In patients with community-acquired bacterial pneumonia (CABP), the first-in-class pleuromutilin antibiotic lefamulin may offer a much-needed intravenous (IV)/oral empiric monotherapy alternative to other antibiotic classes, such as fluoroquinolones and macrolide, according to results of an analysis published in the journal BMC Pulmonary Medicine. Researchers used pooled data from the double-blind, double-dummy, parallel-group Lefamulin Evaluation Against Pneumonia (LEAP) 1 (ClinicalTrials.gov Identifier: NCT02559310) and LEAP 2 (ClinicalTrials.gov identifier: NCT02813694) studies to examine the efficacy and safety of lefamulin overall and within various subgroups of patients who presented with common clinical comorbidities.
LEAP 1 was an IV-to-oral switch study and LEAP 2 was an oral-only study. In LEAP 1, participants could switch to oral therapy (lefamulin 600 mg every 12 hours) after receiving 6 IV doses (for approximately 3 days). In LEAP 2, participants were treated with oral lefamulin 600 mg every 12 hours (for 5 days) or moxifloxacin 400 mg every 24 hours (for 7 days).
In both studies, early clinical response (ECR) was evaluated at 96±24 hours following the drug dose and investigator assessment of clinical response (IACR) at test of cure (ie, 5 to 10 days after the last dose). Patients who were eligible for enrollment included adults with radiographically diagnosed pneumonia, Pneumonia Outcomes Research Team (PORT) risk class 3 to 5 in LEAP 1 or PORT risk class 2 to 4 in LEAP 2, acute onset of at least 3 symptoms of CABP, at least 2 vital sign abnormalities, and at least 1 additional clinical sign or laboratory finding of CABP.
The pooled intent-to-treat (ITT) population included a total of 1289 patients, of whom 646 were randomly assigned to lefamulin and 643 to moxifloxacin. Baseline disease and demographic characteristics were well balanced between the treatment arms. In the pooled ITT population, ECR rates were high (89.3% with lefamulin vs 90.5% with moxifloxacin; difference of -1.1%; 95% CI, -4.4 to 2.2), with lefamulin noninferior to moxifloxacin. Overall, more than 60% of patients met ECR criteria by day 3, and more than 80% of patients in both treatment arms met ECR criteria by day 4 and further increases through day 7.
Lefamulin was noninferior to moxifloxacin with respect to IACR success in both the modified ITT and clinically evaluable populations, with success rates at test-of-cure similarly high (≥85.0%). High efficacy with both agents was also reported across all well-represented patient subgroups, including individuals with advanced age, diabetes, history of cardiovascular disease (eg, hypertension, arrhythmia, or congestive heart failure), history of chronic lung disease (eg, chronic obstructive pulmonary disease or asthma), mild to moderate renal dysfunction, or elevated liver enzymes.
A major limitation of the current study is the lack of generalizability, as enrollment criteria possibly excluded some patients typically seen in clinical practice, including those at risk for major cardiac events, individuals with severely impaired renal function, and those with significant hepatic disease.
The investigators concluded that lefamulin may be a promising empiric monotherapy option for both inpatients and outpatients with CABP. In view of escalating antibacterial resistance with macrolides, tolerability concerns with other classes of antibiotics (eg, fluoroquinolones and beta-lactams), and/or failure of other classes of antibiotics, lefamulin may provide a welcome alternative.
Disclosure: This research was supported by Nabriva Therapeutics. Please see the original reference for a full list of authors’ disclosures.
File TM Jr, Alexander E, Goldberg L, et al. Lefamulin efficacy and safety in a pooled phase 3 clinical trial population with community-acquired bacterial pneumonia and common clinical comorbidities. BMC Pulm Med. 2021;21(1):154. doi:10.1186/s12890-021-01472-z