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

Kawaguchi, Nao; Katsube, Takayuki; Echols, Roger; Wajima, Toshihiro; Nicolau, David P.

doi:10.1002/jcph.1986

Cited by 14 publications

(10 citation statements)

References 36 publications

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“…The MICs for cefiderocol ranged between 0.75 and 1 mg/L. According to EUCAST, the clinical breakpoint for cefiderocol is established at 2 mg/L for enterobacterales [ 18 ]; therefore, for treatment, serum concentrations of 8 mg/L were assumed to be effective [ 19 , 20 ].…”

Section: Resultsmentioning

confidence: 99%

Feasibility of Continuous Infusion of Cefiderocol in Conjunction with the Establishment of Therapeutic Drug Monitoring in Patients with Extensively Drug-Resistant Gram-Negative Bacteria

et al. 2023

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Background and Objective Resistance to antibacterial substances is a huge and still emerging issue, especially with regard to Gram-negative bacteria and in critically ill patients. We report a study in six patients infected with extensively drug-resistant Gram-negative bacteria in a limited outbreak who were successfully managed with a quasi-continuous infusion of cefiderocol. Methods Patients were initially treated with prolonged infusions of cefiderocol over 3 h every 8 h, and the application mode was then switched to a quasi-continuous infusion of 2 g over 8 h, i.e. 6 g in 24 h. Therapeutic drug monitoring (TDM) was established using an in-house liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Results Determined trough plasma concentrations were a median of 50.00 mg/L [95% confidence interval (CI) 27.20, 74.60] and steady-state plasma concentrations were a median of 90.96 mg/L [95% CI 37.80, 124]. No significant differences were detected with respect to acute kidney injury/continuous renal replacement therapy. Plasma concentrations determined from different modes of storage were almost equal when frozen or cooled, but markedly reduced when stored at room temperature. Conclusions (Quasi) continuous application of cefiderocol 6 g/24 h in conjunction with TDM is a feasible mode of application; the sample for TDM should either be immediately analyzed, cooled, or frozen prior to analysis.

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Section: Resultsmentioning

confidence: 99%

Feasibility of Continuous Infusion of Cefiderocol in Conjunction with the Establishment of Therapeutic Drug Monitoring in Patients with Extensively Drug-Resistant Gram-Negative Bacteria

et al. 2023

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“…Finally, several PopPK models of CEF demonstrated the power of validated PK/PD models. They served to predict PTA in different disease states and, adding slightly more complexity, for different degrees of renal function [ 129 , 130 , 131 , 132 ]. Notably, they did not deploy PBPK models, although this might have also enabled the prediction of compound concentrations in different target compartments, such as the lung or kidney.…”

Section: Discussionmentioning

confidence: 99%

“…Kawaguchi and colleagues performed a series of studies on CEF utilizing compartmental modeling [ 129 , 130 , 131 , 132 , 134 ], with the most recent study utilizing an intrapulmonary PK model that adequately described the concentrations of the drug in ELF [ 132 ]. Data from 20 healthy subjects and 7 patients with pneumonia requiring mechanical ventilation were used to develop the model.…”

Section: New Routes With Cefiderocol: From In Silico Studies To Marketmentioning

confidence: 99%

All Roads Lead to Rome: Enhancing the Probability of Target Attainment with Different Pharmacokinetic/Pharmacodynamic Modelling Approaches

Khalid

2023

Antibiotics

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In light of rising antimicrobial resistance and a decreasing number of antibiotics with novel modes of action, it is of utmost importance to accelerate development of novel treatment options. One aspect of acceleration is to understand pharmacokinetics (PK) and pharmacodynamics (PD) of drugs and to assess the probability of target attainment (PTA). Several in vitro and in vivo methods are deployed to determine these parameters, such as time-kill-curves, hollow-fiber infection models or animal models. However, to date the use of in silico methods to predict PK/PD and PTA is increasing. Since there is not just one way to perform the in silico analysis, we embarked on reviewing for which indications and how PK and PK/PD models as well as PTA analysis has been used to contribute to the understanding of the PK and PD of a drug. Therefore, we examined four recent examples in more detail, namely ceftazidime-avibactam, omadacycline, gepotidacin and zoliflodacin as well as cefiderocol. Whereas the first two compound classes mainly relied on the ‘classical’ development path and PK/PD was only deployed after approval, cefiderocol highly profited from in silico techniques that led to its approval. Finally, this review shall highlight current developments and possibilities to accelerate drug development, especially for anti-infectives.

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“…Cefiderocol PK-PD studies demonstrate comparable ELF exposures to other cephalosporins in ventilated patients [ 119 ]. Population PK modeling suggests a high probability of achieving PK-PD targets ( f T > MIC) in ELF when cefiderocol MICs are ≤2 mg/L [ 120 ]; however, it is notable that targets are considerably higher for CRAB (88% f T > MIC) than for other carbapenem-resistant pathogens (≤70% f T > MIC) [ 121 ]. Moreover, determining accurate cefiderocol susceptibility results in clinical practice has proven to be a major challenge given concerns with the reproducibility of results, which is further complicated by varying breakpoints set forth by CLSI, EUCAST, and the FDA [ 102 ].…”

Section: Have High Hopes For Cefiderocol To Treat Crab Infections Bee...mentioning

confidence: 99%

Navigating Available Treatment Options for Carbapenem-ResistantAcinetobacter baumannii-calcoaceticusComplex Infections

Shields

Paterson

2023

Clinical Infectious Diseases

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Carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (CRAB) is one of the top-priority pathogens for new antibiotic development. Unlike other antibiotic-resistant threats, none of the available therapies have been shown to consistently reduce mortality or improve patient outcomes in clinical trials. Antibiotic combination therapy is routinely used in clinical practice; however, the preferred combination has not been defined. This narrative review focuses on evidence-based solutions for the treatment of invasive CRAB infections. We dissect the promise and perils of traditional agents used in combination, such as colistin, sulbactam, and the tetracyclines, and offer clinical pearls based on our interpretation of the available data. Next, we investigate the merits of newly developed β-lactam agents like cefiderocol and sulbactam-durlobactam, which have demonstrated contrasting results in recent randomized clinical trials. The review concludes with the authors’ perspective on the evolving treatment landscape for CRAB infections, which is complicated by limited clinical data, imperfect treatment options, and a need for future clinical trials. We propose that effective treatment for CRAB infections requires a personalized approach that incorporates host factors, the site of infection, pharmacokinetic-pharmacodynamic principles, local molecular epidemiology of CRAB isolates, and careful interpretation of antibiotic susceptibility testing results. In most clinical scenarios, a dose-optimized, sulbactam-based regimen is recommended with the addition of at least one other in vitro active agent. Should sulbactam-durlobactam receive regulatory approval, recommendations will need to be re-evaluated with the most recent evidence.

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

Cited by 14 publications

References 36 publications

Feasibility of Continuous Infusion of Cefiderocol in Conjunction with the Establishment of Therapeutic Drug Monitoring in Patients with Extensively Drug-Resistant Gram-Negative Bacteria

Feasibility of Continuous Infusion of Cefiderocol in Conjunction with the Establishment of Therapeutic Drug Monitoring in Patients with Extensively Drug-Resistant Gram-Negative Bacteria

All Roads Lead to Rome: Enhancing the Probability of Target Attainment with Different Pharmacokinetic/Pharmacodynamic Modelling Approaches

Navigating Available Treatment Options for Carbapenem-ResistantAcinetobacter baumannii-calcoaceticusComplex Infections

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