A novel antibiotic, lefamulin, may not be inferior to moxifloxacin in efficacy and safety for the treatment of community-acquired bacterial pneumonia (CABP), according to a study published in Clinical Infectious Disease.
CABP produces significant morbidity and mortality. In the United States, Streptococcus pneumoniae causes approximately 5% to 15% of all CABP, with higher rates seen in Europe. As a result of an approximately 40% resistance rate of S pneumoniae to existing antibiotics, including B-lactams, clindamycin, tetracyclines, and macrolides, new therapies are needed. Lefamulin, a novel pleuromutilin antibiotic, has a spectrum of activity that is targeted to bacteria that cause CABP, including methicillin-resistant Staphylococcus aureus (MRSA); its activity is unaffected by mechanisms of resistance to the previously mentioned antibiotics. Lefamulin has shown favorable pharmacokinetic and pharmacodynamic profiles. Therefore, researchers developed the Lefamulin Evaluation Against Pneumonia (LEAP 1), phase 3 study, a global inferiority trial that evaluated the safety and efficacy of intravenous-to-oral lefamulin monotherapy compared with moxifloxacin for the treatment of CABP in adults (ClinicalTrials.gov identifier: NCT02559310).
A total of 551 patients with CABP of Pneumonia Outcomes Research Team risk class ³III were randomly assigned 1:1 to receive either lefamulin 150 mg intravenously (IV) every 12 hours (n=276) or moxifloxacin 400 mg IV every 24 hours (n=275). To maintain blinding, moxifloxacin patients received alternating doses of placebo. After 6 doses of IV treatment, patients could be switched to either lefamulin 600 mg every 12 hours or moxifloxacin 400 mg every 24 hours. If MRSA was suspected at screening, blinded linezolid 600 mg IV every 12 hours was added to the moxifloxacin group and a linezolid placebo was added to the lefamulin group; if MRSA was not confirmed in baseline culture, the linezolid and corresponding placebo were discontinued. Patients without MRSA underwent treatment for 7 days, whereas patients with MRSA received active therapy for 10 days. The primary endpoint was early clinical response 96 ± 24 hours after the first dose of study drug in the intent-to-treat population. Other co-primary endpoints were investigator assessment of clinical response, 5 to 10 days after last dose of the study drug in the modified intent-to-treat population, and clinically evaluable populations.
Lefamulin monotherapy showed noninferiority to moxifloxacin for efficacy and was generally safe. For early clinical response, lefamulin was noninferior to moxifloxacin (87.3% vs 90.2%, respectively); this similar result was seen for investigator assessment of clinical response (modified intent-to-treat population, 81.7% vs 84.2%, respectively). In both groups, rates of treatment-emergent adverse events were similar and were mild or moderate in severity. In the lefamulin group, the most common treatment-emergent adverse events were hypokalemia, insomnia, nausea, and infusion site pain. In the moxifloxacin group, the most common treatment-emergent adverse event was diarrhea. Discontinuation because of treatment-emergent adverse events that were study drug-related were 4.4% for moxifloxacin and 2.9% for lefamulin.
Overall, the study authors concluded, “Lefamulin is an IV and oral empiric monotherapy that provides targeted antimicrobial activity against the most prevalent CABP pathogens, providing clinicians a potential CABP treatment option that aligns with the principles of antimicrobial stewardship.”
File Jr. TM, Goldberg L, Das A, et al. Efficacy and safety of IV-to-oral lefamulin, a pleuromutilin antibiotic, for treatment of community-acquired bacterial pneumonia: a phase 3 LEAP 1 trial [published online February 4, 2019]. Clin Infect Dis. doi: 10.1093/cid/ciz090/5306243