ArticleThe Journal of antimicrobial chemotherapy2019
In vivo pharmacodynamics of lefamulin, the first systemic pleuromutilin for human use, in a neutropenic murine thigh infection model.
Article in The Journal of antimicrobial chemotherapy, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers, 1 of them a synthesis that pooled it.
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Who cites it
19 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Systematic review of antimicrobial pharmacokinetic/pharmacodynamic indices in murine thigh and hollow fibre dose fractionation studies analysed with a standard method.The Journal of antimicrobial chemotherapy · 2026Pooled it
- Pharmacokinetics and tolerability of lefamulin following intravenous and oral dosing.The Journal of antimicrobial chemotherapy · 2019Trial
- PK/PD Modeling of a Novel Pleuromutilin Derivative Pleuro2-4 against Mycoplasma gallisepticum in Chicks.Journal of agricultural and food chemistry · 2026Article
- One Health Perspective of Mycoplasmas: Proposals for Standardizing In Vitro PK/PD Models of Human Mycoplasma Species by Referencing Veterinary Experiences.Microorganisms · 2026Review
- Pharmacokinetic/pharmacodynamic relationship of a novel pleuromutilin derivative APTM against Mycoplasma gallisepticum.Poultry science · 2026Article
- Establishment and validation of downsized hollow-fibre infection model and pharmacokinetics/pharmacodynamics analysis of VAN on Enterococcus faecium.The Journal of antimicrobial chemotherapy · 2025Article
- Target attainment of intravenous lefamulin for treatment of acute bacterial skin and skin structure infections.The Journal of antimicrobial chemotherapy · 2024Article
- Phage activity against Staphylococcus aureus is impaired in plasma and synovial fluid.Scientific reports · 2023Article
- Pharmacokinetic, Pharmacokinetic/Pharmacodynamic, and Safety Investigations of Lefamulin in Healthy Chinese Subjects.Antibiotics (Basel, Switzerland) · 2023Article
- Lefamulin: a New Hope in the Field of Community-Acquired Bacterial Pneumonia.Current pharmacology reports · 2022Review
- Pharmacodynamic evaluation of lefamulin in the treatment of gonorrhea using a hollow fiber infection model simulatingFrontiers in pharmacology · 2022Article
- Lefamulin in Patients with Community-Acquired Bacterial Pneumonia Caused by Atypical Respiratory Pathogens: Pooled Results from Two Phase 3 Trials.Antibiotics (Basel, Switzerland) · 2021Article
- Clinical Pharmacokinetics and Pharmacodynamics of Lefamulin.Clinical pharmacokinetics · 2021Review
- Review
- Model-Informed Drug Development, Pharmacokinetic/Pharmacodynamic Cutoff Value Determination, and Antibacterial Efficacy of Benapenem againstAntimicrobial agents and chemotherapy · 2020Article
- Leave it to Lefamulin: A Pleuromutilin Treatment Option in Community-Acquired Bacterial Pneumonia.Drugs · 2019Review
- Pharmacokinetics/pharmacodynamics of lefamulin in a neutropenic murine pneumonia model with Staphylococcus aureus and Streptococcus pneumoniae.The Journal of antimicrobial chemotherapy · 2019Article
- Introduction: lefamulin and pharmacokinetic/pharmacodynamic rationale to support the dose selection of lefamulin.The Journal of antimicrobial chemotherapy · 2019Article
- Pharmacokinetic/pharmacodynamic target attainment analyses to support intravenous and oral lefamulin dose selection for the treatment of patients with community-acquired bacterial pneumonia.The Journal of antimicrobial chemotherapy · 2019Article
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Authors and funding
3 authors.
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No grant is acknowledged in the PubMed record.
Abstract
objectivesTo characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of lefamulin in the neutropenic murine thigh infection model to ascertain (i) which PK/PD index best correlates with efficacy and (ii) whether the magnitude of the index that drives efficacy varies for different pathogens.
methodsWe evaluated the in vivo PK/PD of lefamulin against five Streptococcus pneumoniae and five Staphylococcus aureus strains using a neutropenic murine thigh infection model. The relationships between bacterial burden in the thigh of normal and neutropenic mice after 24 h of lefamulin treatment and various PK/PD indices were determined.
resultsThe kinetics of the three doses was linear by AUC. Rate of killing was maximal at concentrations near the MIC; suppression of regrowth was dose dependent, with a post-antibiotic effect of 3.0-3.5 and 1.0-1.5 h against S. pneumoniae and S. aureus, respectively. The efficacy of lefamulin correlated most strongly with the AUC0-24/MIC ratio; coefficient of determination was 79.9% for S. pneumoniae and 78.3% for S. aureus. The magnitude of the 24 h AUC/MIC of total drug required ranged from 9.92 to 32.1 for S. pneumoniae and 40.2 to 82.5 for S. aureus, corresponding to free drug values (∼20% free fraction) of 1.98-6.42 and 8.04-16.5, respectively.
conclusionsLefamulin, the first systemically available pleuromutilin in humans, exhibits time- and concentration-dependent killing. The presence of white blood cells had only a slight effect in enhancing the activity of the drug, indicating a leucocyte-independent effect. The identified driver of efficacy, the AUC0-24/MIC ratio and the ratios determined against various S. aureus and S. pneumoniae strains, will inform further non-clinical and clinical trials.
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