Cefiderocol
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| Non-proprietary name | Cefiderocol | |||||||||||||||
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| Molecular formula | C 30 H 34 ClN 7 O 10 S 2 | |||||||||||||||
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| Molar mass | 752.21 g mol −1 | |||||||||||||||
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| As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . | ||||||||||||||||
Cefiderocol is an antibiotic from the group of cephalosporins .
Indications
Cefiderocol was approved in the United States in 2019 under the trade name Fetroja ( Shionogi ) for the parenteral treatment of complicated urinary tract infections when other treatment options are limited.
The approval of cefiderocol in the USA includes the treatment of complicated urinary tract infections, including pyelonephritis , caused by certain gram-negative bacteria in patients aged 18 and over. It is used by intravenous injection and should be used when the cause of the disease can be assumed to be bacterial and other treatment options are limited in order to counteract the development of antibiotic resistance.
In April 2020, it was approved in the EU under the name Fetcroja for the treatment of infections in adults caused by aerobic gram-negative organisms.
The most common undesirable effects observed were diarrhea, reactions at the infusion site, constipation, rash, candidiasis , cough, increased liver values, headache, decreased potassium levels, and nausea and vomiting.
Working principle
The β-lactam molecule contains a structural part called a siderophore , via which it is able to bind to iron (III) ions. As a result, it can get into the gram-negative bacterial cell via an active Fe 3+ transport system in the bacterial cell wall , including those from multi-resistant strains. In addition, cefiderocol enters the bacterial cell through passive diffusion. It is stable to all known classes of β-lactamases . The antibiotic effect arises from the inhibition of the biosynthesis of peptidoglycans , which are important components of the bacterial cell wall.
Cefiderocol has a broad antimicrobial spectrum in vitro against gram-negative pathogens, including those that the World Health Organization gives top priority for the development of new therapeutic options ( carbapenem -resistant strains of Acinetobacter baumannii , Pseudomonas aeruginosa , Enterobacteriaceae ). It is not very active against gram-positive and anaerobic bacteria.
The global increase in carbapenem-resistant gram-negative bacteria is seen by some scientists as a threat to public health. Bacteria with this level of resistance can not only break down almost all β-lactam antibiotics and thus render them ineffective, but are also often resistant to other treatment options due to the frequent simultaneous acquisition of non-β-lactam resistance genes. Novel therapy options therefore play a special role in the treatment of infections caused by such germs.
properties
Pharmaceutical-chemical description
The active ingredient is used pharmaceutically as cefiderocol sulfate tosilate hydrate, i.e. as a salt of sulfuric acid and toluenesulfonic acid containing water of crystallization .
Structurally, cefiderocol is similar to the cephalosporins ceftazidime and cefepime , which is why, like them, it can withstand hydrolysis by β-lactamases. A special feature is the addition of a catecholic unit to the side chain at C-3, which chelates iron and mimics naturally occurring siderophores.
Pharmacokinetic data
- Plasma protein binding : 40-60%
- Elimination half-life : 2-3 hours
- Apparent volume of distribution: 18 liters
- Metabolism : less than 10%
- Elimination route : renal (98.6%, of which 90.6% unchanged), via the faeces (2.8%)
Individual evidence
- ↑ a b Ambeed: Cefiderocol , accessed on January 24, 2020
- ^ Novel Drug Approvals for 2019 . FDA .
- ^ Drugs @ FDA: FDA Approved Drug Products . FDA .
- ↑ Summary of opinion: Fetcroja. CHMP, February 27, 2020 ( PDF ), accessed on March 3, 2020.
- ↑ a b c Prescribing Information 'Fertoja' , as of November 2019 ( PDF ).
- ↑ a b c T. Sato, K. Yamawaki: Cefiderocol: Discovery, Chemistry, and In Vivo Profiles of a Novel Siderophore Cephalosporin. In: Clinical Infectious Diseases . Volume 69, Supplement November 7, 2019, pp. S538 – S543, doi : 10.1093 / cid / ciz826 , PMID 31724047 , PMC 6853759 (free full text).
- ↑ a b B. Gensthaler: New antibiotic against gram-negative bacteria , Pharmazeutische Zeitung, February 28, 2020.
- ↑ Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics , WHO , February 2017. (English)
- ↑ T. Tängdén, CG Giske: Global dissemination of extensively drug-resistant carbapenemase-producing Enterobacteriaceae: clinical perspectives on detection, treatment and infection control. Journal of Internal Medicine , Volume 277 (2015), pp. 501-12.T, doi : 10.1111 / joim.12342
- ↑ External identifiers or database links for cefiderocol sulfate silate (3: 1: 4), anhydrous : CAS number: 2009350-94-9, PubChem : 131801106 , Wikidata : Q89910616 . Molar mass: 3043.50 g · mol −1 ; UNII : 2V3QJ9TGE5
- ↑ External identifiers of or database links for cefiderocol sulfate silate hydrate : CAS number: 2135543-94-9, PubChem : 131839616 , DrugBank : DBSALT002912 , Wikidata : Q89909615 . UNII : TTP8LBP45D ; Formula: 3 C 30 H 34 ClN 7 O 10 S 2 · 4 C 7 H 8 O 3 S · H 2 SO 4 · x H 2 O.