cefiderocol

Cefiderocol is used to treat adults with complicated urinary tract infections, including kidney infections caused by susceptible Gram-negative microorganisms, who have limited or no alternative treatment options.{{cite press release | title=FDA approves new antibacterial drug to treat complicated urinary tract infections as part of ongoing efforts to address antimicrobial resistance | website=U.S. Food and Drug Administration (FDA) | date=14 November 2019 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-antibacterial-drug-treat-complicated-urinary-tract-infections-part-ongoing-efforts | archive-url=https://web.archive.org/web/20191116072805/https://www.fda.gov/news-events/press-announcements/fda-approves-new-antibacterial-drug-treat-complicated-urinary-tract-infections-part-ongoing-efforts | archive-date=16 November 2019 | url-status=live | access-date=15 November 2019}} {{PD-notice}}

In the United States, cefiderocol is indicated in adults 18 years of age or older who have limited or no alternative treatment options for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex.

For the treatment of severe pneumonia (HABP and VABP), it is indicated in patients 18 years of age and older whose pneumonia is not responding to other, more commonly used antibiotics and is confirmed to be caused by one of the following Gram-negative organisms:

• Acinetobacter baumannii complex
• Escherichia coli
• Enterobacter cloacae complex
• Klebsiella pneumoniae
• Pseudomonas aeruginosa
• Serratia marcescens

This indication is supported by a study in which cefiderocol was not inferior to meropenem in treating nosocomial pneumonia caused by Gram-negative bacteria. The primary endpoint of the study was mortality due to any cause at day 14, where both antibiotics were shown to be equally effective.{{Cite journal |vauthors=Matsunaga Y, Echols R, Katsube T, Yamano Y, Ariyasu M, Nagata TD |date=May 2018|title=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 |journal=American Journal of Respiratory and Critical Care Medicine |type=Abstract |url=https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2018.197.1_MeetingAbstracts.A3290 |url-access=subscription|access-date=20 September 2020 |article-number=A3290 |doi=10.1164/ajrccm-conference.2018.197.1_MeetingAbstracts.A3290|doi-broken-date=1 November 2024}}

Cefiderocol has been associated with the emergence of heteroresistance, especially in A. baumannii and P. aeruginosa.{{cite journal | vauthors = Choby JE, Ozturk T, Satola SW, Jacob JT, Weiss DS | title = Does cefiderocol heteroresistance explain the discrepancy between the APEKS-NP and CREDIBLE-CR clinical trial results? | journal = The Lancet. Microbe | volume = 2 | issue = 12 | pages = e648–e649 | date = December 2021 | pmid = 35544102 | pmc = 9743357 | doi = 10.1016/S2666-5247(21)00271-8 }} In A. baumannii, the main mechanism identified so far involves mutations in the TonB-dependent receptor gene piuA.{{cite journal | vauthors = Shields RK, Dorazio AJ, Tiseo G, Squires KM, Leonildi A, Giordano C, Kline EG, Barnini S, Iovleva A, Griffith MP, Van Tyne D, Doi Y, Falcone M | title = Frequency of cefiderocol heteroresistance among patients treated with cefiderocol for carbapenem-resistant Acinetobacter baumannii infections | journal = JAC-antimicrobial Resistance | volume = 6 | issue = 5 | pages = dlae146 | date = October 2024 | pmid = 39253335 | pmc = 11382143 | doi = 10.1093/jacamr/dlae146 }} In other Enterobacteriales, amplification of beta-lactamase genes, such as bla_SHV, contributes to heteroresistance development.{{cite journal | vauthors = Liu C, Yi J, Lu M, Yang P, Du C, Jiang F, Du P, Shen N | title = Dynamic within-host cefiderocol heteroresistance caused by bla_SHV-12 amplification in pandrug-resistant and hypervirulent Klebsiella pneumoniae sequence type 11 | journal = Drug Resistance Updates | volume = 73 | pages = 101038 | date = March 2024 | pmid = 38181587 | doi = 10.1016/j.drup.2023.101038 }}

As of 2020, cefiderocol is indicated in the European Union for the treatment of infections due to aerobic Gram-negative bacteria in adults with limited treatment options.{{cite web | title=Fetcroja EPAR | website=European Medicines Agency (EMA) | date=24 February 2020 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/fetcroja | access-date=29 April 2020}} {{PD-notice}}

Cefiderocol may cause serious and life-threatening allergic reactions, severe diarrhea caused by C. difficile and seizures.

An increased rate of mortality was observed in people treated with cefiderocol as compared to other antibiotics in a separate clinical trial in critically ill people with multidrug-resistant Gram-negative bacterial infections. The higher rate was observed in people treated for hospital-acquired/ventilator-associated pneumonia (i.e., nosocomial pneumonia), bloodstream infections, or sepsis. The cause of death has not been established, but some of the deaths were a result of worsening or complications of infection, or underlying co-morbidities. The safety and efficacy of cefiderocol has not been established for the treatment of these types of infections. Hence, cefiderocol label includes a warning regarding the higher all-cause mortality rate.

In 2021, the first cases of antibiotic resistance were reported,Choby JE, Ozturk T, Satola SW, et al. Widespread cefiderocol heteroresistance in carbapenem- resistant Gram-negative pathogens. Lancet Infect Dis 2021; 21: 597-598 and as of 2022 alarming proportions of up to 50% of resistance in some cohorts have been reported. In September 2022, the German RKI reported victims of the Russian invasion of Ukraine with cefiderocol resistant surgical infections (Klebsiella species and Acinetobacter baumannii) who had been treated in Germany.{{Cite journal |date=2022-09-08 |title=Infektionsmedizinische und chirurgische Herausforderungen durch Carbapenem-resistente bakterielle Erreger bei der Versorgung Kriegsverletzter aus der Ukraine |url=https://www.rki.de/DE/Content/Infekt/EpidBull/Archiv/2022/Ausgaben/36_22.pdf |journal=Epidemiologisches Bulletin 36/2022}}

Its structure is similar to cefepime and ceftazidime, but a chlorocatechol group at the end of the C-3 side chain further enhances its β-lactamase stability and renders it a siderophore.{{cite journal | vauthors = Karakonstantis S, Rousaki M, Kritsotakis EI | title = Cefiderocol: Systematic Review of Mechanisms of Resistance, Heteroresistance and In Vivo Emergence of Resistance | journal = Antibiotics | volume = 11 | issue = 6 | page = 723 | date = May 2022 | pmid = 35740130 | pmc = 9220290 | doi = 10.3390/antibiotics11060723 | doi-access = free }}

This means it enters into bacterial cells by binding to iron, which is actively transported into the bacterial cells.{{cite journal | vauthors = Sato T, Yamawaki K | title = Cefiderocol: Discovery, Chemistry, and In Vivo Profiles of a Novel Siderophore Cephalosporin | journal = Clinical Infectious Diseases | volume = 69 | issue = Suppl 7 | pages = S538–S543 | date = November 2019 | pmid = 31724047 | pmc = 6853759 | doi = 10.1093/cid/ciz826 }}{{Cite news|url=https://www.independent.co.uk/news/health/antibiotic-resistance-bacteria-infection-superbug-ecoli-uti-symptoms-lancet-a8601641.html|title=Antibiotic 'Trojan horse' could defeat superbugs causing global medical crisis, trial finds| vauthors = Matthews-King A |date=2018-10-26|work=The Independent|access-date=2018-10-26 }}{{Cite news|url=https://www.telegraph.co.uk/news/2018/10/26/new-trojan-horse-drug-proves-effective-against-antibiotic-resistant/|title=New 'Trojan horse' drug proves effective against antibiotic resistant bacteria| vauthors = Newey S |date=2018-10-26|work=The Telegraph|access-date=2018-10-26|issn=0307-1235 }}{{cite book| vauthors = Simpson DH, Scott P |chapter=Antimicrobial Metallodrugs | veditors = Lo KK |title=Inorganic and Organometallic Transition Metal Complexes with Biological Molecules and Living Cells|date=2017 |publisher=Elsevier|isbn=978-0-12-803887-1|chapter-url=https://www.elsevier.com/books/inorganic-and-organometallic-transition-metal-complexes-with-biological-molecules-and-living-cells/lo/978-0-12-803814-7 }} It was the first siderophore antibiotic to be approved by the U.S. Food and Drug Administration (FDA).{{cite journal | vauthors = Saisho Y, Katsube T, White S, Fukase H, Shimada J | title = Pharmacokinetics, Safety, and Tolerability of Cefiderocol, a Novel Siderophore Cephalosporin for Gram-Negative Bacteria, in Healthy Subjects | journal = Antimicrobial Agents and Chemotherapy | volume = 62 | issue = 3 | pages = 1–12 | date = March 2018 | pmid = 29311072 | pmc = 5826143 | doi = 10.1128/AAC.02163-17 }} It bypasses the bacterial porin channels by using the bacteria's own iron-transport system for being transported in.{{cite journal | vauthors = Ito A, Nishikawa T, Matsumoto S, Yoshizawa H, Sato T, Nakamura R, Tsuji M, Yamano Y | title = Siderophore Cephalosporin Cefiderocol Utilizes Ferric Iron Transporter Systems for Antibacterial Activity against Pseudomonas aeruginosa | journal = Antimicrobial Agents and Chemotherapy | volume = 60 | issue = 12 | pages = 7396–7401 | date = December 2016 | pmid = 27736756 | pmc = 5119021 | doi = 10.1128/AAC.01405-16 }} Once within the periplasmic space, cefiderocol dissociates from the iron and binds to PBPs, inhibiting peptidoglycan cell wall synthesis.{{cite journal | vauthors = Principe L, Lupia T, Andriani L, Campanile F, Carcione D, Corcione S, De Rosa FG, Luzzati R, Stroffolini G, Steyde M, Decorti G, Di Bella S | title = 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 | journal = Pharmaceuticals | volume = 15 | issue = 4 | pages = 463 | date = April 2022 | pmid = 35455461 | pmc = 9028825 | doi = 10.3390/ph15040463 | doi-access = free }}

Cefiderocol shows high stability against β-lactamases, with a broad spectrum of activity against all classes of carbapenemases, including serine-carbapenemases (class A such as KPC and class D such as OXA-48) and metallo-β-lactamases (class B such as VIM, NDM, and IMP).{{cite journal | vauthors = El-Lababidi RM, Rizk JG | title = Cefiderocol: A Siderophore Cephalosporin | journal = The Annals of Pharmacotherapy | volume = 54 | issue = 12 | pages = 1215–1231 | date = December 2020 | pmid = 32522005 | doi = 10.1177/1060028020929988 | s2cid = 219586396 }}

Cefiderocol utilises the iron transport system of the bacteria using the “Trojan horse” mechanism. To ensure accurate antibiotic susceptibility testing, cefiderocol requires liquid growth media with low iron levels.{{cite journal | vauthors = Hackel MA, Tsuji M, Yamano Y, Echols R, Karlowsky JA, Sahm DF | title = Reproducibility of broth microdilution MICs for the novel siderophore cephalosporin, cefiderocol, determined using iron-depleted cation-adjusted Mueller-Hinton broth | journal = Diagnostic Microbiology and Infectious Disease | volume = 94 | issue = 4 | pages = 321–325 | date = August 2019 | pmid = 31029489 | doi = 10.1016/j.diagmicrobio.2019.03.003 | doi-access = free }} According to European Committee on Antimicrobial Susceptibility Testing guidelines, broth microdilution should be performed using iron-depleted Mueller-Hinton broth and specific criteria apply for reading and interpreting the results; specifically, trailing should be disregarded and a growth button of less than 1 mm or light turbidity should be considered as growth.The European Committee on Antimicrobial Susceptibility Testing. EUCAST Guidance document on broth microdilution testing of cefiderocol. 2024.

https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Guidance_documents/Cefiderocol_MIC_testing_EUCAST_guidance_document_January_2024.pdf

Cefiderocol received a Qualified Infectious Disease Product designation from the U.S. Food and Drug Administration (FDA) and was granted priority review. In November 2019, the FDA granted approval of cefiderocol to Shionogi & Co. as an antibacterial drug for treatment of adults 18 years of age or older with complicated urinary tract infections, including kidney infections caused by susceptible Gram-negative microorganisms, who have limited or no alternative treatment options.

The safety and effectiveness of cefiderocol was demonstrated in a study of 448 participants with complicated urinary tract infections. Of the participants who were administered cefiderocol, 72.6% had resolution of symptoms and eradication of the bacteria approximately seven days after completing treatment, compared with 54.6% in participants who received an alternative antibiotic. The clinical response rates were similar between the two treatment groups. The trial included participants from Europe, United States and Mexico.

In the clinical trial, participants with complicated urinary tract infections were chosen at random to receive cefiderocol or another antibacterial drug called imipenem/cilastatin. Both treatments were given intravenously for 7–14 days and neither the participants nor the health care professionals knew which drugs were given until after the trial was complete. Participants could not be switched to an oral antibacterial drug to complete the treatment. The benefit of cefiderocol was measured by the proportion of participants who achieved cure or improvement in their symptoms related to complicated urinary tract infections and a negative urine culture test in comparison to imipenem/cilastatin.

In April 2020, cefiderocol was approved for medical use in the European Union.

{{reflist}}

• {{cite web | vauthors=((Committee for Medicinal Products for Human Use)) | url=https://www.ema.europa.eu/documents/assessment-report/fetcroja-epar-public-assessment-report_en.pdf | title=Fetcroja: EPAR - Public assessment report | publisher=European Medicines Agency (EMA) | date=27 February 2020 | id=EMA/136096/2020 | author-link=Committee for Medicinal Products for Human Use }}

• {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/cefiderocol | publisher = U.S. National Library of Medicine| work = Drug Information Portal| title = Cefiderocol }}
• {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/rn/2009350-94-9 | publisher = U.S. National Library of Medicine| work = Drug Information Portal| title = Cefiderocol sulfate tosylate }}
• {{ClinicalTrialsGov|NCT02321800|A Study of Efficacy and Safety of Intravenous Cefiderocol (S-649266) Versus Imipenem/Cilastatin in Complicated Urinary Tract Infections (APEKS-cUTI)}}

{{Cell wall disruptive antibiotics}}

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Category:Cephalosporin antibiotics

Category:Siderophores

Category:World Health Organization essential medicines

Category:Ketoxime ethers