Resistance to Lefamulin: An Evaluation of Data from In Vitro Antimicrobial Susceptibility Studies

Lefamulin, a new, first-in-class pleuromutilin antibiotic, was recently approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of patients with community-acquired bacterial pneumonia (CABP). In this context, this review aimed to evaluate its activity against the most common pathogens causing this infection. A thorough search was performed in five databases (Embase, Scopus, Web of Science, PubMed, PubMed Central) from their inception to 14th of October 2025. Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) resistance breakpoints were applied. Out of a total of 224 articles identified, 11 were deemed eligible for inclusion. Resistance among <i>Streptococcus pneumoniae</i>, <i>Haemophilus influenzae</i>, and <i>Staphylococcus aureus</i> isolates was 0-2.6%, 0-2.4%, and 0-4.3%, respectively. Even among isolates with specific mechanisms of resistance, such as β-lactamase-producing <i>H. influenzae</i> and methicillin-resistant <i>S. aureus</i>, resistance was below 2.4% and 3.4%, respectively. Among isolates for which no breakpoints were available (<i>Moraxella catarrhalis,</i> atypical pathogens, <i>Enterococcus</i> spp., <i>Streptococcus</i> spp., <i>Haemophilus</i> spp., and <i>Staphylococcus</i> spp.), MIC₉₀ values were low. An exception were isolates belonging to <i>Enterococcus</i> spp., which displayed MIC₉₀ values ranging from 0.25 to >16 mg/L in the two studies with relevant data. Lefamulin demonstrated broad in vitro activity against key pathogens causing CABP, making it a considerable addition to the therapeutic options for such infections, especially in cases where first-line agents cannot be used for reasons such as allergy or previous failure.