696. Mechanism of Cefiderocol high MIC mutants obtained in non-clinical FoR studies

Ito, Akinobu; Nishikawa, Toru; Ishii, Ryuta; Kuroiwa, Miho; Ishioka, Yoshino; Kurihara, Naoko; Sakikawa, Ikue; Ota, Tsuguhito; Rokushima, Masatomo; Tsuji, Masakatsu; Sato, Takafumi; Yamano, Yoshinori

doi:10.1093/ofid/ofy210.703

Cited by 28 publications

(24 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous investigation comparing the frequency of resistance at drug concentrations of 4 × and 10 × the MIC in P. aeruginosa PAO1 strain and detected spontaneous mutation rates of 2.9 × 10 −8 and <7.1 × 10 −9 to cefiderocol, and higher rates of 3.1 × 10 −7 and 3.4 × 10 −7 to ceftazidime, respectively [20]. Mutations in the bacterial iron uptake systems associated with a 4-fold elevated cefiderocol MIC (from 0.5 to 2 μg/mL) were identified in this study, although none of the mutations appeared in the responsible iron transporter gene piuA [32]. The mutations were identified in the upstream regions of pvdS (a gene regulating pyoverdine synthesis), and/or fecI (a gene regulating the ferric citrate transporter, FecA).…”

Section: Mechanism Of Resistancementioning

confidence: 92%

“…The mutations were identified in the upstream regions of pvdS (a gene regulating pyoverdine synthesis), and/or fecI (a gene regulating the ferric citrate transporter, FecA). These mutations resulted in an overexpression of pyoverdine and FecA protein, respectively, and conferred a 32-fold increase in cefiderocol MICs, whereas ceftazidime MICs were not affected [32]. In another study, the spontaneous mutation rates for 7 strains (ie, 2 multidrug-resistant [MDR] P. aeruginosa [MDRP; 1 IMP-1 producer, 1 ceftazidime resistant], 2 KPC-producing K. pneumoniae , and 3 Enterobacteriaceae [susceptible to ceftazidime-avibactam]) ranged from <1.4 × 10 −8 to 1.6 × 10 −6 for cefiderocol and from <1.0 × 10 −8 to 2.2 × 10 −5 for ceftazidime at drug concentrations of 10 × the MIC [33].…”

Section: Mechanism Of Resistancementioning

confidence: 99%

See 1 more Smart Citation

Cefiderocol: Discovery, Chemistry, and In Vivo Profiles of a Novel Siderophore Cephalosporin

Sato

Yamawaki

2019

Clinical Infectious Diseases

Self Cite

226

201

View full text Add to dashboard Cite

The emergence of antimicrobial resistance is a significant public health issue worldwide, particularly for healthcare-associated infections caused by carbapenem-resistant gram-negative pathogens. Cefiderocol is a novel siderophore cephalosporin targeting gram-negative bacteria, including strains with carbapenem resistance. The structural characteristics of cefiderocol show similarity to both ceftazidime and cefepime, which enable cefiderocol to withstand hydrolysis by β-lactamases. The unique chemical component is the addition of a catechol moiety on the C-3 side chain, which chelates iron and mimics naturally occurring siderophore molecules. Following the chelation of iron, cefiderocol is actively transported across the outer membrane of the bacterial cell to the periplasmic space via specialized iron transporter channels. Furthermore, cefiderocol has demonstrated structural stability against hydrolysis by both serine- and metallo-β-lactamases, including clinically relevant carbapenemases such as Klebsiella pneumoniae carbapenemase, oxacillin carbapenemase-48, and New Delhi metallo-β-lactamase. Cefiderocol has demonstrated promising in vitro antibacterial and bactericidal activity, which correlates with its in vivo efficacy in several animal models. This article reviews the discovery and chemistry of cefiderocol, as well as some of the key microbiological and in vivo findings on cefiderocol from recently conducted investigations.

show abstract

Section: Mechanism Of Resistancementioning

confidence: 92%

Section: Mechanism Of Resistancementioning

confidence: 99%

Cefiderocol: Discovery, Chemistry, and In Vivo Profiles of a Novel Siderophore Cephalosporin

Sato

Yamawaki

2019

Clinical Infectious Diseases

Self Cite

226

201

View full text Add to dashboard Cite

show abstract

“…Little is known about the mechanism of resistance of cefiderocol in clinical isolates. Ito et al 57 investigated the frequency of resistance of P aeruginosa isolates to cefiderocol and the mechanism of resistance observed. They demonstrated that the frequency of selecting resistant mutants with cefiderocol was much lower than that observed with ceftazidime at concentrations that were 4 and 10 times the MIC of each these agents.…”

Section: Mechanism Of Resistancementioning

confidence: 99%

Cefiderocol: A Siderophore Cephalosporin

El-Lababidi¹,

Rizk

2020

Ann Pharmacother

View full text Add to dashboard Cite

Objective: This article reviews the available data on the chemistry, spectrum of activity, pharmacokinetic and pharmacodynamic properties, clinical efficacy, and potential place in therapy of cefiderocol. Data Sources: A literature search through PubMed, Google Scholar, and ClinicalTrials.gov was conducted (2009 to March 2020) using the search terms cefiderocol and S-649266. Abstracts presented at recent conferences, prescribing information, and information from the US Food and Drug Administration (FDA) and the manufacturer’s website were reviewed. Study Selection and Data Extraction: All relevant published articles, package inserts, and unpublished meeting abstracts on cefiderocol were reviewed. Data Synthesis: Cefiderocol is the first siderophore antibiotic to be approved by the FDA. It was shown to be active against a wide range of resistant Gram-negative pathogens, including multidrug-resistant (MDR) Pseudomonas aeruginosa, Acinetobacter baumannii, Enterobacteriaceae, and Stenotrophomonas maltophilia. Cefiderocol was studied in the treatment of adult patients with complicated urinary tract infections (cUTIs) and nosocomial pneumonia and was well tolerated. In a recently completed prospective study, higher mortality was observed with cefiderocol in the treatment of serious infections caused by carbapenem-resistant (CR) Gram-negative pathogens. Relevance to Patient Care and Clinical Practice: The approval of cefiderocol provides a new option in the treatment of cUTIs and potentially treatment of nosocomial pneumonia caused by resistant Gram-negative pathogens. Given the higher mortality observed with cefiderocol, its use in the treatment of CR Gram-negative infections should be carefully considered. Conclusion: Cefiderocol shows promising activity against MDR Gram-negative pathogens. Its use in the treatment of serious infections caused by CR Gram-negative bacteria needs further evaluation in phase III clinical studies.

show abstract

“…The siderophore-associated structure of CFDC not only allows a unique mechanism of action, but also opens up the possibility of unique resistance mechanisms not commonly associated with other beta-lactam agents. 54 CFDC's structural characteristics, such as a modified C-3 and modified C-7 side chain, allow itself to withstand hydrolysis by most beta-lactamase enzymes. 25 Importantly, it has been shown that CFDC remains stable against many clinically relevant metallo-and serine-beta-lactamases, including NDMs, KPCs, and OXA-48s.…”

Section: Resistancementioning

confidence: 99%

Cefiderocol: A Novel Siderophore Cephalosporin against Multidrug‐Resistant Gram‐Negative Pathogens

et al. 2020

View full text Add to dashboard Cite

Cefiderocol (CFDC), (formerly S-649266), is a novel injectable siderophore cephalosporin developed by Shionogi & Co., Ltd., with potent in vitro activity against Gram-negative pathogens including multidrug-resistant (MDR) Enterobacteriaceae and non-fermenting organisms, such as Pseudomonas aeruginosa, Acinetobacter baumannii, Burkholderia cepacia, and Stenotrophomonas maltophilia. Characterized by its siderophore catechol-moiety, CFDC uses a "trojan-horse approach" to navigate through the bacterial periplasmic space, thus evading various beta-lactam degrading enzymes and other mechanisms of resistance present in Gram-negative bacteria. More specifically in carbapenem-resistant Enterobacteriaceae, CFDC has been shown to have activity against extended spectrum beta-lactamases (ESBLs), such as CTX-type, SHV-type, and TEM-type, as well as the Ambler classes of beta-lactamases, including class A (KPC), class B (NDM, IMP, and VIM), class C (AmpC), and class D (OXA, OXA-24, OXA-48, and OXA-48-like). In addition to the strong activity that CFDC has been shown to have against MDR P. aeruginosa, it has also displayed activity against the OXA-23, OXA-24, and OXA-51, beta-lactamases commonly found in MDR A. baumannii. Cefiderocol was recently approved by the US Food and Drug Administration (FDA) for use in complicated urinary tract infections (cUTI), including pyelonephritis, for use in patients 18 years or older with limited or no alternative options for treatment, and is currently being evaluated in a phase III trial for use in nosocomial pneumonia caused by Gram-negative pathogens. The unique features and enhanced activity of CFDC suggest that it is likely to serve as a viable therapeutic option in the treatment of MDR Gram-negative infections. The purpose of this review is to provide an overview of previously published literature explaining CFDC's pharmacology, pharmacokinetic / pharmacodynamic (PK / PD) properties, microbiologic activity, resistance mechanisms, safety parameters, dosing and administration, clinical data, and potential place in therapy. KEY WORDS siderophore, multidrug-resistant Gram-negative pathogens, Acinetobacter baumannii, Pseudomonas aeruginosa, trojan horse, cefiderocol, enterobacterales.

show abstract

696. Mechanism of Cefiderocol high MIC mutants obtained in non-clinical FoR studies

Cited by 28 publications

References 0 publications

Cefiderocol: Discovery, Chemistry, and In Vivo Profiles of a Novel Siderophore Cephalosporin

Cefiderocol: Discovery, Chemistry, and In Vivo Profiles of a Novel Siderophore Cephalosporin

Cefiderocol: A Siderophore Cephalosporin

Cefiderocol: A Novel Siderophore Cephalosporin against Multidrug‐Resistant Gram‐Negative Pathogens

Contact Info

Product

Resources

About