New antimicrobials – particularly those with novel mechanism of action – are rare. Lefamulin, a pleuromutilin class antibiotic, is not new, but it’s new to humans – or, even more specifically, new to oral and intravenous availability in humans.
This article in JAMA details LEAP-2, the sequel (of course) to LEAP-1. This clinical trial demonstrates the non-inferiority of oral lefamulin to oral moxifloxacin for the treatment of generally mild community-acquired pneumonia. LEAP-1, as I’m certain you recall, demonstrated its non-inferiority as an intravenous-to-oral regimen for slightly-less-mild CAP in whom hospitalization was reasonable. Without belaboring the results too greatly, “early clinical response in the intention to treat population” and “test of cure in modified intention to treat populations” were generally similar, with response rates of about 90% for each arm. However, lefamulin is certainly less well-tolerated – diarrhea, nausea, and vomiting far exceeded the frequency observed in the moxifloxacin cohort.
These are likely valid results with respect to efficacy and a 10% non-inferiority margin, considering pleuromutilin antibiotics have been used effectively in animals for decades. This was, however, a tightly-controlled trial, narrowly targeted at meeting the threshold for approval in Europe and the United States (i.e., 50% of patients required to be PORT Class II, so 50.4% of them were). All authors, study procedures, and analyses were overseen by the sponsor, and trial sites were scattered across the (somewhat) developing world. Irregularities regarding efficacy differences and assessments were seen at several sites and addressed in the supplementary appendix, noting mostly the exclusion of results from these sites would not have affected the overall trial outcome. All these signals, however, do raise concerns regarding underreporting of adverse events and systematic minimization of any efficacy differences.
It’s splendid to have a new option for cases of multidrug resistance. For $200 to $300 a day, however, no need to indulge unnecessarily – or be the first on your block to drive the new hotness.
“Oral Lefamulin vs Moxifloxacin for Early Clinical Response Among Adults With Community-Acquired Bacterial Pneumonia”
https://jamanetwork.com/journals/jama/fullarticle/2752331