新型铁载体偶联头孢菌素——Cefiderocol

doi:10.12092/j.issn.1009-2501.2026.01.015

摘要/Abstract

摘要：

Cefiderocol为全球首个铁载体偶联头孢菌素，凭借独特的作用机制和不依赖β-内酰胺酶抑制剂的高稳定性，Cefiderocol展现了对多重耐药革兰氏阴性菌或碳青霉烯类耐药革兰氏阴性菌的强大活性，是当前临床上治疗此类病原体的重要选择。本文对其作用机制、抗菌活性、药动学/药效学、临床研究、安全性及耐药机制等方面进行综述，以期为临床抗耐药革兰氏阴性菌感染提供参考。

关键词: Cefiderocol, 铁载体, β-内酰胺类, 多重耐药革兰氏阴性菌, 碳青霉烯类耐药革兰氏阴性菌

Abstract:

Cefiderocol is the first-in-class siderophore cephalosporin. With its unique mechanism of action and high stability independent of β-lactamase inhibitor, Cefiderocol exhibits potent activity against multidrug-resistant gram-negative bacilli or carbapenem-resistant gram-negative bacilli, making it an important choice for the treatment of such pathogens in current clinical practice. This article provides a review of its mechanism of action, antibacterial activity, pharmacokinetics/pharmacodynamics, clinical research, safety, and resistance mechanisms, in order to provide reference for clinical anti drug-resistance gram-negative bacilli infections.

Key words: cefiderocol, siderophore, β-lactams, multidrug-resistant gram-negative bacilli, carbapenem-resistant gram-negative bacilli

中图分类号:

R969

赵世峰, 曹恒斌, 汪荣华, 袁玉梅. 新型铁载体偶联头孢菌素——Cefiderocol[J]. 中国临床药理学与治疗学, 2026, 31(1): 133-144.

Shifeng ZHAO, Hengbin CAO, Ronghua WANG, Yumei YUAN. Cefiderocol: a novel siderophore cephalosporin[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(1): 133-144.

图/表 6

参考文献 57

1	World Health Organization. WHO Bacterial Priority Pathogens List, 2024: bacterial pathogens of public health importance to guide research, development and strategies to prevent and control antimicrobial resistance [EB/OL]. (2024-05-17) [2024/11/11]. https://www.who.int/publications/i/item/9789240093461.
2	GBD 2021 Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance 1990-2021: a systematic analysis with forecasts to 2050[J]. Lancet, 2024, 404 (10459): 1199- 1226.
3	姜道利, 丑晓华, 刘志东, 等. 头孢他啶阿维巴坦治疗多重耐药革兰阴性菌感染的真实世界研究[J]. 中国临床药理学与治疗学, 2023, 28 (9): 1008- 1017.
4	查娴, 陈大宇, 邵华. 替加环素和多黏菌素B治疗重症患者耐碳青霉烯类肠杆菌科细菌肺炎的疗效和安全性分析[J]. 中国临床药理学与治疗学, 2024, 29 (2): 154- 163. doi: 10.12092/j.issn.1009-2501.2024.02.005
5	Jean SS, Harnod D, Hsueh PR. Global threat of carbapenem-resistant gram-negative bacteria [J]. Front Cell Infect Microbiol, 2022, 15, 12: 823684.
6	Tompkins K, van Duin D. Treatment for carbapenem-resistant enterobacterales infections: recent advances and future directions[J]. Eur J Clin Microbiol Infect Dis, 2021, 40 (10): 2053- 2068. doi: 10.1007/s10096-021-04296-1
7	Zeng M, Xia J, Zong Z, et al. Society of Bacterial Infection and Resistance of Chinese Medical Association; Expert Committee on Clinical Use of Antimicrobial Agents and Evaluation of Antimicrobial Resistance of the National Health Commission; Infectious Diseases Society of Chinese Medical Education Association. Guidelines for the diagnosis, treatment, prevention and control of infections caused by carbapenem-resistant gram-negative bacilli[J]. J Microbiol Immunol Infect, 2023, 56 (4): 653- 671.
8	Shionogi Inc. Cefiderocol FDA briefing document [EB/OL]. (2021-11-12) [2024/11/11]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/209445s004lbl.pdf.
9	European Medicine Company. Fetcroja [EB/OL]. (2020-04-29) [2024/11/11]. https://www.ema.europa.eu/en/medicines/human/EPAR/fetcroja#overview-section.
10	Kramer J, Özkaya Ö, Kümmerli R. Bacterial siderophores in community and host interactions[J]. Nat Rev Microbiol, 2020, 18 (3): 152- 163.
11	Bilitewski U, Blodgett JAV, Duhme-Klair AK, et al. Chemical and biological aspects of nutritional immunity-perspectives for new anti-infectives that target iron uptake systems[J]. Angew Chem Int Ed Engl, 2017, 56 (46): 14360- 14382.
12	Aoki T, Yoshizawa H, Yamawaki K, et al. Cefiderocol (S-649266), a new siderophore cephalosporin exhibiting potent activities against Pseudomonas aeruginosa and other gram-negative pathogens including multi-drug resistant bacteria: structure activity relationship[J]. Eur J Med Chem, 2018, 15 (155): 847- 868.
13	Zhanel GG, Golden AR, Zelenitsky S, et al. Cefiderocol: A siderophore cephalosporin with activity against carbapenem-resistant and multidrug-resistant gram-negative bacilli[J]. Drugs, 2019, 79 (3): 271- 289.
14	Ito A, Sato T, Ota M, et al. In vitro antibacterial properties of cefiderocol, a novel siderophore cephalosporin, against gram-negative bacteria[J]. Antimicrob Agents Chemother, 2017, 62 (1): e01454- 17.
15	Ito A, Nishikawa T, Matsumoto S, et al. Siderophore cephalosporin cefiderocol utilizes ferric iron transporter systems for antibacterial activity against pseudomonas aeruginosa[J]. Antimicrob Agents Chemother, 2016, 60 (12): 7396- 7401.
16	Yamano Y. In vitro activity of cefiderocol against a broad range of clinically important gram-negative bacteria[J]. Clin Infect Dis, 2019, 69 (Suppl7): S544- S551.
17	Clinical & Laboratory Standards Institute. AST News Update June 2023: The Latest on Testing Cefiderocol [EB/OL]. (2023-6-16) [2024/11/24]. https://clsi.org/about/blog/ast-news-update-june-2023-the-latest-on-testing-cefiderocol.
18	The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version14.0, 2024 [EB/OL]. (2024-1-1) [2024/11/26]. https://www.eucast.org/clinical_breakpoints.
19	Food and Drug Administration. Cefiderocol injection [EB/OL]. (2024-11-12) [2024/11/27]. https://www.fda.gov/drugs/development-resources/cefiderocol-injection.
20	Karlowsky JA, Hackel MA, Takemura M, et al. In vitro susceptibility of gram-negative pathogens to cefiderocol in five consecutive annual multinational SIDERO-WT surveillance studies, 2014 to 2019[J]. Antimicrob Agents Chemother, 2022, 66 (2): e0199021.
21	Wise MG, Karlowsky JA, Hackel MA, et al. In vitro activity of cefiderocol against meropenem-nonsusceptible gram-negative bacilli with defined β-lactamase carriage: SIDERO-WT surveillance studies, 2014-2019[J]. Microb Drug Resist, 2023, 29 (8): 360- 370.
22	Liu X, Lei T, Yang Y, et al. Structural basis of PER-1-mediated cefiderocol resistance and synergistic inhibition of PER-1 by cefiderocol in combination with avibactam or durlobactam in acinetobacter baumannii [J]. Antimicrob Agents Chemother, 2022, 20, 66(12): e0082822.
23	Saisho Y, Katsube T, White S, et al. Pharmacokinetics, safety, and tolerability of cefiderocol, a novel siderophore cephalosporin for gram-negative bacteria, in healthy subjects[J]. Antimicrob Agents Chemother, 2018, 62 (3): e02163- 17.
24	Miyazaki S, Katsube T, Shen H, et al. Metabolism, excretion, and pharmacokinetics of [¹⁴C]-cefiderocol (S-649266), a siderophore cephalosporin, in healthy subjects following intravenous administration[J]. J Clin Pharmacol, 2019, 59 (7): 958- 967.
25	Katsube T, Echols R, Arjona Ferreira JC, et al. Cefiderocol, a siderophore cephalosporin for gram-negative bacterial infections: pharmacokinetics and safety in subjects with renal impairment[J]. J Clin Pharmacol, 2017, 57 (5): 584- 591.
26	Katsube T, Wajima T, Ishibashi T, et al. Pharmacokinetic/pharmacodynamic modeling and simulation of cefiderocol, a parenteral siderophore cephalosporin, for dose adjustment based on renal function [J]. Antimicrob Agents Chemother, 2016, 27, 61(1): e01381-16.
27	Katsube T, Saisho Y, Shimada J, et al. Intrapulmonary pharmacokinetics of cefiderocol, a novel siderophore cephalosporin, in healthy adult subjects[J]. J Antimicrob Chemother, 2019, 74 (7): 1971- 1974.
28	Kawaguchi N, Katsube T, Echols R, et al. Intrapulmonary pharmacokinetic modeling and simulation of cefiderocol, a parenteral siderophore cephalosporin, in patients with pneumonia and healthy subjects[J]. J Clin Pharmacol, 2022, 62 (5): 670- 680.
29	Bradley JS, Orchiston E, Portsmouth S, et al. Pharmacokinetics, safety and tolerability of single-dose or multiple-dose cefiderocol in hospitalized pediatric patients three months to less than eighteen years old with infections treated with standard-of-care antibiotics in the PEDI-CEFI phase 2 study[J]. Pediatr Infect Dis J, 2025, 44 (2): 136- 142.
30	Kidd JM, Abdelraouf K, Nicolau DP. Development of neutropenic murine models of iron overload and depletion to study the efficacy of siderophore-antibiotic conjugates [J]. Antimicrob Agents Chemother, 2019, 20, 64(1): e01961-19.
31	Matsumoto S, Singley CM, Hoover J, et al. Efficacy of cefiderocol against carbapenem-resistant gram-negative bacilli in immunocompetent-rat respiratory tract infection models recreating human plasma pharmacokinetics [J]. Antimicrob Agents Chemother, 2017, 24, 61(9): e00700-17.
32	Goutelle S, Ammour N, Ferry T, et al. Optimal dosage regimens of cefiderocol administered by short, prolonged or continuous infusion: a PK/PD simulation study[J]. J Antimicrob Chemother, 2024, 23, dkae464.
33	Portsmouth S, van Veenhuyzen D, Echols R, et al. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial[J]. Lancet Infect Dis, 2018, 18 (12): 1319- 1328.
34	Wunderink RG, Matsunaga Y, Ariyasu M, et al. Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial[J]. Lancet Infect Dis, 2021, 21 (2): 213- 225.
35	Bassetti M, Ariyasu M, Binkowitz B, et al. Designing A pathogen-focused study to address the high unmet medical need represented by carbapenem-resistant gram-negative pathogens-the international, multicenter, randomized, open-Label, phase 3 CREDIBLE-CR study [J]. Infect Drug Resist, 2019, 12: 3607-3623.
36	Bassetti M, Echols R, Matsunaga Y, et al. 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[J]. Lancet Infect Dis, 2021, 21 (2): 226- 240.
37	Paterson DL, Kinoshita M, Baba T, et al. Outcomes with cefiderocol treatment in patients with bacteraemia enrolled into prospective phase 2 and phase 3 randomised clinical studies[J]. Infect Dis Ther, 2022, 11 (2): 853- 870.
38	Timsit JF, Paul M, Shields RK, et al. Cefiderocol for the treatment of infections due to metallo-B-lactamase-producing pathogens in the CREDIBLE-CR and APEKS-NP phase 3 randomized studies[J]. Clin Infect Dis, 2022, 75 (6): 1081- 1084.
39	Sanabria C, Migoya E, Mason JW, et al. Effect of cefiderocol, a siderophore cephalosporin, on QT/QTc interval in healthy adult subjects [J]. Clin Ther, 2019, 41(9): 1724-1736. e4.
40	Katsube T, Miyazaki S, Narukawa Y, et al. Drug-drug interaction of cefiderocol, a siderophore cephalosporin, via human drug transporters[J]. Eur J Clin Pharmacol, 2018, 74 (7): 931- 938.
41	Wang L, Zhu J, Chen L, et al. Cefiderocol: clinical application and emergence of resistance[J]. Drug Resist Updat, 2024, 72, 101034.
42	Iovleva A, Fowler VG Jr, Doi Y. Treatment approaches for carbapenem-resistant acinetobacter baumannii infections[J]. Drugs, 2025, 85 (1): 21- 40.
43	Risco-Risco C, Henriquez-Camacho C, Herrera-Rueda M, et al. Cefiderocol versus best available therapy in the treatment of critically ill patients with severe infections due to resistant gram-negative bacteria: a systematic review and meta-analysis [J]. Antibiotics (Basel), 2024, 5, 13(11): 1048.
44	Karakonstantis S, Rousaki M, Kritsotakis EI. Cefiderocol: systematic review of mechanisms of resistance, heteroresistance and in vivo emergence of resistance [J]. Antibiotics (Basel), 2022, 27, 11(6): 723.
45	Kohira N, Hackel MA, Oota M, et al. In vitro antibacterial activities of cefiderocol against Gram-negative clinical strains isolated from China in 2020[J]. J Glob Antimicrob Resist, 2023, 32, 181- 186.
46	Zhao J, Pu D, Li Z, et al. In vitro activity of cefiderocol, a siderophore cephalosporin, against carbapenem-resistant hypervirulent Klebsiella pneumoniae in China [J]. Antimicrob Agents Chemother, 2023, 67(12): e0073523.
47	Liu X, Li Z, Zhang F, et al. In vitro antimicrobial activity of six novel β-lactam and β-lactamase inhibitor combinations and cefiderocol against NDM-producing Enterobacterales in China [J]. Int J Antimicrob Agents, 2024, 65(2): 107407.
48	Bianco G, Boattini M, Cricca M, et al. Updates on the activity, efficacy and emerging mechanisms of resistance to cefiderocol [J]. Curr Issues Mol Biol, 2024, 46(12): 14132-14153.
49	Galdino ACM, Vaillancourt M, Celedonio D, et al. Siderophores promote cooperative interspecies and intraspecies cross-protection against antibiotics in vitro[J]. Nat Microbiol, 2024, 9 (3): 631- 646.
50	Hobson CA, Cointe A, Jacquier H, et al. Cross-resistance to cefiderocol and ceftazidime-avibactam in KPC β-lactamase mutants and the inoculum effect [J]. Clin Microbiol Infect, 2021, 27(8): 1172. e7-1172. e10.
51	Tamma PD, Heil EL, Justo JA, et al. Infectious diseases society of America 2024 guidance on the treatment of antimicrobial-resistant gram-negative infections [J]. Clin Infect Dis, 2024: ciae403.
52	Wright H, Harris PNA, Chatfield MD, et al. Investigator-driven randomised controlled trial of cefiderocol versus standard therapy for healthcare-associated and hospital-acquired gram-negative bloodstream infection: Study protocol (the GAME CHANGER trial): study protocol for an open-label, randomised controlled trial[J]. Trials, 2021, 22 (1): 889.
53	Onorato L, de Luca I, Monari C, et al. Cefiderocol either in monotherapy or combination versus best available therapy in the treatment of carbapenem-resistant acinetobacter baumannii infections: a systematic review and meta-analysis[J]. J Infect, 2024, 88 (3): 106113.
54	Karakonstantis S, Rousaki M, Vassilopoulou L, et al. Global prevalence of cefiderocol non-susceptibility in Enterobacterales, Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia: a systematic review and meta-analysis[J]. Clin Microbiol Infect, 2024, 30 (2): 178- 188.
55	Lewis RE, Palombo M, Diani E, et al. Synergistic activity of cefiderocol in combination with avibactam, sulbactam or tazobactam against carbapenem-resistant gram-negative bacteria[J]. Cells, 2024, 13 (16): 1315.
56	Clinicaltrials. gov. A DDI study to investigate PK and safety of cefiderocol in combination with xeruborbactam in healthy adult participants [EB/OL]. (2024-9-19) [2025/1/11]. https://clinicaltrials.gov/study/NCT06547554?cond=cefiderocol&page=2&rank=17.
57	Chinese Clinical Trial Registry. A multicenter, randomized, double-blind clinical study of cefiderocol for the treatment of complicated urinary tract infections caused by a gram-negative pathogen in Chinese adults in comparison with intravenous imipenem/cilastatin [EB/OL]. (2024-10-8) [2025/2/2]. https://www.chictr.org.cn/showprojEN.html?proj=222918.

Organisms	MIC breakpoint (μg/mL)
	CLSI			FDA			EUCAST
	S	I	R	S	I	R	S	R
Enterobacterales*	≤4	8	≥16	≤4	8	≥16	≤2	>2
Pseudomonas aeruginosa	≤4	8	≥16	≤1	2	≥4	≤2	>2
Acinetobacter baumannii	≤4	8	≥16	≤1	2	≥4	IE	IE
Stenotrophomonas maltophilia	≤1	-	-	-	-	-	IE	IE

Organisms	MIC breakpoint (μg/mL)
	CLSI			FDA			EUCAST
	S	I	R	S	I	R	S	R
Enterobacterales*	≤4	8	≥16	≤4	8	≥16	≤2	>2
Pseudomonas aeruginosa	≤4	8	≥16	≤1	2	≥4	≤2	>2
Acinetobacter baumannii	≤4	8	≥16	≤1	2	≥4	IE	IE
Stenotrophomonas maltophilia	≤1	-	-	-	-	-	IE	IE

Organism (no. of isolates)	Antimicrobial agents	MIC (μg/mL)			CLSI MIC interpretation*
Organism (no. of isolates)	Antimicrobial agents	MIC₅₀	MIC₉₀	Range	% S	% I	% R
Enterobacterales (31896)	Cefiderocol	0.12	1	≤0.002 to >256	99.8	0.2	0.1
	Cefepime	≤0.12	16	≤0.06 to >64	85.9	3.0	11.2
	Ceftazidime-avibactam	0.12	0.5	≤0.03 to >64	99.2	NA	0.8
	Ceftolozane-tazobactam	0.25	2	≤0.06 to >64	91.7	1.8	6.6
	Ciprofloxacin	≤0.12	>8	≤0.06 to >8	74.5	3.2	22.3
	Meropenem	≤0.06	0.12	≤0.06 to >64	96.8	0.4	2.9
P. aeruginosa (7700)	Cefiderocol	0.12	0.5	≤0.002 to 8	99.9	0.1	0
	Cefepime	4	16	≤0.06 to >64	82.9	9.1	8.0
	Ceftazidime-avibactam	2	8	≤0.03 to >64	93.8	NA	6.2
	Ceftolozane-tazobactam	0.5	2	≤0.06 to >64	94.0	1.0	5.0
	Ciprofloxacin	0.25	>8	≤0.06 to >8	70.8	6.5	22.7
	Meropenem	0.5	16	≤0.06 to >64	77.2	5.8	17.0
A. baumannii complex (5225)	Cefiderocol	0.12	1	≤0.002 to >256	96.0	1.3	2.7
	Cefepime	8	>64	≤0.06 to >64	52.0	9.5	38.5
	Ceftazidime-avibactam	16	>64	≤0.06 to >64	NA	NA	NA
	Ceftolozane-tazobactam	8	>64	≤0.06 to >64	NA	NA	NA
	Ciprofloxacin	>8	>8	≤0.12 to >8	40.0	0.7	59.3
	Meropenem	16	>64	≤0.06 to >64	46.2	1.3	52.5

Organism (no. of isolates)	Antimicrobial agents	MIC (μg/mL)			CLSI MIC interpretation*
Organism (no. of isolates)	Antimicrobial agents	MIC₅₀	MIC₉₀	Range	% S	% I	% R
Enterobacterales (31896)	Cefiderocol	0.12	1	≤0.002 to >256	99.8	0.2	0.1
	Cefepime	≤0.12	16	≤0.06 to >64	85.9	3.0	11.2
	Ceftazidime-avibactam	0.12	0.5	≤0.03 to >64	99.2	NA	0.8
	Ceftolozane-tazobactam	0.25	2	≤0.06 to >64	91.7	1.8	6.6
	Ciprofloxacin	≤0.12	>8	≤0.06 to >8	74.5	3.2	22.3
	Meropenem	≤0.06	0.12	≤0.06 to >64	96.8	0.4	2.9
P. aeruginosa (7700)	Cefiderocol	0.12	0.5	≤0.002 to 8	99.9	0.1	0
	Cefepime	4	16	≤0.06 to >64	82.9	9.1	8.0
	Ceftazidime-avibactam	2	8	≤0.03 to >64	93.8	NA	6.2
	Ceftolozane-tazobactam	0.5	2	≤0.06 to >64	94.0	1.0	5.0
	Ciprofloxacin	0.25	>8	≤0.06 to >8	70.8	6.5	22.7
	Meropenem	0.5	16	≤0.06 to >64	77.2	5.8	17.0
A. baumannii complex (5225)	Cefiderocol	0.12	1	≤0.002 to >256	96.0	1.3	2.7
	Cefepime	8	>64	≤0.06 to >64	52.0	9.5	38.5
	Ceftazidime-avibactam	16	>64	≤0.06 to >64	NA	NA	NA
	Ceftolozane-tazobactam	8	>64	≤0.06 to >64	NA	NA	NA
	Ciprofloxacin	>8	>8	≤0.12 to >8	40.0	0.7	59.3
	Meropenem	16	>64	≤0.06 to >64	46.2	1.3	52.5

Organism	Genotype (no. of isolates)	MIC (μg/mL)			CLSI MIC interpretation
Organism	Genotype (no. of isolates)	MIC₅₀	MIC₉₀	Range	% S	% I	% R
Enterobacterales	MBL (211)^a	2	4	0.06 to 128	91.5	5.7	2.8
	VIM (113)^a	1	4	0.12 to 16	96.5	1.8	1.8
	NDM (96)^a	2	8	0.12 to 128	85.4	10.4	4.2
	KPC (382)^b	1	4	0.015 to 8	98.4	1.6	0
	OXA-48 group (256)^c	0.5	4	0.015 to 16	97.3	2.3	0.4
	Carbapenemase negative (154)^d	0.5	2	0.008 to 8	98.7	1.3	0
P. aeruginosa	MBL (227)^a	0.25	2	0.008 to 4	100	0	0
	VIM (200)^a	0.25	1	0.008 to 4	100	0	0
	IMP (25)^a	2	4	0.12 to 4	100	0	0
	GES (carbapenemase) (34)^e	0.25	1	0.06 to 1	100	0	0
	Carbapenemase negative (1497)^d	0.25	1	≤0.002 to 8	99.8	0.2	0
A. baumannii complex	MBL (25)^a	4	8	0.12 to >64	60.0	32.0	8.0
	OXA-23 group (1783)^f	0.25	2	≤0.002 to >256	95.6	1.9	2.6
	OXA-24 group (570)^f	0.5	8	0.004 to >256	89.5	1.9	8.6
	OXA-58 group (69)^f	1	1	0.06 to 4	100	0	0
	OXA-23and24 group (19)^f	0.5	2	0.06 to 2	100	0	0
	OXA-23and58 group (34)^f	0.25	0.5	0.06 to 0.5	100	0	0
	PER/VEB (103)^g	128	>256	0.12 to >256	15.5	10.7	73.8
	Carbapenemase negative (309)^d	0.25	2	0.008 to >256	95.5	2.6	1.9