Importance: New antibacterials are needed to treat community-acquired bacterial pneumonia (CABP) because of growing antibacterial resistance and safety concerns with standard care.
Objective: To evaluate the efficacy and adverse events of a 5-day oral lefamulin regimen in patients with CABP.
Design, Setting, and Participants: A phase 3, noninferiority randomized clinical trial conducted at 99 sites in 19 countries that included adults aged 18 years or older with a Pneumonia Outcomes Research Team (PORT) risk class of II, III, or IV; radiographically documented pneumonia; acute illness; 3 or more CABP symptoms; and 2 or more vital sign abnormalities. The first patient visit was on August 30, 2016, and patients were followed up for 30 days; the final follow-up visit was on January 2, 2018.
Interventions: Patients were randomized 1:1 to receive oral lefamulin (600 mg every 12 hours for 5 days; n = 370) or moxifloxacin (400 mg every 24 hours for 7 days; n = 368).
Main Outcomes and Measures: The US Food and Drug Administration (FDA) primary end point was early clinical response at 96 hours (within a 24-hour window) after the first dose of either study drug in the intent-to-treat (ITT) population (all randomized patients). Responders were defined as alive, showing improvement in 2 or more of the 4 CABP symptoms, having no worsening of any CABP symptoms, and not receiving any nonstudy antibacterial drug for current CABP episode. The European Medicines Agency coprimary end points (FDA secondary end points) were investigator assessment of clinical response at test of cure (5-10 days after last dose) in the modified ITT population and in the clinically evaluable population. The noninferiority margin was 10% for early clinical response and investigator assessment of clinical response.
Results: Among 738 randomized patients (mean age, 57.5 years; 351 women [47.6%]; 360 had a PORT risk class of III or IV [48.8%]), 707 (95.8%) completed the trial. Early clinical response rates were 90.8% with lefamulin and 90.8% with moxifloxacin (difference, 0.1% [1-sided 97.5% CI, -4.4% to 8]). Rates of investigator assessment of clinical response success were 87.5% with lefamulin and 89.1% with moxifloxacin in the modified ITT population (difference, -1.6% [1-sided 97.5% CI, -6.3% to 8]) and 89.7% and 93.6%, respectively, in the clinically evaluable population (difference, -3.9% [1-sided 97.5% CI, -8.2% to 8]) at test of cure. The most frequently reported treatment-emergent adverse events were gastrointestinal (diarrhea: 45/368 [12.2%] in lefamulin group and 4/368 [1.1%] in moxifloxacin group; nausea: 19/368 [5.2%] in lefamulin group and 7/368 [1.9%] in moxifloxacin group).
Conclusions and Relevance: Among patients with CABP, 5-day oral lefamulin was noninferior to 7-day oral moxifloxacin with respect to early clinical response at 96 hours after first dose.
Trial Registrations: ClinicalTrials.gov Identifier: NCT02813694; European Clinical Trials Identifier: 2015-004782-92.
|Family Medicine (FM)/General Practice (GP)|
|General Internal Medicine-Primary Care(US)|
The problem in treating presumed community-acquired bacterial pneumonia is common in primary care. This study, with authors who are employees of Nabriva Therapeutics (the maker of Lefamulin), found that a newer medication, Lefamulin, was "non-inferior" to Moxifloxacin. In fact, the effectiveness appeared similar at 90.8% in both groups. The group receiving Lefamulin had a higher rate of diarrhea (12 % vs 1%) and other gastrointestinal side effects.
The concept of a treatment being noninferior is sometimes confusing to practitioners. This obviously asserts that if the treatment is not inferior, it could be inferior. Is that the same as equivalent or possibly superior? Not trying to be to appear noncognizant of a word, but is there not a better way to express the conclusion?
Welcome news to soon have another antibiotic class that is active against respiratory pathogens.
Useful information if the cost will not be prohibitive for regular use.
Potentially interesting to internists, hospitalists, and general practitioners; however, the limiting factor re relevance is the availability of this new antibiotic agent.
As a hospitalist, new treatments for pneumonia are always welcome. Respiratory fluoroquinolones can be effective but carry risks for C. difficile and tendons as well as confusion in the elderly. In this industry-sponsored study, a new antibiotic from a new class (a pleuromutilin) was found to be not inferior to moxifloxacin for CAP. the positive aspects of this new antibiotic are that it gets MRSA and is a narrower spectrum. The negatives are: 1. it may not get gram negatives like Pseudomonas, so it may not be right for the worst pneumonias; and 2. diarrhea and nausea were much more common (9x and 4x more common, respectively). It is nice to have an alternative for community-acquired pneumonia but from what I see, this should not yet be a 1st-line choice. Not yet ready for "prime time" in my mind.
Useful and adds another agent for treatment.
The rationale for introducing lefamulin to address the growing antibiotic resistance to other antibiotic classes is appropriate. The study was well designed to prove non-inferiority of lefamulin compared with moxifloxacin. One wonders, though, whether there is a significant cost differential between the drugs that will affect selection in any given case. The article does not discuss cost.
Well done multicenter study comparing lufamulin (a new class of antibiotics) to a respiratory quinolone. Results showed non-inferiority in a well defined group of patients with CAP. The drug was well tolerated with modest GI side effects. This drug will clearly have a place in the treatment of moderate-to-severe CAP.