Resistance to Lefamulin Explained: Insights from In Vitro Antimicrobial 🔬🦠 #pencis #researchawards

Introduction

Lefamulin represents a significant advancement in antimicrobial therapy as a first-in-class pleuromutilin antibiotic approved by both the FDA and EMA for the treatment of community-acquired bacterial pneumonia (CABP). With rising global antimicrobial resistance and limitations associated with existing first-line agents, the development of novel antibiotics targeting respiratory pathogens is a critical research priority. Lefamulin’s unique mechanism of action, targeting the peptidyl transferase center of the bacterial ribosome, reduces cross-resistance with other antibiotic classes and positions it as a promising alternative in modern pneumonia management.

Methodological Approach to Evidence Synthesis

This review employed a comprehensive and systematic literature search across five major biomedical databases—Embase, Scopus, Web of Science, PubMed, and PubMed Central—covering studies from inception to October 14, 2025. By applying standardized resistance breakpoints from CLSI and EUCAST, the analysis ensured methodological rigor and comparability across studies. Out of 224 identified articles, only 11 met strict inclusion criteria, underscoring both the selectivity of the review and the need for further primary research on lefamulin susceptibility patterns.

Activity Against Core CABP Pathogens

The in vitro susceptibility data demonstrated consistently low resistance rates among the most prevalent CABP pathogens. Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus showed resistance ranges of 0–2.6%, 0–2.4%, and 0–4.3%, respectively. These findings highlight lefamulin’s robust antibacterial activity against both Gram-positive and Gram-negative respiratory pathogens, supporting its role as a reliable option in empiric and targeted CABP therapy.

Performance Against Resistant Phenotypes

A key research focus was lefamulin’s efficacy against organisms with established resistance mechanisms. Notably, β-lactamase–producing H. influenzae and methicillin-resistant Staphylococcus aureus (MRSA) exhibited resistance rates below 2.4% and 3.4%, respectively. This suggests that lefamulin retains activity where traditional agents may fail, making it particularly valuable in settings with high resistance prevalence or in patients with prior antibiotic exposure.

MIC Profiles in Pathogens Lacking Breakpoints

For several clinically relevant organisms lacking established CLSI or EUCAST breakpoints—such as Moraxella catarrhalis, atypical pathogens, and various Streptococcus, Staphylococcus, and Haemophilus species—MIC90 values were generally low, indicating favorable in vitro potency. However, Enterococcus spp. emerged as an exception, with MIC90 values ranging widely from 0.25 to >16 mg/L across two studies, highlighting interspecies variability and the need for further pharmacodynamic and clinical outcome research.

Clinical and Research Implications

Overall, lefamulin demonstrated broad-spectrum in vitro activity against key CABP pathogens, reinforcing its value as an alternative therapeutic option, especially for patients with allergies, intolerance, or failure of first-line treatments. From a research perspective, these findings support continued surveillance, expanded clinical trials, and real-world effectiveness studies to better define lefamulin’s role in pneumonia treatment algorithms and antimicrobial stewardship strategies.

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