Cefiderocol
Cefiderocol is a novel siderophore cephalosporin antibiotic designed to combat multidrug-resistant Gram-negative bacterial infections, particularly those caused by carbapenem-resistant pathogens such as Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacterales.[1] It functions by mimicking iron-chelating siderophores, enabling active transport across the bacterial outer membrane via iron uptake systems, where it then binds to penicillin-binding proteins to inhibit cell wall synthesis and induce bacterial death.[2] This unique mechanism confers stability against many β-lactamases, including metallo-β-lactamases like NDM and VIM, broadening its efficacy against pathogens resistant to conventional antibiotics.[1] Approved by the U.S. Food and Drug Administration (FDA) in November 2019 under the brand name Fetroja for intravenous use in adults, cefiderocol was initially indicated for complicated urinary tract infections (cUTIs), including pyelonephritis.[3] In September 2020, the FDA expanded its approval to include hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) caused by susceptible Gram-negative bacteria.[2] The European Medicines Agency (EMA) granted marketing authorization in April 2020 for Fetcroja to treat aerobic Gram-negative infections in adults with limited or no alternative therapeutic options, aligning closely with FDA indications.[4] In 2021, it was added to the World Health Organization's Model List of Essential Medicines as a reserve group antibiotic for priority carbapenem-resistant pathogens.[5] Clinical trials, such as APEKS-cUTI and APEKS-NP, demonstrated non-inferiority to comparators like imipenem-cilastatin for cUTIs and pneumonia, respectively, though higher all-cause mortality was observed in some patients with carbapenem-resistant infections outside approved uses.[1] Administered as a 2-gram intravenous infusion over three hours every eight hours (with adjustments for renal impairment), cefiderocol exhibits a favorable pharmacokinetic profile, achieving high plasma concentrations and stability in human plasma with low to moderate protein binding (approximately 40-60%).[2] It is primarily eliminated renally, necessitating dose reductions in patients with creatinine clearance below 60 mL/min.[4] Key adverse effects include hypersensitivity reactions (contraindicated in those with β-lactam allergies), Clostridioides difficile-associated diarrhea, and potential for seizures or elevated mortality in off-label use against resistant strains.[2] Ongoing surveillance highlights emerging resistance mechanisms, such as mutations in iron transport genes, underscoring the need for susceptibility testing and stewardship to preserve its utility.[1]Clinical Use
Indications and Efficacy
Cefiderocol is approved for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis, and hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP) in adults aged 18 years or older when limited or no alternative treatment options are available.[2] It targets susceptible Gram-negative pathogens, including Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii complex, and Enterobacter cloacae complex, particularly those resistant to other antibiotics.[2] The efficacy of cefiderocol was established in two pivotal phase 3 trials. In the APEKS-cUTI trial (2019), cefiderocol demonstrated non-inferiority to imipenem-cilastatin for cUTIs, with a primary composite endpoint of clinical cure and microbiological eradication at test-of-cure achieved in 72.6% of patients in the microbiological intent-to-treat population compared to 54.6% in the comparator group; clinical cure rates were 89.7% versus 84.9%, respectively.[6][7] In the APEKS-NP trial (2020), cefiderocol was non-inferior to high-dose extended-infusion meropenem for HABP/VABP, meeting the primary endpoint of all-cause mortality at day 14 (12.4% versus 11.6%); clinical cure rates at test-of-cure were similar at 64.8% for cefiderocol and 66.7% for meropenem. However, subgroup analysis showed higher 28-day mortality (37.5% vs. 21.4%) and lower clinical cure rates (50% vs. 57.1%) in patients with Acinetobacter baumannii infections.[8][9] A separate trial (CREDIBLE-CR, 2021) for serious carbapenem-resistant infections reported increased all-cause mortality with cefiderocol (33.7% vs. 20.4% at 49 days vs. best available therapy), particularly in Acinetobacter cases and those with nosocomial pneumonia or bloodstream infections; the FDA warns to monitor clinical response closely.[10][11] Real-world studies from 2024-2025 have shown improved outcomes with early use of cefiderocol in multidrug-resistant infections among seriously ill patients, with clinical response or cure rates ranging from 70% to 80% overall, and higher rates (up to 73.7%) when administered empirically before pathogen identification.[12][13] Heteroresistance to cefiderocol has been observed in some A. baumannii and P. aeruginosa isolates, potentially contributing to reduced efficacy and higher mortality in certain cases, particularly in carbapenem-resistant strains.[14][15]Dosage and Administration
Cefiderocol is administered intravenously as a 2 g dose every 8 hours in patients with normal renal function (creatinine clearance [CrCl] of 60–119 mL/min), infused over 3 hours.[2] For patients with augmented renal clearance (CrCl ≥120 mL/min), the dose is increased to 2 g every 6 hours to maintain efficacy.[4] Dosage adjustments are required for renal impairment to prevent accumulation: 1.5 g every 8 hours for CrCl 30–59 mL/min; 1 g every 8 hours for CrCl 15–29 mL/min; and 0.75 g every 12 hours for CrCl <15 mL/min or end-stage renal disease, with the dose administered after hemodialysis if applicable.[2] In patients receiving continuous renal replacement therapy (CRRT), dosing varies by effluent rate: 1.5 g every 12 hours for ≤2 L/hour; 2 g every 12 hours for 2.1–3 L/hour; 1.5 g every 8 hours for 3.1–4 L/hour; and 2 g every 8 hours for >4 L/hour.[2] Renal function should be monitored regularly, with CrCl estimated using the Cockcroft-Gault formula, and doses adjusted accordingly.[4] For preparation, each 1 g vial is reconstituted with 10 mL of 0.9% sodium chloride injection or 5% dextrose injection, gently shaken to dissolve, and further diluted in 100 mL of the same compatible diluent to achieve the required concentration.[2] The solution is stable for 6 hours at room temperature or 24 hours under refrigeration (2–8°C) after dilution, followed by an additional 6 hours at room temperature.[4] Cefiderocol is compatible only with 0.9% sodium chloride or 5% dextrose for infusion and should not be mixed with other medications in the same line; flush intravenous lines between administrations of different drugs.[2] In critically ill patients, continuous infusion (e.g., 4 g over 24 hours) has been used in select cases with continuous venovenous hemofiltration to optimize pharmacokinetics, though this is not standard and requires individualized assessment.[16] The typical duration of therapy is 7–14 days, tailored to the infection site and clinical response; for hospital-acquired or ventilator-associated pneumonia, treatment may extend up to 21 days if necessary.[4] There is no oral formulation available, limiting use to intravenous administration.[2] Therapeutic drug monitoring is recommended in special populations such as those with obesity or augmented renal clearance to ensure adequate exposure, particularly given variability in pharmacokinetics in critically ill patients.[17]Safety Profile
Adverse Effects
Cefiderocol is generally well-tolerated, with most adverse effects being mild to moderate in clinical trials. In the APEKS-cUTI trial for complicated urinary tract infections, the most common adverse reactions (occurring in ≥2% of patients) included diarrhea (4%), infusion site reactions (4%), constipation (3%), rash (3%), nausea (2%), and elevated liver enzymes (2%).[2] In the APEKS-NP trial for hospital-acquired and ventilator-associated pneumonia, higher incidences were observed for elevated liver enzymes (16%), hypokalemia (11%), and diarrhea (9%), reflecting the more critically ill patient population.[2] Infusion site reactions, such as phlebitis, occurred in approximately 4-7% of patients across trials, often related to intravenous administration.[2] Serious adverse effects are less frequent but can include hypersensitivity reactions, such as rash or anaphylaxis, reported in up to 1-2% of patients in clinical studies, consistent with cephalosporin class risks.[2] Clostridioides difficile-associated diarrhea has been noted as a potential risk, though specific incidence rates were low (<1%) in trials and align with broader antibiotic use.[2] Seizures and other central nervous system effects are rare (<1%), warranting neurological evaluation if they occur.[2] Hypokalemia, observed in 11% of pneumonia trial participants, may require monitoring in at-risk patients.[2] In the CREDIBLE-CR trial for carbapenem-resistant infections, all-cause mortality at 28 days was higher in the cefiderocol arm (34% overall, 34/101) compared to best available therapy (18%, 9/49), with numerically higher mortality particularly in patients with Acinetobacter baumannii infections (34.6%, 9/26 per FDA analysis of the subgroup), but this difference was attributed to underlying disease severity rather than a direct causal link to the drug.[18][2] Post-marketing surveillance through 2024-2025 has identified additional concerns, including renal adverse events such as acute kidney injury and tubulointerstitial nephritis, as well as emerging bacterial resistance and superinfections like candidiasis, based on FDA Adverse Event Reporting System data.[19][20]Contraindications and Interactions
Cefiderocol is contraindicated in patients with a known history of severe hypersensitivity (e.g., anaphylaxis or other type IV hypersensitivity reactions) to cefiderocol or to other beta-lactam antibacterial drugs, including cephalosporins, penicillins, monobactams, or carbapenems, as well as to any components of the formulation.[2][4] Patients with a history of penicillin allergy should be administered cefiderocol with caution due to potential cross-reactivity with cephalosporins, which occurs in approximately 2% of cases based on shared beta-lactam ring structures, though the risk is negligible with later-generation cephalosporins like cefiderocol that lack similar R1 side chains to penicillin.[21][22] Close monitoring for hypersensitivity reactions is recommended, and skin testing or graded challenge may be considered in high-risk patients.[2] Dose adjustment is required in patients with renal impairment to avoid accumulation, as cefiderocol is primarily eliminated renally; for example, in severe impairment (creatinine clearance <15 mL/min), the dose is reduced to 0.75 g every 12 hours, with administration after hemodialysis if applicable.[2] Regular monitoring of renal function is essential during therapy, particularly in patients with changing renal status or those on continuous renal replacement therapy.[4] Use in pregnancy is not well-studied, with no adequate human data available; however, animal reproduction studies in rats and mice at exposures up to 1.3 times the human exposure showed no evidence of direct or indirect harmful effects on embryo-fetal development.[2] Cefiderocol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.[4] In breastfeeding, cefiderocol is unknown whether it is excreted in human milk, but it was detected in the milk of lactating rats; the effects on breastfed infants and milk production are unknown, so a decision should be made to discontinue nursing or the drug, considering the importance of the therapy to the mother.[2][4] Cefiderocol has no significant pharmacokinetic drug-drug interactions anticipated with CYP450 substrates or inhibitors, nor with common antibiotics such as meropenem, based on in vitro studies and phase 1 clinical trials.[4] It exhibits minimal involvement with hepatic transporters like OATP1B1/1B3, with no clinically relevant interaction observed with probe substrates such as rosuvastatin.[4] Cefiderocol may interfere with certain laboratory tests, causing false-positive results for urine protein, ketones, or occult blood via dipstick methods; confirmatory testing with alternative methods is advised.[2] A positive direct Coombs test has been reported during treatment, which may interfere with cross-matching procedures.[4]Pharmacology
Mechanism of Action
Cefiderocol is a siderophore cephalosporin antibiotic designed to combat multidrug-resistant Gram-negative bacteria through a dual mechanism that enhances cellular penetration and targets cell wall synthesis.[23] The molecule features a beta-lactam core typical of cephalosporins, which binds to penicillin-binding proteins (PBPs) to inhibit peptidoglycan cross-linking during bacterial cell wall formation, ultimately leading to bactericidal activity.[24] Specifically, cefiderocol exhibits high affinity for PBP3, the primary target in Gram-negative pathogens, with lower inhibitory concentration (IC50) values compared to ceftazidime, contributing to its potent activity against strains resistant to other beta-lactams.[24] A key innovation in cefiderocol's design is its catechol side chain at the C-3 position, which acts as a siderophore by chelating ferric iron (Fe³⁺) in a 1:1 complex.[23] This iron-bound form mimics natural bacterial siderophores, such as enterobactin, allowing active transport across the outer membrane via specific iron-uptake receptors, including CirA and FepA in Escherichia coli and PiuA in Pseudomonas aeruginosa.[23] Once in the periplasmic space, the complex dissociates, releasing free cefiderocol to interact with PBPs while the iron is utilized by the bacterium, effectively hijacking the pathogen's iron acquisition system under iron-limiting conditions common in infections.[25] This Trojan horse strategy overcomes low outer membrane permeability and efflux-mediated resistance, enabling superior penetration into Gram-negative bacteria compared to non-siderophore cephalosporins.[24] Cefiderocol demonstrates remarkable stability against hydrolysis by a broad spectrum of beta-lactamases, including class A enzymes (e.g., extended-spectrum beta-lactamases [ESBLs] and Klebsiella pneumoniae carbapenemases [KPCs]), class C (AmpC), class D (OXA-48-like), and most metallo-beta-lactamases (e.g., NDM, VIM, IMP), due to its optimized C-7 and C-3 side chain configurations that reduce enzymatic access.[23] It is a poor substrate for common efflux pumps, further enhancing intracellular accumulation.[25] However, susceptibility to certain NDM variants has been noted, though overall, this stability profile supports its efficacy against carbapenem-resistant Enterobacterales, P. aeruginosa, and Acinetobacter baumannii.[24] The agent's activity is largely restricted to Gram-negative aerobes, with minimal effects on Gram-positive or anaerobic bacteria due to reliance on siderophore-mediated uptake absent in those organisms.[25]Pharmacokinetics
Cefiderocol is administered exclusively via intravenous infusion, achieving 100% bioavailability, as it is not absorbed orally.[2] The drug exhibits linear pharmacokinetics across clinically relevant doses of 100 to 2000 mg.[26] The steady-state volume of distribution of cefiderocol is approximately 18 L, consistent with distribution primarily into extracellular fluid, while plasma protein binding ranges from 40% to 60%, mainly to albumin.[2] Cefiderocol penetrates well into urine, achieving high concentrations (e.g., mean of 2710 μg/mL at 2 hours post-infusion in patients with complicated urinary tract infections), supporting its efficacy against urinary pathogens.[27] In the lungs, penetration into epithelial lining fluid reaches approximately 34% of plasma levels in patients with pneumonia, with AUC ratios of 0.239 relative to unbound plasma concentrations in healthy volunteers.[28] Penetration into the central nervous system is limited, with cerebrospinal fluid-to-plasma ratios typically below 10% in non-inflamed meninges, though higher (up to 68%) in cases of meningitis.[29] Cefiderocol undergoes minimal metabolism, with less than 10% of the administered dose transformed, and over 90% excreted as unchanged drug.[2] Elimination occurs predominantly via the kidneys, with 90.6% of the dose recovered unchanged in urine through a combination of glomerular filtration and active tubular secretion; fecal excretion accounts for less than 3%.[2] The terminal elimination half-life is 2 to 3 hours in individuals with normal renal function (creatinine clearance ≥90 mL/min), but it prolongs significantly in renal impairment (e.g., up to 9.6 hours in end-stage renal disease).[26] No dose adjustments are required for hepatic impairment, as the liver plays a negligible role in cefiderocol elimination.[2] In renal impairment, dosing must be reduced based on creatinine clearance to avoid accumulation (e.g., AUC increases 4.7-fold when clearance falls below 15 mL/min).[2] Population pharmacokinetic analyses in critically ill patients reveal higher unbound clearance (approximately 7.4 L/h versus 5.2 L/h in healthy subjects), often necessitating augmented dosing to maintain therapeutic exposure, particularly in those with augmented renal clearance.[30]Pharmacodynamics
Cefiderocol demonstrates time-dependent antibacterial activity against Gram-negative pathogens, with the percentage of the dosing interval during which unbound (free) plasma concentrations exceed the minimum inhibitory concentration (fT>MIC) serving as the primary pharmacodynamic index linking drug exposure to efficacy.[26] In preclinical models, fT>MIC targets of approximately 60-75% achieve bacteriostasis, while values exceeding 75-100% are associated with bactericidal effects, such as 1- to 2-log10 reductions in bacterial burden against Enterobacterales and Pseudomonas aeruginosa.[31] These targets vary by pathogen and infection site, with lower thresholds (around 45-65%) sufficient for stasis in lung models compared to thigh models (50-80%), reflecting differences in tissue penetration and bacterial burden.[32] The siderophore moiety of cefiderocol enhances its pharmacodynamic profile by facilitating active transport into bacteria via iron uptake systems, particularly in iron-depleted environments that mimic infection sites.[33] Antibacterial activity is optimal under low-iron conditions, where minimum inhibitory concentrations (MICs) decrease significantly (e.g., from 0.125 μg/mL in iron-sufficient media to 0.031 μg/mL in iron-depleted broth against Pseudomonas aeruginosa), as extracellular ferric iron complexes with the drug to promote uptake.[33] Elevated iron levels antagonize this effect by increasing MICs up to 4-fold, underscoring the importance of host iron sequestration during infection for maximizing efficacy; however, no clinically significant alterations in plasma iron occur with standard dosing.[32] In clinical trials, pharmacodynamic modeling supports fT>MIC thresholds of >75% as predictors of success, with Monte Carlo simulations indicating >95% probability of target attainment for MICs ≤4 mg/L using 2 g every 8 hours over 3 hours in patients with normal renal function.[24] For complicated urinary tract infections (cUTIs), the APEKS-cUTI trial showed microbiological eradication rates of 73% with cefiderocol, correlated with sustained fT>MIC exposures exceeding 75% in most patients.[26] Similarly, in nosocomial pneumonia (APEKS-NP trial), 97% of patients achieved 100% fT>MIC, linking this exposure to clinical cure rates of approximately 65-70% against multidrug-resistant Gram-negatives.[26]Microbiology
In Vitro Activity
Cefiderocol susceptibility testing requires the use of iron-depleted media to mimic the iron-limited conditions that facilitate its siderophore-mediated uptake, with iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB, iron ≤0.03 μg/mL) being the standard for broth microdilution (BMD).[34] Broth microdilution is the preferred method for determining minimum inhibitory concentrations (MICs), as it provides reproducible results that predict in vivo activity against Gram-negative pathogens.[34] Disk diffusion is not recommended due to variability in iron content across media brands and the frequent appearance of colonies within inhibition zones, which complicates zone diameter interpretation and leads to categorical agreement rates of only 75-90% with BMD.[34] Interpretive breakpoints for cefiderocol have been established by both the FDA/CLSI and EUCAST. The FDA recognizes CLSI breakpoints of susceptible (S) at MIC ≤4 mg/L for Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii complex, with no intermediate (I) or resistant (R) categories defined beyond that threshold.[35] EUCAST breakpoints are more conservative, setting S at MIC ≤2 mg/L and R >4 mg/L for Enterobacterales, S ≤2 mg/L and R >2 mg/L for P. aeruginosa, and S ≤0.5 mg/L (with insufficient clinical data noted) and R >2 mg/L for Acinetobacter spp.[36] In vitro surveillance data demonstrate broad activity of cefiderocol against Gram-negative pathogens. Against Enterobacterales, including carbapenem-resistant Enterobacterales (CRE), the MIC90 ranges from 2 to 4 mg/L, with 96.6-99.8% of isolates susceptible by CLSI criteria in U.S. and European collections from 2020-2021.[37] For P. aeruginosa, the MIC90 is 0.5-1 mg/L, achieving 98.6-99.3% susceptibility among multidrug-resistant (MDR) and carbapenem-nonsusceptible strains.[37] Activity against Acinetobacter baumannii is potent, with MIC90 values of 1-2 mg/L reported in 2024-2025 surveillance, yielding 97.1% susceptibility for MDR and carbapenemase-producing isolates.[37][38]| Pathogen Group | MIC50/MIC90 (mg/L) | % Susceptible (CLSI) |
|---|---|---|
| Enterobacterales (incl. CRE) | 0.5/2-4 | 96.6-100% |
| P. aeruginosa (MDR) | 0.12/1 | 98.6% |
| A. baumannii (MDR/CRAB) | 0.5/1-2 | 97.1% |