Oral Lefamulin vs Moxifloxacin for Early Clinical Response Among Adults With Community-Acquired Bacterial Pneumonia

Abstract

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 PARTICIPANTSA 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 MEASURESThe 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 ϱ]). 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 ϱ]) and 89.7% and 93.6%, respectively, in the clinically evaluable population (difference, -3.9% [1-sided 97.5% CI, -8.2% to ϱ]) 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.

Clinical Utility of Lefamulin: If Not Now, When?

“…Diarrhea was less common with IV lefamulin compared to moxifloxacin (1 vs 8%), yet more common in LEAP-2 with the oral formulation (12% vs 1%), The rationale for this large difference is currently unknown. Hepatic enzyme elevations, nausea, hypokalemia, insomnia, and headache occurred with both formulations of lefamulin at rates similar to those with moxifloxacin [47]. In the Phase II ABSSSI trial, more headache, nausea, infusion site phlebitis, and pruritus were observed in the vancomycin arm when compared to the lefamulin arms, although statistical significance was not noted [48].…”

“…With potent activity against CABP pathogens and high pulmonary concentrations, lefamulin demonstrates antimicrobial properties ideal for respiratory tract infections. The Lefamulin Evaluation Against Pneumonia (LEAP)-1 and -2 studies were similarly designed multicenter randomized controlled trials that tested non-inferiority of lefamulin against moxifloxacin in adults with CABP [46,47]. Study details and comparisons of population characteristics and endpoints are in Tables 2 and 3.…”

“…LEAP-2 evaluated similar endpoints of ECR and IACR, except only using fixed durations of oral formulations for lefamulin (5 days) and moxifloxacin (7 days) in both inpatient and outpatient settings and a non-inferiority margin of 10% for both FDA and EMA endpoints [47]. A major difference in study design from LEAP-1 and LEAP-2 was the focus on the use of PO agents only without the addition of linezolid in the moxifloxacin group.…”

“…Lefamulin's spectrum of Gram-positive, atypical, and limited Gram-negative organisms is similar to tetracyclines, which as a class are far less implicated in CDI [61]. There were no significant differences in incidence of C. difficile or multi-drug-resistant organisms when compared to moxifloxacin, and interestingly, more diarrhea with oral lefamulin (but less with IV) [46,47]. This could be advantageous if adopted as CABP therapy in comparison to other recommended agents.…”

<p>Investigational and Experimental Drugs for Community-Acquired Pneumonia: the Current Evidence</p>

“…38 The LEAP 2 study compared the safety and efficacy of oral lefamulin twice daily for 5 days versus oral moxifloxacin once daily for 7 days in 738 adult patients with moderate CAP, and also demonstrated non-inferiority between the two therapeutic options. 39 On August of 2019, based on the results of these trials, the FDA announced the approval of lefamulin for the treatment of CAP. 40 Despite this approval the ATS and the IDSA demand further validation in the outpatient setting.…”