<i>In vitro</i>antimicrobial activity of S-649266, a catechol-substituted siderophore cephalosporin, when tested against non-fermenting Gram-negative bacteria

Ito, Akinobu; Kohira, Naoki; Bouchillon, S.; West, Joshua; Rittenhouse, Stephen; Sader, Hélio S.; Rhomberg, Paul R.; Jones, Ronald N.; Yoshizawa, Hidekazu; Nakamura, Rio; Tsuji, Masakatsu; Yamano, Yoshinori

doi:10.1093/jac/dkv402

Cited by 164 publications

(127 citation statements)

References 40 publications

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“…To establish a dose regimen for patients with normal renal function (i.e., a standard dose regimen), PTA values for 50% T fϾMIC and 75% T fϾMIC as the target T fϾMIC for bacteriostatic and bactericidal effects, respectively, from the animal infection models (5-7) were calculated by Monte Carlo simulation using the HS model with an unbound fraction (f u ) of 0.422 at 1 g q8h or 2 g q8h with a 1-h or 3-h infusion. In the calculation, the MIC range was set to 0.25 to 16 g/ml, which included 4 g/ml, where 98% of the target pathogens were susceptible (1,2).…”

Section: Population Pharmacokinetic Analyses (I) Model Development Fmentioning

confidence: 99%

Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Cefiderocol, a Parenteral Siderophore Cephalosporin, for Dose Adjustment Based on Renal Function

Katsube

Wajima

Ishibashi

et al. 2017

Antimicrob Agents Chemother

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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 (T fϾMIC ) for an MIC range of 0.25 to 16 g/ml. For the simulations, dose regimens were selected to compare cefiderocol exposure among groups with different levels of renal function. The developed models well described the PK of cefiderocol for each renal function group. A dose of 2 g every 8 h with 3-h infusions provided Ͼ90% PTA for 75% T fϾMIC for an MIC of Յ4 g/ml for patients with normal renal function, while a more frequent dose (every 6 h) could be used for patients with augmented renal function. A reduced dose and/or extended dosing interval was selected for patients with impaired renal function. A supplemental dose immediately after intermittent hemodialysis was proposed for patients requiring intermittent hemodialysis. The PK of cefiderocol could be adequately modeled, and the modeling-and-simulation approach suggested dose regimens based on renal function, ensuring drug exposure with adequate bactericidal effect.

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Section: Population Pharmacokinetic Analyses (I) Model Development Fmentioning

confidence: 99%

Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Cefiderocol, a Parenteral Siderophore Cephalosporin, for Dose Adjustment Based on Renal Function

Katsube

Wajima

Ishibashi

et al. 2017

Antimicrob Agents Chemother

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“…The ability to cross the outer membrane through the active iron-transport system overcomes resistance due to porin channel mutations and efflux pump overproducers. It results that cefiderocol exhibits potent in vitro and in vivo activity against all species of Gramnegative bacteria, including carbapenem-resistant strains of Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii, and even Stenotrophomonas maltophilia [15]. Here, we evaluated the antimicrobial activity of cefiderocol and other Gram-negative antibiotics (aztreonam, amikacin, cefepime, ceftazidime, ceftazidime-avibactam, ceftolozane-tazobactam, ciprofloxacin, meropenem, colistin, and tigecycline) against a panel of 753 multidrug-resistant bacterial isolates from human clinical sources with characterized antibiotic resistance mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Activity of the novel siderophore cephalosporin cefiderocol against multidrug-resistant Gram-negative pathogens

Dobiáš

Denervaud-Tendon

Poirel

et al. 2017

Eur J Clin Microbiol Infect Dis

139

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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

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“…The iron-binding moiety of beta-lactam siderophore conjugates is frequently a small catechol-type siderophore, such as dihydroxypyridone or a mixed catechol-hydroxamate (7). Such conjugates have been developed with aminopenicillins (8), cephems (KP-736 and S-649266) (9)(10)(11), and monocyclic beta-lactams (pirazmonam, BAL30072, and MC-1) (12)(13)(14)(15). In particular, the monobactam conjugates show potent activity against the Gram-negative nonfermenters P. aeruginosa and A. baumannii (15)(16)(17)(18).…”

mentioning

confidence: 99%

Structure and Function of the PiuA and PirA Siderophore-Drug Receptors from Pseudomonas aeruginosa and Acinetobacter baumannii

Moynié

Lüscher

Rolo

et al. 2017

Antimicrob Agents Chemother

106

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The outer membrane of Gram-negative bacteria presents an efficient barrier to the permeation of antimicrobial molecules. One strategy pursued to circumvent this obstacle is to hijack transport systems for essential nutrients, such as iron. BAL30072 and MC-1 are two monobactams conjugated to a dihydroxypyridone siderophore that are active against Pseudomonas aeruginosa and Acinetobacter baumannii. Here, we investigated the mechanism of action of these molecules in A. baumannii. We identified two novel TonB-dependent receptors, termed Ab-PiuA and Ab-PirA, that are required for the antimicrobial activity of both agents. Deletion of either piuA or pirA in A. baumannii resulted in 4-to 8-fold-decreased susceptibility, while their overexpression in the heterologous host P. aeruginosa increased susceptibility to the two siderophore-drug conjugates by 4-to 32-fold. The crystal structures of PiuA and PirA from A. baumannii and their orthologues from P. aeruginosa were determined. The structures revealed similar architectures; however, structural differences between PirA and PiuA point to potential differences between their cognate siderophore ligands. Spontaneous mutants, selected upon exposure to BAL30072, harbored frameshift mutations in either the ExbD3 or the TonB3 protein of A. baumannii, forming the cytoplasmic-membrane complex providing the energy for the siderophore translocation process. The results of this study provide insight for the rational design of novel siderophore-drug conjugates against problematic Gramnegative pathogens.

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In vitroantimicrobial activity of S-649266, a catechol-substituted siderophore cephalosporin, when tested against non-fermenting Gram-negative bacteria

Abstract: S-649266 is a novel antibiotic with potent in vitro activity against a range of non-fermenting Gram-negative bacteria, including MDR strains.

Cited by 164 publications

References 40 publications

Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Cefiderocol, a Parenteral Siderophore Cephalosporin, for Dose Adjustment Based on Renal Function

Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Cefiderocol, a Parenteral Siderophore Cephalosporin, for Dose Adjustment Based on Renal Function

Activity of the novel siderophore cephalosporin cefiderocol against multidrug-resistant Gram-negative pathogens

Structure and Function of the PiuA and PirA Siderophore-Drug Receptors from Pseudomonas aeruginosa and Acinetobacter baumannii

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