 hospitals in 16 countries in North America, South America, Europe, and Asia. We enrolled patients aged 18 years or older admitted to hospital with nosocomial pneumonia, bloodstream infections or sepsis, or complicated urinary tract infections (UTI), and evidence of a carbapenem-resistant Gram-negative pathogen. Participants were randomly assigned (2:1 by interactive web or voice response system) to receive either a 3-h intravenous infusion of Cefiderocol 2 g every 8 h or best available therapy (pre-specified by the investigator before randomisation and comprised of a maximum of three drugs) for 7-14 days. For patients with pneumonia or bloodstream infection or sepsis, Cefiderocol treatment could be combined with one adjunctive antibiotic (excluding polymyxins, cephalosporins, and carbapenems). The primary endpoint for patients with nosocomial pneumonia or bloodstream infection or sepsis was clinical cure at test of cure (7 days [plus or minus 2] after the end of treatment) in the carbapenem-resistant microbiological intention-to-treat population (ITT; ie, patients with a confirmed carbapenem-resistant Gram-negative pathogen receiving at least one dose of study drug). For patients with complicated UTI, the primary endpoint was microbiological eradication at test of cure in the carbapenem-resistant microbiological ITT population. Safety was evaluated in the safety population, consisting of all patients who received at least one dose of study drug. Mortality was reported through to the end of study visit (28 days [plus or minus 3] after the end of treatment). Summary statistics, including within-arm 95% CIs calculated using the Clopper-Pearson method, were collected for the primary and safety endpoints. This trial is registered with ClinicalTrials.gov (NCT02714595) and EudraCT (2015-004703-23). Findings: Between Sept 7, 2016, and April 22, 2019, we randomly assigned 152 patients to treatment, 101 to Cefiderocol, 51 to best available therapy. 150 patients received treatment: 101 Cefiderocol (85 [85%] received monotherapy) and 49 best available therapy (30 [61%] received combination therapy). In 118 patients in the carbapenem-resistant microbiological ITT population, the most frequent carbapenem-resistant pathogens were Acinetobacter baumannii (in 54 patients [46%]), Klebsiella pneumoniae (in 39 patients [33%]), and Pseudomonas aeruginosa (in 22 patients [19%]). In the same population, for patients with nosocomial pneumonia, clinical cure was achieved by 20 (50%, 95% CI 33·8-66·2) of 40 patients in the Cefiderocol group and ten (53%, 28·9-75·6) of 19 patients in the best available therapy group; for patients with bloodstream infection or sepsis, clinical cure was achieved by ten (43%, 23·2-65·5) of 23 patients in the Cefiderocol group and six (43%, 17·7-71·1) of 14 patients in the best available therapy group. For patients with complicated UTIs, microbiological eradication was achieved by nine (53%, 27·8-77·0) of 17 patients in the Cefiderocol group and one (20%, 0·5-71·6) of five patients in the best available therapy group. In the safety population, treatment-emergent adverse events were noted for 91% (92 patients of 101) of the Cefiderocol group and 96% (47 patients of 49) of the best available therapy group. 34 (34%) of 101 patients receiving Cefiderocol and nine (18%) of 49 patients receiving best available therapy died by the end of the study; one of these deaths (in the best available therapy group) was considered to be related to the study drug. Interpretation: Cefiderocol had similar clinical and microbiological efficacy to best available therapy in this heterogeneous patient population with infections caused by carbapenem-resistant Gram-negative bacteria. Numerically more deaths occurred in the Cefiderocol group, primarily in the patient subset with Acinetobacter spp infections. Collectively, the findings from this study support Cefiderocol as an option for the treatment of carbapenem-resistant infections in patients with limited treatment options. Funding: Shionogi.
Treatment Options for Carbapenem-resistant Gram-negative Bacterial Infections
Clin Infect Dis 2019 Nov 13;69(Suppl 7):S565-S575.PMID:31724043DOI:10.1093/cid/ciz830.
Antimicrobial resistance has become one of the greatest threats to public health, with rising resistance to carbapenems being a particular concern due to the lack of effective and safe alternative treatment options. Carbapenem-resistant gram-negative bacteria of clinical relevance include the Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii, and more recently, Stenotrophomonas maltophilia. Colistin and tigecycline have been used as first-line agents for the treatment of infections caused by these pathogens; however, there are uncertainties regarding their efficacy even when used in combination with other agents. More recently, several new agents with activity against certain carbapenem-resistant pathogens have been approved for clinical use or are reaching late-stage clinical development. They include ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, plazomicin, eravacycline, and Cefiderocol. In addition, fosfomycin has been redeveloped in a new intravenous formulation. Data regarding the clinical efficacy of these new agents specific to infections caused by carbapenem-resistant pathogens are slowly emerging and appear to generally favor newer agents over previous best available therapy. As more treatment options become widely available for carbapenem-resistant gram-negative infections, the role of antimicrobial stewardship will become crucial in ensuring appropriate and rationale use of these new agents.
Cefiderocol: A Siderophore Cephalosporin with Activity Against Carbapenem-Resistant and Multidrug-Resistant Gram-Negative Bacilli
Drugs 2019 Feb;79(3):271-289.PMID:30712199DOI:10.1007/s40265-019-1055-2.
Cefiderocol is an injectable siderophore cephalosporin discovered and being developed by Shionogi & Co., Ltd., Japan. As with other β-lactam antibiotics, the principal antibacterial/bactericidal activity of Cefiderocol occurs by inhibition of Gram-negative bacterial cell wall synthesis by binding to penicillin binding proteins; however, it is unique in that it enters the bacterial periplasmic space as a result of its siderophore-like property and has enhanced stability to β-lactamases. The chemical structure of Cefiderocol is similar to both ceftazidime and cefepime, which are third- and fourth-generation cephalosporins, respectively, but with high stability to a variety of β-lactamases, including AmpC and extended-spectrum β-lactamases (ESBLs). Cefiderocol has a pyrrolidinium group in the side chain at position 3 like cefepime and a carboxypropanoxyimino group in the side chain at position 7 of the cephem nucleus like ceftazidime. The major difference in the chemical structures of Cefiderocol, ceftazidime and cefepime is the presence of a catechol group on the side chain at position 3. Together with the high stability to β-lactamases, including ESBLs, AmpC and carbapenemases, the microbiological activity of Cefiderocol against aerobic Gram-negative bacilli is equal to or superior to that of ceftazidime-avibactam and meropenem, and it is active against a variety of Ambler class A, B, C and D β-lactamases. Cefiderocol is also more potent than both ceftazidime-avibactam and meropenem versus Acinetobacter baumannii, including meropenem non-susceptible and multidrug-resistant (MDR) isolates. Cefiderocol's activity against meropenem-non-susceptible and Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriales is comparable or superior to ceftazidime-avibactam. Cefiderocol is also more potent than both ceftazidime-avibactam and meropenem against all resistance phenotypes of Pseudomonas aeruginosa and against Stenotrophomonas maltophilia. The current dosing regimen being used in phase III studies is 2 g administered intravenously every 8 h (q8 h) using a 3-h infusion. The pharmacokinetics of Cefiderocol are best described by a three-compartment linear model. The mean plasma half-life (t½) was ~ 2.3 h, protein binding is 58%, and total drug clearance ranged from 4.6-6.0 L/h for both single- and multi-dose infusions and was primarily renally excreted unchanged (61-71%). Cefiderocol is primarily renally excreted unchanged and clearance correlates with creatinine clearance. Dosage adjustment is thus required for both augmented renal clearance and in patients with moderate to severe renal impairment. In vitro and in vivo pharmacodynamic studies have reported that as with other cephalosporins the pharmacodynamic index that best predicts clinical outcome is the percentage of time that free drug concentrations exceed the minimum inhibitory concentration (%fT > MIC). In vivo efficacy of Cefiderocol has been studied in a variety of humanized drug exposure murine and rat models of infection utilizing a variety of MDR and extremely drug resistant strains. Cefiderocol has performed similarly to or has been superior to comparator agents, including ceftazidime and cefepime. A phase II prospective, multicenter, double-blind, randomized clinical trial assessed the safety and efficacy of Cefiderocol 2000 mg q8 h versus imipenem/cilastatin 1000 mg q8 h, both administered intravenously for 7-14 days over 1 h, in the treatment of complicated urinary tract infection (cUTI, including pyelonephritis) or acute uncomplicated pyelonephritis in hospitalized adults. A total of 452 patients were initially enrolled in the study, with 303 in the Cefiderocol arm and 149 in the imipenem/cilastatin arm. The primary outcome measure was a composite of clinical cure and microbiological eradication at the test-of-cure (TOC) visit, that is, 7 days after the end of treatment in the microbiological intent-to-treat (MITT) population. Secondary outcome measures included microbiological response per pathogen and per patient at early assessment (EA), end of treatment (EOT), TOC, and follow-up (FUP); clinical response per pathogen and per patient at EA, EOT, TOC, and FUP; plasma, urine and concentrations of Cefiderocol; and the number of participants with adverse events. The composite of clinical and microbiological response rates was 72.6% (183/252) for Cefiderocol and 54.6% (65/119) for imipenem/cilastatin in the MITT population. Clinical response rates per patient at the TOC visit were 89.7% (226/252) for Cefiderocol and 87.4% (104/119) for imipenem/cilastatin in the MITT population. Microbiological eradication rates were 73.0% (184/252) for Cefiderocol and 56.3% (67/119) for imipenem/cilastatin in the MITT population. Additionally, two phase III clinical trials are currently being conducted by Shionogi & Co., Ltd., Japan. The two trials are evaluating the efficacy of Cefiderocol in the treatment of serious infections in adult patients caused by carbapenem-resistant Gram-negative pathogens and evaluating the efficacy of Cefiderocol in the treatment of adults with hospital-acquired bacterial pneumonia, ventilator-associated pneumonia or healthcare-associated pneumonia caused by Gram-negative pathogens. Cefiderocol appears to be well tolerated (minor reported adverse effects were gastrointestinal and phlebitis related), with a side effect profile that is comparable to other cephalosporin antimicrobials. Cefiderocol appears to be well positioned to help address the increasing number of infections caused by carbapenem-resistant and MDR Gram-negative bacilli, including ESBL- and carbapenemase-producing strains (including metallo-β-lactamase producers). A distinguishing feature of Cefiderocol is its activity against resistant P. aeruginosa, A. baumannii, S. maltophilia and Burkholderia cepacia.