Lefamulin: Review of a promising novel pleuromutilin antibiotic.
Pharmacotherapy. 2018 Jul 18;:
Authors: Veve MP, Wagner JL
The emergence and spread of antimicrobial resistance has led to a global public health emergency requiring development of new antimicrobial classes. Lefamulin (formally BC-3781) is a novel pleuromutilin antibiotic currently undergoing Food and Drug Administration review for community-acquired bacterial pneumonia (CABP) as intravenous (IV) and oral (PO) formulations. While pleuromutilin antibiotics were first developed in the 1950s, lefamulin is the first to be used for systemic treatment of bacterial infections in humans. Lefamulin exhibits a unique mechanism of action through inhibition of protein synthesis by binding to the peptidyl transferase center of the 50s bacterial ribosome, thus preventing the binding of tRNA for peptide transfer. Lefamulin displays activity against Gram-positive and atypical organisms associated with CABP (i.e., Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumonia, Legionella pneumophila, and Chlamydophila pneumoniae), with an expanded Gram-positive spectrum including Staphylococcus aureus (i.e., methicillin-resistant, vancomycin-intermediate, and heterogeneous strains) and vancomycin-resistant Enterococcus faecium. Lefamulin has also shown to retain activity against multidrug-resistant Neisseria gonorrhoeae and Mycoplasma genitalium. Lefamulin exhibits time-dependent killing and the pharmacodynamic target best associated with antibacterial activity is ƒAUC0-24 /MIC. Pre-clinical and Phase 2 trials indicate that lefamulin concentrates in lung tissue, is well-tolerated at an IV dose of 150 mg twice daily over 1 hour or a PO dose of 600 mg twice daily, and preliminary Phase 3 data suggest similar efficacy when compared to moxifloxacin with or without linezolid in CABP. Documented resistance and cross-resistance with other Gram-positive antibacterials remains low. Additional published in vitro, in vivo, and pre-clinical trial data suggest further exploration of lefamulin in various infectious disease states (e.g., acute bacterial skin and skin structure infections, sexually transmitted infections). This review is intended to discuss the pertinent bacterial spectrum of activity, pre-clinical and on-going clinical data, and potential roles in therapy for lefamulin. This article is protected by copyright. All rights reserved.
PMID: 30019769 [PubMed – as supplied by publisher]