Effect of Cefiderocol, a Siderophore Cephalosporin, on QT/QTc Interval in Healthy Adult Subjects

Sanabria, Carlos; Migoya, Elizabeth; Mason, Jay W.; Stanworth, Stephanie H.; Katsube, Takayuki; Machida, Mitsuaki; Narukawa, Yukitoshi; Nagata, Tsutae Den

doi:10.1016/j.clinthera.2019.07.006

Cited by 21 publications

(26 citation statements)

References 18 publications

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“…The pharmacokinetics, safety, and tolerability of cefiderocol were evaluated in phase 1 single- and multiple-dose studies in healthy subjects [27–29] and in uninfected subjects with renal impairment [30]. Additionally, a thorough QT/QTc study was conducted to assess the potential effects of a 2 g (therapeutic) and 4 g (supratherapeutic) dose of cefiderocol on the QT interval [31], and a drug-interaction study evaluated the inhibitory effects of cefiderocol on organic anion drug transporters (OAT) [32]. Pharmacokinetics and safety of cefiderocol were evaluated in patients with complicated urinary tract infection (cUTIs) enrolled into the phase 2 APEKS (Acinetobacter, Pseudomonas, Escherichia, Klebsiella, Stenotrophomonas)-cUTI clinical study [33, 34].…”

Section: Pharmacokinetic and Safety Assessments Of Cefiderocol In Humansmentioning

confidence: 99%

“…In a thorough QT/QTc study, all point estimates for the time-matched placebo- and baseline-adjusted QT interval corrected using the Fridericia formula (ddQTcF interval), with moxifloxacin being positive control, were <5 msec, and the upper bound of the 90% confidence interval (CI) was well <10 msec at each time point after initiation of the infusion. Thus, single 2 g and 4 g doses of cefiderocol did not prolong the ddQTcF interval, which would have been considered as clinically relevant, and met the criteria associated with a negative thorough QT/QTc assessment [31].…”

Section: Pharmacokinetics Safety and Tolerability In Healthy Subjectsmentioning

confidence: 99%

“…The phase 1 studies indicated that the single cefiderocol dose of up to 4000 mg and the multiple dose of up to 2000 mg were well tolerated in healthy subjects [27, 31]. In the single-dose part of the study, 9 adverse events that might have been related to study drug (ie, diarrhea, abdominal pain, nausea, rash, blood present in urine, increased white blood cells) were reported in the cefiderocol group [27].…”

Section: Pharmacokinetics Safety and Tolerability In Healthy Subjectsmentioning

confidence: 99%

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Pharmacokinetic and Pharmacodynamic Profiles of Cefiderocol, a Novel Siderophore Cephalosporin

Katsube

Echols

Wajima

2019

Clinical Infectious Diseases

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Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent in vitro activity and in vivo efficacy against most gram-negative bacteria, including carbapenem-resistant strains of Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia. In phase 1 studies, cefiderocol demonstrated linear pharmacokinetics, primarily urinary excretion, an elimination half-life of 2–3 hours, and a protein binding of 58% in human plasma. Cefiderocol is a time-dependent cephalosporin; the probability of a target attainment at ≥75% of the dosing interval during which the free drug concentration exceeds the minimum inhibitory concentration (ƒT/MIC) for bacterial strains with an MIC of ≤4 μg/mL is likely to be achieved at the therapeutic dose of 2 g over 3-hour infusion every 8 hours in most patients. As expected, renal function markers were the most influential covariates for the pharmacokinetics of cefiderocol for patients with renal impairment or augmented renal clearance (ARC). Dose adjustment is recommended for patients with impaired renal function, and additionally, in ARC patients with creatinine clearance >120 mL/minute, a more frequent dosing regimen (ie, 2 g every 6 hours) was predicted to achieve the target fT > MIC. The single and multiple doses of cefiderocol tested were well tolerated in both healthy subjects and those with renal impairment. Furthermore, neither QT interval prolongation nor drug–drug interaction via organic anion transporters was demonstrated in healthy subjects. Cefiderocol is being investigated in phase 3 clinical studies for the treatment of infections caused by carbapenem-resistant bacteria.

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Section: Pharmacokinetic and Safety Assessments Of Cefiderocol In Humansmentioning

confidence: 99%

Section: Pharmacokinetics Safety and Tolerability In Healthy Subjectsmentioning

confidence: 99%

Section: Pharmacokinetics Safety and Tolerability In Healthy Subjectsmentioning

confidence: 99%

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Pharmacokinetic and Pharmacodynamic Profiles of Cefiderocol, a Novel Siderophore Cephalosporin

Katsube

Echols

Wajima

2019

Clinical Infectious Diseases

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“…This is likely due to the slow-growing nature of S. maltophilia , the inherently static nature of time-kill experiments, and the drug concentrations utilized. Although supratherapeutic concentrations of cefiderocol as high as 4× MIC were utilized, these concentrations are still ≥10-fold lower than the fC max values observed after a 2-g dose administered to healthy volunteers over 3 h (∼45 mg/liter) ( 29 ). Since the primary objective of this study was to evaluate synergy in combination with cefiderocol, drugs were utilized at concentrations multiplicative of the MIC for the respective isolate rather than at human physiologic concentrations.…”

Section: Discussionmentioning

confidence: 99%

Activity of Cefiderocol Alone and in Combination with Levofloxacin, Minocycline, Polymyxin B, or Trimethoprim-Sulfamethoxazole against Multidrug-Resistant Stenotrophomonas maltophilia

Biagi

Vialichka

Jurkovic

et al. 2020

Antimicrob Agents Chemother

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Objectives: The production of a metallo-(L1) and serine-(L2) β-lactamase precludes the use of β-lactams for the treatment of Stenotrophomonas maltophilia infections. Pre-clinical data suggest cefiderocol is the first approved β-lactam with reliable activity against S. maltophilia, but data against strains resistant to current first -line agents are limited and no studies have assessed cefiderocol-based combinations. The objective of this study was to evaluate and compare the in vitro activity of cefiderocol alone and in combination with levofloxacin, minocycline, polymyxin B, and trimethoprim-sulfamethoxazole (TMP-SMZ) against a collection of highly resistant clinical S. maltophilia isolates. Methods: The minimum inhibitory concentrations (MICs) of 37 S. maltophilia isolates not susceptible to levofloxacin and/or TMP-SMZ were determined for cefiderocol, ceftazidime, levofloxacin, minocycline, polymyxin B, and TMP-SMZ. Nine strains with varying MICs to cefiderocol were then tested in time-kill experiments alone and in combination with comparators. Results: The only agents with susceptibility rates exceeding 40% were cefiderocol (100%) and minocycline (97.3%). Cefiderocol displayed the lowest MIC50 and MIC90 values (0.125 and 0.5 mg/L, respectively). In time-kill experiments, synergy was observed when cefiderocol was combined with levofloxacin, minocycline, polymyxin B, and TMP-SMZ against 4/9 (44.4%), 6/9 (66.7%), 5/9 (55.5%), and 6/9 (66.7%) isolates, respectively. Conclusions: These data suggest that cefiderocol displays potent in vitro activity against S. maltophilia, including strains resistant to currently preferred agents. Future dynamic and in vivo studies of cefiderocol alone and in combination are warranted to further define cefiderocol's synergistic capabilities and place in therapy for S. maltophilia infections.

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“…No clinically significant effect was found on the QTcF interval or other ECG parameters with any cefiderocol dose. Moxifloxacin resulted in a prolongation of the QTcF interval for all time points [46].…”

Section: Safety and Tolerabilitymentioning

confidence: 90%

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

2020

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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 b-lactamases, including extended spectrum b-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 lactosefermenting 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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Effect of Cefiderocol, a Siderophore Cephalosporin, on QT/QTc Interval in Healthy Adult Subjects

Cited by 21 publications

References 18 publications

Pharmacokinetic and Pharmacodynamic Profiles of Cefiderocol, a Novel Siderophore Cephalosporin

Pharmacokinetic and Pharmacodynamic Profiles of Cefiderocol, a Novel Siderophore Cephalosporin

Activity of Cefiderocol Alone and in Combination with Levofloxacin, Minocycline, Polymyxin B, or Trimethoprim-Sulfamethoxazole against Multidrug-Resistant Stenotrophomonas maltophilia

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

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