Cefiderocol: A Novel Agent for the Management of Multidrug-Resistant Gram-Negative Organisms

Wu, Janet Y.; Srinivas, Pavithra; Pogue, Jason M.

doi:10.1007/s40121-020-00286-6

Cited by 195Antibiotic Resistance in BacteriaAntibiotics Pharmacokinetics and EfficacyUrinary Tract Infections Management

Cefiderocol: A Novel Agent for the Management of Multidrug-Resistant Gram-Negative Organisms

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Wu, Janet Y., Srinivas, Pavithra, Pogue, Jason M.·2020·Infectious Diseases and Therapy

DOI 10.1007/s40121-020-00286-6PMC PMC7054475

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Abstract

Cefiderocol, formerly S-649266, is a first in its class, an injectable siderophore cephalosporin that combines a catechol-type siderophore and cephalosporin core with side chains similar to cefepime and ceftazidime. This structure and its unique mechanism of action confer enhanced stability against hydrolysis by many β-lactamases, including extended spectrum β-lactamases such as CTX-M, and carbapenemases such as KPC, NDM, VIM, IMP, OXA-23, OXA-48-like, OXA-51-like and OXA-58. Cefiderocol's spectrum of activity encompasses both lactose-fermenting and non-fermenting Gram-negative pathogens, including carbapenem-resistant Enterobacterales. Cefiderocol recently received US Food and Drug Administration approval for the treatment of complicated urinary tract infections, including pyelonephritis, and is currently being evaluated in phase III trials for nosocomial pneumonia and infections caused by carbapenem-resistant Gram-negative pathogens. The purpose of this article is to review existing data on the mechanism of action, microbiology, pharmacokinetics, pharmacodynamics, efficacy, and safety of cefiderocol to assist clinicians in determining its place in therapy.

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Apart from binding their primary ligand, FeEnt, with high affinity, and its aposiderophore Ent with 100-200-fold lower affinity, KpnFepA_1658, KpnIroN, and KpnFepA_4984 showed different preferences for ferric catecholate complexes and siderophore antibiotics cefiderocol [FeFDC] and FeMB-1.
“Apart from binding their primary ligand, FeEnt, with high affinity, and its aposiderophore Ent with 100-200-fold lower affinity (38), KpnFepA_1658, KpnIroN, and KpnFepA_4984 showed different preferences for ferric catecholate complexes and siderophore antibiotics cefiderocol [FeFDC (40,41)] and FeMB-1 (42,43):”
From Siderophore-mediated iron acquisition by Klebsiella pneumoniae (2024) · cites this paper as [41]

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Optimization of Artificial Siderophores as 68Ga-Complexed PET Tracers for In Vivo Imaging of Bacterial Infections
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Siderophore-mediated iron acquisition by Klebsiella pneumoniae
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Elucidating the effect of iron acquisition systems in Klebsiella pneumoniae on susceptibility to the novel siderophore-cephalosporin cefiderocol
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Cefiderocol: An Overview of Its in-vitro and in-vivo Activity and Underlying Resistant Mechanisms
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The Burden of the Serious and Difficult-to-Treat Infections and a New Antibiotic Available: Cefiderocol
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An Overview of Cefiderocol’s Therapeutic Potential and Underlying Resistance Mechanisms
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Evaluating Cefiderocol in the Treatment of Multidrug-Resistant Gram-Negative Bacilli: A Review of the Emerging Data
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Trojan Horse Siderophore Conjugates Induce Pseudomonas aeruginosa Suicide and Qualify the TonB Protein as a Novel Antibiotic Target
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Antimicrobial Activity of Ceftazidime-Avibactam, Ceftolozane-Tazobactam, Cefiderocol, and Novel Darobactin Analogs against Multidrug-Resistant Pseudomonas aeruginosa Isolates from Pediatric and Adolescent Cystic Fibrosis Patients
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Navigating the Current Treatment Landscape of Metallo-β-Lactamase-Producing Gram-Negative Infections: What are the Limitations?
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High Prevalence of Antibiotic Resistance among Opportunistic Pathogens Isolated from Patients with COVID-19 under Mechanical Ventilation: Results of a Single-Center Study
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Fluorescent sensors of siderophores produced by bacterial pathogens
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Antimicrobial and Diagnostic Stewardship of the Novel β-Lactam/β-Lactamase Inhibitors for Infections Due to Carbapenem-Resistant Enterobacterales Species and Pseudomonas aeruginosa
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Novel Antibacterial Approaches and Therapeutic Strategies
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Present and Future Perspectives on Therapeutic Options for Carbapenemase-Producing Enterobacterales Infections
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The Antimicrobial Peptide Esc(1-21) Synergizes with Colistin in Inhibiting the Growth and in Killing Multidrug Resistant Acinetobacter baumannii Strains
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Zinc Chelators as Carbapenem Adjuvants for Metallo-β-Lactamase-Producing Bacteria: In Vitro and In Vivo Evaluation
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Cefiderocol Resistance Conferred by Plasmid-Located Ferric Citrate Transport System in Klebsiella pneumoniae Carbapenemase – Producing K. pneumoniae
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Inhibition of Isoleucyl-tRNA Synthetase by the Hybrid Antibiotic Thiomarinol
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Cefiderocol for treatment of an empyema due to extensively drug-resistant Pseudomonas aeruginosa: Clinical observations and susceptibility testing considerations
Kufel, W. D., Steele, J. M., Riddell, S. W., Jones, Z., Shakeraneh, P., & Endy, T. P. (2020) · IDCases · doi:10.1016/j.idcr.2020.e00863 · Cited by 27 · see citing works
Natural sideromycins and siderophore-conjugated natural products as inspiration for novel antimicrobial agents
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Difficult-to-Treat Pseudomonas aeruginosa Infections in Critically Ill Patients: A Comprehensive Review and Treatment Proposal
Vidal, P., Fernández, S. C., Fito, E. C., Carbajo, L. D. R., Fernández‐Ugidos, P., López-Ciudad, V. J., Olmo, J. N.-D., Rodríguez-Vázquez, A., & Varela, A. I. T. (2025) · Antibiotics · doi:10.3390/antibiotics14020178 · Cited by 27 · see citing works
Cefiderocol Treatment for Severe Infections due to Difficult-to-Treat-Resistant Non-Fermentative Gram-Negative Bacilli in ICU Patients: A Case Series and Narrative Literature Review
Wicky, P.-H., Poiraud, J., Alves, M., Patrier, J., d’Humières, C., Lê, M., Kramer, L., de Montmollin, É., Massias, L., Armand-Lefèvre, L., et al. (2023) · Antibiotics · doi:10.3390/antibiotics12060991 · Cited by 25 · see citing works
Metallotherapeutics development in the age of iron-clad bacteria
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Clinical efficacy and safety of cefiderocol for resistant Gram-negative infections: a real-life, single-centre experience
Karruli, A., Massa, A., Andini, R., Marrazzo, T., Ruocco, G., Zampino, R., & Durante‐Mangoni, E. (2023) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2023.106723 · Cited by 24 · see citing works
Iron Acquisition and Metabolism as a Promising Target for Antimicrobials (Bottlenecks and Opportunities): Where Do We Stand?
Stelitano, G., Cocorullo, M., Mori, M., Villa, S., Meneghetti, F., & Chiarelli, L. R. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076181 · Cited by 23 · see citing works
Semisynthesis: An Essential Tool for Antibiotics Drug Discovery
Goel, B., Tripathi, N., Bhardwaj, N., Singh, I. P., & Jain, S. K. (2024) · ChemistrySelect · doi:10.1002/slct.202400554 · Cited by 23 · see citing works
Stereochemically altered cephalosporins as potent inhibitors of New Delhi metallo-β-lactamases
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Detection of NDM Variants (blaNDM-1, blaNDM-2, blaNDM-3) from Carbapenem-Resistant Escherichia coli and Klebsiella pneumoniae: First Report from Nepal
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Resistance to beta-lactams in Gram-negative bacilli: relevance and potential therapeutic alternatives
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American Society of Transplantation and Cellular Therapy Series, 1: Enterobacterales Infection Prevention and Management after Hematopoietic Cell Transplantation
Satlin, M. J., Weissman, S. J., Carpenter, P. A., Seo, S. K., & Shelburne, S. A. (2021) · Transplantation and Cellular Therapy · doi:10.1016/j.jtct.2020.10.001 · Cited by 21 · see citing works
Antibacterial spectrum of cefiderocol
Cordero, D., Castillo-Polo, J. A., Ruíz-Garbajosa, P., & Cantón, R. (2022) · Revista Española de Quimioterapia · doi:10.37201/req/s02.03.2022 · Cited by 21 · see citing works
Enterobactin: A key player in bacterial iron acquisition and virulence and its implications for vaccine development and antimicrobial strategies
Amiri, M., Golchin, M., Jamshidian-Mojaver, M., Farzin, H., & Hajizadeh, A. (2025) · Virulence · doi:10.1080/21505594.2025.2563018 · Cited by 23 · see citing works
Rejuvenating the Activity of Usual Antibiotics on Resistant Gram-Negative Bacteria: Recent Issues and Perspectives
Tabcheh, J., Vergalli, J., Davin‐Regli, A., Ghanem, N., Pagès, J., Al-Bayssari, C., & Brunel, J. M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24021515 · Cited by 21 · see citing works
Evaluation of Variability in Interpretation of Disk Diffusion Testing for Cefiderocol Using Different Brands of Mueller–Hinton Agar
Potter, R. F., Wallace, M. A., Muenks, C. E., Alvarado, K., Yarbrough, M. L., & Burnham, C. D. (2023) · The Journal of Applied Laboratory Medicine · doi:10.1093/jalm/jfac131 · Cited by 20 · see citing works
Natural products in antibiotic development: is the success story over?
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Siderophore conjugation with cleavable linkers boosts the potency of RNA polymerase inhibitors against multidrug-resistant E. coli
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Ceftolozane/Tazobactam and Ceftazidime/Avibactam for Multidrug-Resistant Gram-Negative Infections in Immunocompetent Patients: A Single-Center Retrospective Study
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Cefiderocol as Salvage Therapy for Carbapenem-Resistant Klebsiella pneumoniae Sepsis in an Extremely Preterm Neonate
Bawankule, S., Nabar, N., Joshi, P., & Singhal, T. (2023) · The Indian Journal of Pediatrics · doi:10.1007/s12098-022-04468-7 · Cited by 16 · see citing works
Novel South African Rare Actinomycete Kribbella speibonae Strain SK5: A Prolific Producer of Hydroxamate Siderophores Including New Dehydroxylated Congeners
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A Novel Antibiotic Agent, Cefiderocol, for Multidrug-Resistant Gram-Negative Bacteria
Rahman, M. S., & Koh, Y. S. (2020) · Journal of Bacteriology and Virology · doi:10.4167/jbv.2020.50.4.218 · Cited by 16 · see citing works
1,2-Isoselenazol-3(2H)-one derivatives as NDM-1 inhibitors displaying synergistic antimicrobial effects with meropenem on NDM-1 producing clinical isolates
Yue, K., Chen, X., Wang, Z., Liu, W., Liu, C., Xu, X., Xing, Y., Chen, S., Li, X., & Wan, S. (2022) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2022.106153 · Cited by 15 · see citing works
Successful Use of Cefiderocol to Treat a Multidrug-resistant Stenotrophomonas maltophilia Ventilator-associated Pneumonia in an Extremely Preterm Neonate
Koirala, A., Krishnappa, B., Banh, C., Brandenburg, U., Findlay, M., & Williams, P. C. M. (2023) · The Pediatric Infectious Disease Journal · doi:10.1097/inf.0000000000004051 · Cited by 15 · see citing works
Cefiderocol treatment of Pseudomonas aeruginosa and extensively drug-resistant Acinetobacter baumannii retained spinal hardware infection causing reversible acute interstitial nephritis
Cipko, K., Gordon, A. K., Adhikari, S., & Koneçny, P. (2021) · International Journal of Infectious Diseases · doi:10.1016/j.ijid.2021.06.035 · Cited by 14 · see citing works
Synthesis and antimicrobial activity of an SO2-releasing siderophore conjugate
Black, C. M., Chu, A. J., Thomas, G. H., Routledge, A., & Duhme‐Klair, A. (2022) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2022.111875 · Cited by 14 · see citing works
Pharmacokinetic of Cefiderocol in Critically Ill Patients Receiving Renal Replacement Therapy: A Case Series
Pinna, S. M., Corcione, S., Nicolò, A. D., Montrucchio, G. G., Scabini, S., Vita, D., Benedetto, I. D., Lupia, T., Mula, J., Perri, G. D., et al. (2022) · Antibiotics · doi:10.3390/antibiotics11121830 · Cited by 14 · see citing works
The role of new antimicrobials for Gram-negative infections in daily clinical practice
Bassetti, M., Vena, A., Battaglini, D., Pelosi, P. P., & Giacobbe, D. R. (2020) · Current Opinion in Infectious Diseases · doi:10.1097/qco.0000000000000686 · Cited by 14 · see citing works
Susceptibility to new antibiotics and genetic characterisation of carbapenemase-producing Enterobacterales: low activity of cefiderocol against NDM-producing isolates
Faxén, L., Müller, V., Chatzopoulou, M., Lindsjö, O. K., Lagerbäck, P., Westmo, K., Åkerlund, A., Tängdén, T., & Fröding, I. (2025) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2025.107553 · Cited by 13 · see citing works
Urgent need for novel antibiotics in Republic of Korea to combat multidrug-resistant bacteria
Lee, H.-J., & Lee, D. (2022) · The Korean Journal of Internal Medicine · doi:10.3904/kjim.2021.527 · Cited by 13 · see citing works
Specificity and mechanism of TonB-dependent ferric catecholate uptake by Fiu
Yang, T., Zou, Y., Ng, H. L., Kumar, A., Newton, S. M., & Klebba, P. E. (2024) · Frontiers in Microbiology · doi:10.3389/fmicb.2024.1355253 · Cited by 11 · see citing works
“The understanding of EcoFiu and its orthologs will aid the further development of siderophore antibiotics (Lasko and Nicolau, 2020; Morris et al., 2020; Wu et al., 2020; Mabayoje et al., 2021) such as FDC.”
Background
Cefiderocol Dosing for Patients Receiving Continuous Renal Replacement Therapy
Wei, X., Naseer, S., Weinstein, E. A., Iarikov, D. E., Nambiar, S., Reynolds, K. S., & Jang, S. H. (2022) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.2703 · Cited by 12 · see citing works
Physicochemical stability of cefiderocol, a novel siderophore cephalosporin, in syringes at 62.5 mg/mL for continuous administration in intensive care units
Loeuille, G., Vigneron, J., D’Huart, É., Charmillon, A., & Demoré, B. (2021) · European Journal of Hospital Pharmacy · doi:10.1136/ejhpharm-2021-002935 · Cited by 13 · see citing works
Successful prolonged treatment of a carbapenem‐resistant Acinetobacter baumannii hip infection with cefiderocol: A case report
Rosé, L., Lai, L., & Byrne, D. D. (2022) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1002/phar.2660 · Cited by 12 · see citing works
The primary pharmacology of ceftazidime/avibactam: resistancein vitro
Nichols, W. W., Lahiri, S. D., Bradford, P. A., & Stone, G. G. (2023) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkac449 · Cited by 11 · see citing works
First report of a blaNDM-producing extensively drug resistant Klebsiella pneumoniae ST437 in Italy
Ranieri, S. C., Fabbrizi, V., Amario, A. M. D., Frascella, M. G., Biase, V. D., Francesco, C. D., Sante, S. D., Berardis, L. D., Martinis, M. D., Partenza, M., et al. (2024) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2024.1426817 · Cited by 11 · see citing works
Comprehensive Insights into Cephalosporins: Spectrum, Generations, and Clinical Applications
Nayeem, A., Ankul Singh, S., Vellapandian, C., Singh, S., Elossaily, G. M., & Prajapati, B. G. (2024) · Current Drug Therapy · doi:10.2174/0115748855339119241204071146 · Cited by 11 · see citing works
Intravenous cefiderocol for neurosurgical meningitis from an extensively drug-resistant New-Delhi metallo-β-lactamase-producing Pseudomonas aeruginosa strain
Stevenson, D. R., Cherian, B. P., Kinzig, M., Sörgel, F., & Wareham, D. W. (2022) · Journal of Global Antimicrobial Resistance · doi:10.1016/j.jgar.2022.11.019 · Cited by 11 · see citing works
What is an ideal antibiotic and what does this mean for future drug discovery and design?
Sandiford, S. K. (2023) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2023.2198701 · Cited by 11 · see citing works
Cefiderocol is Not Sequestered in an Ex Vivo Extracorporeal Membrane Oxygenation (ECMO) Circuit
Berry, A. V., Conelius, A., Gluck, J., Nicolau, D. P., & Kuti, J. L. (2023) · European Journal of Drug Metabolism and Pharmacokinetics · doi:10.1007/s13318-023-00840-w · Cited by 11 · see citing works
Does Cefiderocol Have a Potential Role in Cystic Fibrosis Pulmonary Exacerbation Management?
Gavioli, E. M., Guardado, N., Haniff, F., Deiab, N., & Vider, E. (2021) · Microbial Drug Resistance · doi:10.1089/mdr.2020.0602 · Cited by 11 · see citing works
Natural and engineered precision antibiotics in the context of resistance
Johnston, C. W., & Badran, A. H. (2022) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2022.102160 · Cited by 11 · see citing works
Cefiderocol: A Comprehensive Review of Chemistry, Mechanisms of Resistance, and Clinical Applications in the Era of Multidrug Resistance
Gourabi, M. J. R., Khanbabaei, B., Saki, Y. Y., Nikoo, A., Kargar, M., Hashemi, A., & Sharahi, J. Y. (2025) · Current Microbiology · doi:10.1007/s00284-025-04597-0 · Cited by 10 · see citing works
Emerging green synthetic routes for thiazole and its derivatives: Current perspectives
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Cefiderocol: A Novel Siderophore Cephalosporin against Multidrug‐Resistant Gram‐Negative Pathogens
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Cefiderocol: A Siderophore Cephalosporin with Activity Against Carbapenem-Resistant and Multidrug-Resistant Gram-Negative Bacilli
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Cefiderocol: a first and novel class of siderophore cephalosporin for Carbapenem-resistant Gram-negative infection
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Authors: Wu, J. Y., Srinivas, P., & Pogue, J. M.
Affiliations: Cleveland Clinic (US)
University of Michigan (US)
Corresponding author: Wu, Janet Y.
ORCID: Wu, Janet Y.
Srinivas, Pavithra
Pogue, Jason M.
Venue: Infectious Diseases and Therapy
Publisher: Springer Science and Business Media LLC
Published: 2020-02-18
Volume: 9
Issue: 1
Pages: 17-40
ISSN: 2193-6382 (ISSN-L)
2193-8229
DOI: 10.1007/s40121-020-00286-6
PMC: PMC7054475
OpenAlex: W3008901682
Cited by: 195
References: 45
Citations by year: 2026: 25 · 2025: 25 · 2024: 25 · 2023: 37 · 2022: 36 · 2021: 28 · 2020: 18
FWCI: 2.10
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc
creativecommons.org/licenses/by-nc/4.0 (tdm)
creativecommons.org/licenses/by-nc/4.0 (vor)
Locations: Infectious Diseases and Therapy (publishedVersion, cc-by-nc)
PubMed Central (publishedVersion, cc-by-nc)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
Health Sciences › Medicine › Pharmacology › Antibiotics Pharmacokinetics and Efficacy
Health Sciences › Medicine › Epidemiology › Urinary Tract Infections Management
Keywords: cefiderocol, siderophore cephalosporin, multidrug-resistant Gram-negative bacteria, carbapenem resistance, extended-spectrum beta-lactamase, carbapenemase, mechanism of action, pharmacokinetics, pharmacodynamics, complicated urinary tract infection, nosocomial pneumonia, Enterobacterales, drug safety and efficacy

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Cefiderocol: A Novel Agent for the Management of Multidrug-Resistant Gram-Negative Organisms

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