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Siderophore cephalosporin

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https://www.readbyqxmd.com/read/29683323/a-trojan-horse-strategy-including-a-bacterial-suicide-action-for-the-efficient-use-of-a-specific-gram-positive-antibiotic-on-gram-negative-bacteria
#1
Isabelle J Schalk
In the alarming context of rising bacterial antibiotic resistance, there is an urgent need to discover new antibiotics or increase and/or enlarge the activity of those currently in use. The need for new antibiotics is even more urgent in the case of Gram-negative bacteria, such as Acinetobacter, Pseudomonas, and Enterobacteria, which have become resistant to many antibiotics and have an outer membrane with very low permeability to drugs. Vectorization of antibiotics using siderophores may be a solution to bypass such a bacterial wall: the drugs use the iron transporters of the outer membrane as gates to enter bacteria in a Trojan-horse strategy...
April 23, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29627897/drug-drug-interaction-of-cefiderocol-a-siderophore-cephalosporin-via-human-drug-transporters
#2
Takayuki Katsube, Shiro Miyazaki, Yukitoshi Narukawa, Martha Hernandez-Illas, Toshihiro Wajima
PURPOSE: Cefiderocol, a siderophore cephalosporin, will be used concomitantly with other medications for treatment of bacterial infections. In vitro studies demonstrated inhibition potential of cefiderocol on organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, multidrug and toxin extrusion (MATE) 2-K, and organic anion transporting polypeptide (OATP) 1B3. The aim of this study was to assess in vivo drug-drug interaction (DDI) potential of cefiderocol using probe substrates for these transporters...
April 7, 2018: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29554424/a-synthetic-dual-drug-sideromycin-induces-gram-negative-bacteria-to-commit-suicide-with-a-gram-positive-antibiotic
#3
Rui Liu, Patricia A Miller, Sergei B Vakulenko, Nichole K Stewart, William C Boggess, Marvin J Miller
Many antibiotics lack activity against Gram-negative bacteria because they cannot permeate the outer membrane or suffer from efflux and, in the case of β-lactams, are degraded by β-lactamases. Herein, we describe the synthesis and studies of a dual drug conjugate (1) of a siderophore linked to a cephalosporin with an attached oxazolidinone. The cephalosporin component of 1 is rapidly hydrolyzed by purified ADC-1 β-lactamase to release the oxazolidinone. Conjugate 1 is active against clinical isolates of Acinetobacter baumannii as well as strains producing large amounts of ADC-1 β-lactamase...
May 10, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29471305/humanized-exposures-of-cefiderocol-a-siderophore-cephalosporin-display-sustained-in-vivo-activity-against-siderophore-resistant-pseudomonas-aeruginosa
#4
Islam M Ghazi, Marguerite L Monogue, Masakatsu Tsuji, David P Nicolau
We evaluated the in vivo efficacy of humanized exposures of cefiderocol, a novel siderophore cephalosporin, against a test panel of P. aeruginosa (PSA) previously shown to develop resistance to 2 preclinical candidate siderophores (MB-1 and SMC-3176). In the thigh infection model, the PSA bacterial density in untreated controls grew from 5.54 ± 0.23 to 8.68 ± 0.57 log10 CFU over 24 h. The humanized cefiderocol exposure resulted in >1 log10 CFU reduction in all 8 isolates, while MB-1 and SMC-3176 exhibited variable activity similar to that previously reported...
2018: Pharmacology
https://www.readbyqxmd.com/read/29318906/cefiderocol-a-novel-siderophore-cephalosporin
#5
REVIEW
Justin J Choi, Matthew W McCarthy
The emergence of multidrug-resistant bacterial pathogens has led to a global public health emergency and novel therapeutic options and drug-delivery systems are urgently needed. Cefiderocol is a siderophore cephalosporin antibiotic that has recently been developed to combat a variety of bacterial pathogens, including β-lactam- and carbapenem-resistant organisms. Areas covered: This paper provides an overview of the mutational and plasmid-mediated mechanisms of β-lactam and carbapenem resistance, the biochemical pathways of siderophores in bacterial iron metabolism, and how cefiderocol may be able to provide better targeted antimicrobial therapy that escape these drug-resistant mechanisms...
February 2018: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/29311072/pharmacokinetics-safety-and-tolerability-of-cefiderocol-a-novel-siderophore-cephalosporin-for-gram-negative-bacteria-in-healthy-subjects
#6
Yutaka Saisho, Takayuki Katsube, Scott White, Hiroyuki Fukase, Jingoro Shimada
Cefiderocol is a novel parenteral siderophore cephalosporin that shows potent efficacy against various Gram-negative bacteria, including carbapenem-resistant strains, in vitro and in preclinical models of infection. The aim of the present study was to evaluate the pharmacokinetics (PK), safety, and tolerability of cefiderocol after both single and multiple dosing by intravenous infusion over 60 min in healthy adult subjects. A single-ascending-dose study at doses of 100, 250, 500, 1,000, and 2,000 mg was conducted in 40 healthy Japanese males and females (6 individuals receiving the active drug and 2 individuals receiving a placebo per cohort)...
March 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29158270/-in-vitro-activity-of-the-siderophore-cephalosporin-cefiderocol-against-carbapenem-nonsusceptible-and-multidrug-resistant-isolates-of-gram-negative-bacilli-collected-worldwide-in-2014-to-2016
#7
Meredith A Hackel, Masakatsu Tsuji, Yoshinori Yamano, Roger Echols, James A Karlowsky, Daniel F Sahm
The in vitro activity of the investigational siderophore cephalosporin, cefiderocol (formerly S-649266), was determined against a 2014-2016, 52-country, worldwide collection of clinical isolates of carbapenem-nonsusceptible Enterobacteriaceae ( n = 1,022), multidrug-resistant (MDR) Acinetobacter baumannii ( n = 368), MDR Pseudomonas aeruginosa ( n = 262), Stenotrophomonas maltophilia ( n = 217), and Burkholderia cepacia ( n = 4) using the Clinical and Laboratory Standards Institute (CLSI) standard broth microdilution method...
February 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29111435/pharmacodynamics-of-cefiderocol-a-novel-siderophore-cephalosporin-in-a-pseudomonas-aeruginosa-neutropenic-murine-thigh-model
#8
Islam M Ghazi, Marguerite L Monogue, Masakatsu Tsuji, David P Nicolau
Cefiderocol is a siderophore cephalosporin that displays potent in vitro activity against multidrug-resistant (MDR) Gram-negative bacteria. This study aimed to describe the pharmacokinetics, pharmacodynamics and 24-h efficacy of cefiderocol using dose-ranging methods in a neutropenic murine thigh infection model. Infection was established in neutropenic mice (administered cyclophosphamide 150 mg/kg and 100 mg/kg at 4 days and 1 day prior to inoculation, respectively) with eight Pseudomonas aeruginosa isolates [minimum inhibitory concentration (MIC) range 0...
February 2018: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/29061741/-in-vitro-antibacterial-properties-of-cefiderocol-a-novel-siderophore-cephalosporin-against-gram-negative-bacteria
#9
Akinobu Ito, Takafumi Sato, Merime Ota, Miki Takemura, Toru Nishikawa, Shinsuke Toba, Naoki Kohira, Satoshi Miyagawa, Naoki Ishibashi, Shuhei Matsumoto, Rio Nakamura, Masakatsu Tsuji, Yoshinori Yamano
Cefiderocol (CFDC; S-649266), a novel parenteral siderophore cephalosporin conjugated with a catechol moiety, has a characteristic antibacterial spectrum with a potent activity against a broad range of aerobic Gram-negative bacterial species, including carbapenem-resistant strains of Enterobacteriaceae and nonfermenting bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii Cefiderocol has affinity mainly for penicillin-binding protein 3 (PBP3) of Enterobacteriaceae and nonfermenting bacteria similar to that of ceftazidime...
January 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29038272/population-pharmacokinetic-analysis-of-cefiderocol-a-parenteral-siderophore-cephalosporin-in-healthy-subjects-subjects-with-various-degrees-of-renal-function-and-patients-with-complicated-urinary-tract-infection-or-acute-uncomplicated-pyelonephritis
#10
Nao Kawaguchi, Takayuki Katsube, Roger Echols, Toshihiro Wajima
Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent efficacy against most Gram-negative bacteria, including carbapenem-resistant strains. The aim of this study was to perform a population pharmacokinetic (PK) analysis based on plasma cefiderocol concentrations in healthy subjects, subjects with various degrees of renal function, and patients with complicated urinary tract infection (cUTI) or acute uncomplicated pyelonephritis (AUP) caused by Gram-negative pathogens and to calculate the fraction of the time during the dosing interval where the free drug concentration in plasma exceeds the MIC ( fT MIC )...
February 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28893690/new-agents-for-the-treatment-of-infections-with-gram-negative-bacteria-restoring-the-miracle-or-false-dawn
#11
REVIEW
H Wright, R A Bonomo, D L Paterson
BACKGROUND: Antibiotic resistance in Gram-negative resistance has developed without a commensurate response in the successful development of antibiotic agents, though recent progress has been made. AIMS: This review aims to provide a summary of the existing evidence on efficacy, spectrum of activity and the development of resistance of new agents that have been licensed or have completed advanced clinical trials and that possess activity against resistant Gram-negative organisms...
October 2017: Clinical Microbiology and Infection
https://www.readbyqxmd.com/read/28748397/activity-of-the-novel-siderophore-cephalosporin-cefiderocol-against-multidrug-resistant-gram-negative-pathogens
#12
J Dobias, V Dénervaud-Tendon, L Poirel, P Nordmann
The novel siderophore cephalosporin cefiderocol (S-649266) with potent activity against Gram-negative pathogens was recently developed (Shionogi & Co., Ltd.). Here, we evaluated the activity of this new molecule and comparators against a collection of previously characterized Gram-negative isolates using broth microdilution panels. A total of 753 clinical multidrug-resistant Gram-negative isolates collected from hospitals worldwide were tested against cefiderocol and antibiotic comparators (ceftolozane-tazobactam [CT], meropenem [MEM], ceftazidime [CAZ], ceftazidime-avibactam [CZA], colistin [CST], aztreonam [ATM], amikacin [AMK], ciprofloxacin [CIP], cefepime [FEP], and tigecycline [TGC]) for their susceptibility...
December 2017: European Journal of Clinical Microbiology & Infectious Diseases
https://www.readbyqxmd.com/read/28668680/antimicrobial-activities-of-lcb10-0200-a-novel-siderophore-cephalosporin-against-the-clinical-isolates-of-pseudomonas-aeruginosa-and-other-pathogens
#13
Sang-Hun Oh, Hee-Soo Park, Hye-Shin Kim, Jeong-Yul Yun, Kyuman Oh, Young-Lag Cho, Jin-Hwan Kwak
Infections caused by multidrug-resistant bacteria, including Pseudomonas aeruginosa, are threatening public health worldwide. Therefore, a novel antibacterial agent is needed to treat these infections. Here, we investigated the in vitro and in vivo activities of a novel siderophore-conjugated cephalosporin, LCB10-0200, against the clinical isolates of Gram-negative bacteria, including multidrug-resistant P. aeruginosa. In vitro susceptibility to LCB10-0200 was assessed by performing a two-fold agar dilution method, as described by the Clinical and Laboratory Standards Institute...
June 28, 2017: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/28630181/-in-vitro-activity-of-the-siderophore-cephalosporin-cefiderocol-against-a-recent-collection-of-clinically-relevant-gram-negative-bacilli-from-north-america-and-europe-including-carbapenem-nonsusceptible-isolates-sidero-wt-2014-study
#14
Meredith A Hackel, Masakatsu Tsuji, Yoshinori Yamano, Roger Echols, James A Karlowsky, Daniel F Sahm
Cefiderocol (formerly S-649266) is an investigational siderophore cephalosporin. Iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) was prepared according to the Clinical and Laboratory Standards Institute (CLSI) protocol and used to perform broth microdilution testing of cefiderocol against a 2014-2015 collection of clinical isolates of Gram-negative bacilli from North America ( n = 4,239) and Europe ( n = 4,966). The concentrations of cefiderocol inhibiting 90% of isolates tested (MIC90 s) were 0...
September 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28630178/efficacy-of-cefiderocol-against-carbapenem-resistant-gram-negative-bacilli-in-immunocompetent-rat-respiratory-tract-infection-models-recreating-human-plasma-pharmacokinetics
#15
Shuhei Matsumoto, Christine M Singley, Jennifer Hoover, Rio Nakamura, Roger Echols, Stephen Rittenhouse, Masakatsu Tsuji, Yoshinori Yamano
Cefiderocol (S-649266), a novel siderophore cephalosporin, shows potent activity against carbapenem-resistant Gram-negative bacilli. In this study, we evaluated the efficacy of cefiderocol against carbapenem-resistant Gram-negative bacilli (Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae) in immunocompetent-rat respiratory tract infection models recreating plasma pharmacokinetics (PK) profiles in healthy human subjects. A total of 6 clinical isolates (1 cephalosporin-susceptible P...
September 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28438934/susceptibility-of-imipenem-susceptible-but-meropenem-resistant-bla-imp-6-carrying-enterobacteriaceae-to-various-antibacterials-including-the-siderophore-cephalosporin-cefiderocol
#16
LETTER
Sachi Kanazawa, Takafumi Sato, Naoki Kohira, Tsukasa Ito-Horiyama, Masakatsu Tsuji, Yoshinori Yamano
No abstract text is available yet for this article.
July 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28410852/cefiderocol-mic-quality-control-ranges-in-iron-depleted-cation-adjusted-mueller-hinton-broth-using-a-clsi-m23-a4-multi-laboratory-study-design
#17
Michael D Huband, Akinobu Ito, Masakatsu Tsuji, Helio S Sader, Kelley A Fedler, Robert K Flamm
Cefiderocol (formerly S-649266) is a new catechol-substituted parenteral siderophore cephalosporin with potent in vitro antibacterial activity against Gram-negative isolates including multidrug-resistant strains. A recent study following CLSI M23-A4 quality control guidelines established cefiderocol MIC QC ranges against Escherichia coli ATCC 25922 (0.06-0.5 μg/mL) and Pseudomonas aeruginosa ATCC 27853 (0.06-0.5 μg/mL).
June 2017: Diagnostic Microbiology and Infectious Disease
https://www.readbyqxmd.com/read/28369471/activity-of-cefiderocol-s-649266-against-carbapenem-resistant-gram-negative-bacteria-collected-from-inpatients-in-greek-hospitals
#18
Matthew E Falagas, Tilemachos Skalidis, Konstantinos Z Vardakas, Nicholas J Legakis
Background: Cefiderocol (S-649266), a siderophore cephalosporin, utilizes a novel mechanism of entry into the periplasmic space of Gram-negative bacteria and is broadly stable to ESBLs and carbapenemases. Methods: A collection of carbapenem-resistant Gram-negative bacteria isolated from clinical specimens in 18 Greek hospitals was tested for susceptibility to cefiderocol, meropenem, ceftazidime, cefepime, ceftazidime/avibactam, ceftolozane/tazobactam, aztreonam, amikacin, ciprofloxacin, colistin and tigecycline...
June 1, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/27874971/cefiderocol-a-siderophore-cephalosporin-for-gram-negative-bacterial-infections-pharmacokinetics-and-safety-in-subjects-with-renal-impairment
#19
Takayuki Katsube, Roger Echols, Juan Camilo Arjona Ferreira, Heidi K Krenz, Jolene Kay Berg, Christopher Galloway
Cefiderocol, a new injectable siderophore cephalosporin antibiotic, has promising in vitro and in vivo activity against Gram-negative bacteria including multidrug-resistant Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. Cefiderocol is mainly renally eliminated. The pharmacokinetics and safety of cefiderocol in subjects with renal impairment were assessed following a single 1000-mg intravenous 1-hour infusion of cefiderocol. Subjects with mild, moderate, or severe renal impairment and end-stage renal disease (ESRD) requiring hemodialysis were compared with demographically (age, body mass index, and sex) matched healthy subjects with normal renal function...
May 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27795374/pharmacokinetic-pharmacodynamic-modeling-and-simulation-of-cefiderocol-a-parenteral-siderophore-cephalosporin-for-dose-adjustment-based-on-renal-function
#20
Takayuki Katsube, Toshihiro Wajima, Toru Ishibashi, Juan Camilo Arjona Ferreira, Roger Echols
Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent efficacy against most Gram-negative bacteria, including carbapenem-resistant strains. Since cefiderocol is excreted primarily via the kidneys, this study was conducted to develop a population pharmacokinetics (PK) model to determine dose adjustment based on renal function. Population PK models were developed based on data for cefiderocol concentrations in plasma, urine, and dialysate with a nonlinear mixed-effects model approach. Monte-Carlo simulations were conducted to calculate the probability of target attainment (PTA) of fraction of time during the dosing interval where the free drug concentration in plasma exceeds the MIC (Tf>MIC) for an MIC range of 0...
January 2017: Antimicrobial Agents and Chemotherapy
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