Dataset Information

Intrapulmonary Pharmacokinetic Modeling and Simulation of Cefiderocol, a Parenteral Siderophore Cephalosporin, in Patients With Pneumonia and Healthy Subjects.

ABSTRACT: Cefiderocol is a siderophore cephalosporin for the treatment of infections caused by gram-negative bacteria including carbapenem-resistant strains. The aim of this study was to develop an intrapulmonary pharmacokinetic (PK) model of cefiderocol and assess the PK profile in lungs. An intrapulmonary PK model of cefiderocol was developed using the concentration data in plasma and epithelial lining fluid (ELF) from 7 patients with pneumonia requiring mechanical ventilation and 20 healthy subjects. Subsequently, the model was applied to assess the ELF exposure of 125 patients with nosocomial pneumonia. Monte Carlo simulations were performed to calculate the probability of target attainment for the percentage of time for which free ELF concentrations exceed the minimum inhibitory concentration (MIC) over the dosing interval (%fT_>MIC,ELF ). The developed model adequately described ELF concentrations and suggested the delayed distribution in ELF for patients with pneumonia compared to healthy subjects. Lung penetration ratio of cefiderocol in patients with pneumonia was calculated to be 34%, which was 1.4-fold that in healthy subjects. The estimated %fT_>MIC,ELF was 100% in most of patients with nosocomial pneumonia, and no PK/pharmacodynamic relationship with %fT_>MIC,ELF was found for microbiological or clinical outcome. The probability of target attainment for 100% fT_>MIC,ELF was ≥ 99.5% against MICs ≤2 μg/mL and ≥87.0% against MICs ≤4 μg/mL regardless of renal function. The median of simulated ELF trough concentrations at steady state was >4 μg/mL regardless of renal function. These results reveal the adequacy of cefiderocol exposure in plasma and ELF at the recommended dosing regimens adjusted on the basis of renal function in critically ill patients with pneumonia.

SUBMITTER: Kawaguchi N

PROVIDER: S-EPMC9306831 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Background Cefiderocol (CFDC) is a novel siderophore-cephalosporin, effective against multidrug-resistant Gram-negative bacteria. As it has a siderophore side chain, it can utilize iron acquisition systems for penetration of the bacterial outer membrane. We aimed to elucidate the role of siderophores and iron uptake receptors in defining Klebsiella pneumoniae susceptibility to CFDC. Methods Initially, 103 K. pneumoniae strains were characterized for susceptibility to different antibiotics including CFDC. CFDC minimum inhibitory concentrations (MIC) were determined in iron-depleted and iron-enriched conditions. Iron uptake genes including siderophores, their receptors, ferric citrate (fecA) and iron uptake (kfu) receptors were detected by PCR in all the strains. For 10 selected strains, gene expression was tested in iron-depleted media with or without CFDC treatment and compared to expression in iron-enriched conditions. Results CFDC exhibited 96.1% susceptibility, being superior to all the other antibiotics (MIC50: 0.5 and MIC90: 4 μg/ml). Only three strains (2.9%) were intermediately susceptible and a pandrug resistant strain (0.97%) was resistant to CFDC (MIC: 8 and 256 μg/ml, respectively). The presence of kfu and fecA had a significant impact on CFDC MIC, especially when co-produced, and if coupled with yersiniabactin receptor (fyuA). CFDC MICs were negatively correlated with enterobactin receptor (fepA) expression and positively correlated with expression of kfu and fecA. Thus, fepA was associated with increased susceptibility to CFDC, while kfu and fecA were associated with reduced susceptibility to CFDC. CFDC MICs increased significantly in iron-enriched media, with reduced expression of siderophore receptors, hence, causing less drug uptake. Conclusion Iron acquisition systems have a significant impact on CFDC activity, and their altered expression is a factor leading to reduced susceptibility. Iron concentration is also a major player affecting CFDC susceptibility; therefore, it is essential to explore possible ways to improve the drug activity to facilitate its use to treat infections in iron-rich sites.

Dataset Information

Intrapulmonary Pharmacokinetic Modeling and Simulation of Cefiderocol, a Parenteral Siderophore Cephalosporin, in Patients With Pneumonia and Healthy Subjects.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets