Clinical Utility of Lefamulin: If Not Now, When?

Abstract

Purpose of Review The looming threat of antimicrobial resistance requires robust stewardship and new developments in infectious diseases pharmacotherapy. This review discusses the pertinent spectrum and clinical data of lefamulin (Xenleta®), with a focus on potential real-world use. Recent Findings Lefamulin is a novel pleuromutilin antibiotic that obtained Food and Drug Administration labeling for community-acquired bacterial pneumonia (CABP) in 2019. Lefamulin is available in both intravenous and oral formulations, and it inhibits bacterial protein synthesis inhibition through interactive binding to unique sites of the peptidyl transferase center of the 50s bacterial ribosome subunit. Resistance, including cross-resistance with other antibiotics, is infrequent. Lefamulin demonstrates activity against most Gram-positive pathogens and other organisms commonly associated with CABP, i.e., Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydophila pneumoniae. Lefamulin may also be an option for serious public health threats like methicillin-resistant Staphylococcus aureus, vancomycinresistant Enterococcus faecium, and multi-drug-resistant organisms associated with sexually transmitted infections, e.g., Neisseria gonorrhoeae, Mycoplasma genitalium. Lefamulin lacks activity against Pseudomonas aeruginosa, Acinetobacter baumannii, Enterobacterales, most anaerobes, and E. faecalis. In Phase III trials, lefamulin monotherapy was non-inferior to moxifloxacin with or without linezolid for CABP. Summary Lefamulin is a well-tolerated agent with a unique mechanism, availability in both IV and PO formulations, and it has been rigorously studied for safety and efficacy for CABP.

Novel Therapeutic Trends in Pneumonia: Antibiotics and Mesenchymal Stem Cells

“…Lefamulin is a pleuromutilin antibiotic that inhibits bacterial growth by binding to the peptidyl transferase center of the 50S ribosome, preventing the binding of tRNA for peptide transfer and inhibiting peptide bond formation [13,16,17]. The binding pocket of the bacterial ribosome closes around the pleuromutilin, causing an induced fit and tightening the binding pocket [13,[17][18][19]. This unique binding mechanism is believed to be the reason for the low potential for the development of bacterial resistance and cross-resistance to other antibiotics [13,[17][18][19].…”

“…The binding pocket of the bacterial ribosome closes around the pleuromutilin, causing an induced fit and tightening the binding pocket [13,[17][18][19]. This unique binding mechanism is believed to be the reason for the low potential for the development of bacterial resistance and cross-resistance to other antibiotics [13,[17][18][19]. Lefamulin exhibits both bactericidal and bacteriostatic activity against gram-positive, fastidious gram-negative, atypical pathogens, and some gram-negative anaerobes [13,20].…”

“…Lefamulin has been shown to be an effective and well-tolerated agent, with availability in both oral and IV formulations to treat CAP. Patients who may benefit from lefamulin include those at higher risk of adverse events from fluoroquinolone use, those with a history of C. difficile infection, or those in settings with high prevalence of community-associated methicillin-resistant S. aureus (MRSA) [18].…”

Novel Therapeutic Trends in Pneumonia: Antibiotics and Mesenchymal Stem Cells

“…While their use in severe CAP is not yet completely understood, these novel antibiotics may offer a potential treatment option for patients with resistant pathogens (Table 1 Lefamulin is a pleuromutilin antibiotic that inhibits bacterial growth by binding to the peptidyl transferase center of the 50S ribosome, preventing the binding of tRNA for peptide transfer and inhibiting peptide bond formation [13,20,22]. The binding pocket of the bacterial ribosome closes around the pleuromutilin, causing an induced fit and tightening the binding pocket [13,[22][23][24]. This unique binding mechanism is believed to be the reason for the low potential for the development of bacterial resistance and cross-resistance to other antibiotics [13,[22][23][24].…”

“…The binding pocket of the bacterial ribosome closes around the pleuromutilin, causing an induced fit and tightening the binding pocket [13,[22][23][24]. This unique binding mechanism is believed to be the reason for the low potential for the development of bacterial resistance and cross-resistance to other antibiotics [13,[22][23][24]. Lefamulin exhibits both bactericidal and bacteriostatic activity against grampositive, fastidious gram-negative, atypical pathogens, and some gramnegative anaerobes [13,25].…”