Oral lefamulin noninferior to oral moxifloxacin in treating community-acquired bacterial pneumonia
Approved by the FDA in August, lefamulin is an “important addition to the current antibiotic armamentarium,” although barriers to use will likely include cost and tolerability concerns, an editor's note said.
In adults with community-acquired bacterial pneumonia (CABP), a five-day regimen of oral lefamulin achieved a similar rate of early clinical response as seven days of oral moxifloxacin, an industry-funded randomized clinical trial found.
Lefamulin is active against the most common CABP-causing pathogens and was FDA-approved to treat CABP in August 2019. In a phase 3 noninferiority trial, researchers compared the efficacy and adverse events of oral lefamulin versus oral moxifloxacin in 738 patients with CABP at 99 sites in 19 countries. The trial (Lefamulin Evaluation Against Pneumonia [LEAP] 2) follows a previous phase 3 trial in adults with moderate to severe CABP, which demonstrated noninferiority of lefamulin to moxifloxacin when both groups initiated IV therapy with an optional switch from IV to oral treatment.
Participants were adults with a pneumonia Patient Outcomes Research Team (PORT) risk class of II, III, or IV; radiographically documented pneumonia; acute illness; three or more CABP symptoms; and two or more vital sign abnormalities. Exclusion criteria included receipt of more than one dose of a short-acting oral or IV antibacterial for CABP within 72 hours before randomization and hospitalization for two days or longer within 90 days, among other criteria. The FDA primary end point was early clinical response at 96 hours after first dose of either drug in the intention-to-treat population. The noninferiority margin was 10% for early clinical response and investigator assessment of clinical response. Results were published online on Sept. 27 by JAMA.
Patients were randomized to receive oral lefamulin (600 mg every 12 hours for five days; n=370) or moxifloxacin (400 mg every 24 hours for seven days; n=368) and were followed for 30 days. The mean age of the participants was 57.5 years, and 351 (47.6%) were women. About half had a PORT risk class of II or IV (48.8%), and 707 (95.8%) completed the trial. Early clinical response rates were 90.8% with lefamulin versus 90.8% with moxifloxacin (difference, 0.1%; one-sided 97.5% CI, −4.4% to ∞). Rates of investigator assessment of clinical response success were 87.5% with lefamulin versus 89.1% with moxifloxacin in the modified intention-to-treat population (difference, −1.6%; one-sided 97.5% CI, −6.3% to ∞) and 89.7% versus 93.6%, respectively, in the clinically evaluable population (difference, −3.9%; one-sided 97.5% CI, −8.2% to ∞) at test of cure. Patients in the lefamulin group reported a higher incidence of gastrointestinal-related, treatment-emergent adverse effects (17.9% vs. 7.6% in the moxifloxacin group), primarily diarrhea.
Limitations of the study include the extensive list of exclusion criteria, which may have limited generalizability to patient subpopulations with major diseases, the study authors noted. They added that patients with suspected methicillin-resistant Staphylococcus aureus (MRSA) were excluded due to poor coverage with moxifloxacin (however, three patients whose baseline pathogen was MRSA were enrolled).
An editor's note added that the spectrum of activity of lefamulin is similar to that of fluoroquinolones, although the latter have been associated with serious adverse effects, such as QT prolongation and tendon rupture. Barriers to use of the new drug may include potential tolerability concerns and cost, the editor said. “Despite these concerns, lefamulin is an important addition to the current antibiotic armamentarium, especially because bacterial pneumonia remains one of the most common indications for antibiotic use,” the editor wrote.