Treatment of Community-Acquired Pneumonia: A Focus on Lefamulin

Abstract

The goal of this article is to review the clinical pharmacology, pharmacokinetics, efficacy, and safety of lemafulin. We performed a systematic literature review using the search terms of lefamulin and BC-3781 in the PubMed and EMBASE databases. We also cross-referenced the pertinent articles and searched ClinicalTrials.gov to identify ongoing and nonpublished studies. Published data from 2005 to 2019 evaluating the clinical pharmacology, efficacy, and safety studies of lefamulin were analyzed. In phase 3 clinical trials, two multicenter, randomized double-blinded studies—Lefamulin Evaluation Against Pneumonia 1 and 2 (LEAP 1 and 2)—compared the efficacy and safety of lemafulin with moxifloxacin in patients diagnosed with community-acquired bacterial pneumonia (CABP). Lemafulin given in doses of 600 mg orally or 150 mg intravenously were reported to have comparable efficacy to those of moxifloxacin with or without linezolid in patients with CABP. After the trial, the lefamulin group had an early clinical response (ECR) of 87.3% and the moxifloxacin group had an ECR of 90.2%. The difference of − 2.9% in the ECR was non-significant (CI − 8.5, 2.8). Lemafulin exhibits a unique binding property; therefore, it possess a potentially lower predisposition for the development of bacterial resistance and cross-resistance to other antimicrobial classes. Lefamulin is active against gram-positive including methicillin-resistant strains and atypical organisms which are often implicated in CABP. Lefamulin may be a safe alternative for adult patients with CABP who may not be candidates for respiratory fluoroquinolones. Lefamulin demonstrates both bactericidal and bacteriostatic activity against gram-positive, fastidious gram-negatives, atypical pathogens, and some gram-negative anaerobes. It is bactericidal in vitro against Streptococcus pneumoniae, Haemophilus influenzae, and Mycoplasma pneumoniae (including macrolide-resistant strains) at concentrations of 0.06, 0.5, and 0.008 µg/ml respectively, and bacteriostatic against Staphylococcus aureus and Streptococcus pyogenes. The agent also demonstrates both time- and concentration-dependent killing against the pathogens S. pneumoniae and S. aureus. In vitro susceptibility testing demonstrated an MIC50/90 of 0.06/0.12 µg/ml against S. pneumoniae and S. aureus. The SENTRY Antimicrobial Surveillance Program found that at a concentration ≤ 1 µg/ml, lefamulin inhibited 100% S. pneumoniae isolates, 99.8% of S. aureus isolates, and 99.6% of methicillin-resistant S. aureus isolates. It was not affected by resistance to various antibiotic classes such as beta-lactams, fluoroquinolones, or macrolides. Lefamulin is the first pleuromutilin antibiotic approved for the treatment of bacterial infections in humans. Pleuromutilin antibiotics exert their unique mechanism of action which makes them less susceptible to the development of bacterial resistance and low probability of cross-resistance to the other antimicrobial classes. The authors present a critical review of the pharmacology, pharmacokinetics (PK), pharmacodynamics (PD), and data from two pivotal clinical trials of lefamulin in patients with community-acquired bacterial pneumonia (CABP). Lefamulin exhibits both bactericidal and bacteriostatic activity against gram-positive, fastidious gram-negatives, atypical pathogens, and some gram-negative anaerobes. It has shown activity against organisms known to cause sexually transmitted infections, including Mycoplasma genitalium and drug-resistant Neisseria gonorrhoeae. Lefamulin demonstrated no activity against Enterobacteriaceae or Pseudomonas aeruginosa. Pharmacokinetic studies involving lefamulin in acutely ill patients at least 18 years of age with three or more CABP symptoms failed to reveal any clinically significant differences in the PK parameters on the basis of age, sex, race, weight, or renal impairment. Lefamulin 600 mg tablets had a mean oral bioavailability of 25%. Consumption of high-fat meals may slightly reduce the blood level of the drug. In two phase 3 clinical trials, The Lefamulin Evaluation Against Pneumonia 1 and 2 (LEAP 1 and 2) compared the efficacy and safety of lemafulin with moxifloxacin in patients diagnosed with CABP. Lemafulin administered in doses of 600 mg orally or 150 mg intravenously were reported to have comparable efficacy to those of moxifloxacin with or without linezolid in patients with CABP.

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