The Journal of antimicrobial chemotherapy
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J. Antimicrob. Chemother. · Apr 2019
Randomized Controlled TrialPrediction of lefamulin epithelial lining fluid penetration after intravenous and oral administration using Phase 1 data and population pharmacokinetics methods.
Lefamulin is a semi-synthetic intravenous and oral pleuromutilin antibiotic with activity against pathogens commonly associated with community-acquired bacterial pneumonia. Using data from two Phase 1 studies, a population pharmacokinetics (PPK) model for lefamulin in plasma and epithelial lining fluid (ELF) was constructed. ⋯ The final PPK model allowed precise characterization of plasma and ELF exposures after intravenous and oral administration. The high ELF penetration ratio suggests that the penetration of lefamulin into the effect site is rapid and extensive, irrespective of route of administration.
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J. Antimicrob. Chemother. · Apr 2019
Single- and multiple-dose pharmacokinetics and total removal of colistin in critically ill patients with acute kidney injury undergoing prolonged intermittent renal replacement therapy.
Owing to the emerging problem of MDR bacteria, interest in 'old' antibiotics such as colistin has re-emerged. However, research on the dosing of colistin in patients undergoing renal replacement therapy (RRT), such as prolonged intermittent renal replacement therapy (PIRRT), is scarce. ⋯ PIRRT eliminates about half of the daily administered colistin dose. Even a 6 MIU loading dose of colistin methanesulfonate may not ensure immediate sufficient colistin plasma levels in all critically ill patients. However, we measured significant colistin accumulation, suggesting that the dose of colistin methanesulfonate should be adjusted according to body weight and RRT intensity.
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J. Antimicrob. Chemother. · Apr 2019
Pharmacokinetic/pharmacodynamic target attainment analyses to support intravenous and oral lefamulin dose selection for the treatment of patients with community-acquired bacterial pneumonia.
Lefamulin is a semi-synthetic intravenous (iv) and oral pleuromutilin antibiotic active against community-acquired bacterial pneumonia (CABP) pathogens. Pharmacokinetic/pharmacodynamic (PK/PD) target attainment analyses were carried out to evaluate lefamulin 150 mg iv q12h and 600 mg orally q12h under fed and fasted conditions for the treatment of patients with CABP. ⋯ These data provide support for lefamulin 150 mg iv q12h and 600 mg orally q12h for the treatment of patients with CABP and suggest that doses may not need to be taken under fasted conditions.
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J. Antimicrob. Chemother. · Apr 2019
Introduction: lefamulin and pharmacokinetic/pharmacodynamic rationale to support the dose selection of lefamulin.
Lefamulin is the first semisynthetic pleuromutilin being developed for oral and intravenous administration. The drug selectively inhibits prokaryotic ribosomal protein synthesis by binding to the peptidyl transferase centre via four H-bonds and other interactions, resulting in an 'induced fit' that tightens the binding pocket around lefamulin. ⋯ This Supplement, entitled 'Pharmacokinetic and pharmacodynamic analyses and dose rationale for lefamulin, a novel pleuromutilin antibiotic, for the treatment of community-acquired bacterial pneumonia', is intended to be a valuable resource for both clinicians and researchers. It provides the essential pharmacokinetic and pharmacodynamic data on lefamulin that were used to support the optimal dose selection of lefamulin for the safe and effective treatment of CABP in adults.
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J. Antimicrob. Chemother. · Apr 2019
Pharmacokinetics/pharmacodynamics of lefamulin in a neutropenic murine pneumonia model with Staphylococcus aureus and Streptococcus pneumoniae.
To present results of preclinical studies that supported further development of lefamulin for treating patients with community-acquired bacterial pneumonia (CABP). ⋯ Overall, lefamulin displays desirable pharmacokinetic/pharmacodynamic relationships that are predictive of the clinical effectiveness of lefamulin and other antibacterial agents used to treat CABP.