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Lefamulin in Patients with Community-Acquired Bacterial Pneumonia Caused by Atypical Respiratory Pathogens: Pooled Results from Two Phase 3 Trials.

ABSTRACT: Lefamulin was the first systemic pleuromutilin antibiotic approved for intravenous and oral use in adults with community-acquired bacterial pneumonia based on two phase 3 trials (Lefamulin Evaluation Against Pneumonia [LEAP]-1 and LEAP-2). This pooled analysis evaluated lefamulin efficacy and safety in adults with community-acquired bacterial pneumonia caused by atypical pathogens (Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydia pneumoniae). In LEAP-1, participants received intravenous lefamulin 150 mg every 12 h for 5-7 days or moxifloxacin 400 mg every 24 h for 7 days, with optional intravenous-to-oral switch. In LEAP-2, participants received oral lefamulin 600 mg every 12 h for 5 days or moxifloxacin 400 mg every 24 h for 7 days. Primary outcomes were early clinical response at 96 ± 24 h after first dose and investigator assessment of clinical response at test of cure (5-10 days after last dose). Atypical pathogens were identified in 25.0% (91/364) of lefamulin-treated patients and 25.2% (87/345) of moxifloxacin-treated patients; most were identified by ≥1 standard diagnostic modality (M. pneumoniae 71.2% [52/73]; L. pneumophila 96.9% [63/65]; C. pneumoniae 79.3% [46/58]); the most common standard diagnostic modality was serology. In terms of disease severity, more than 90% of patients had CURB-65 (confusion of new onset, blood urea nitrogen > 19 mg/dL, respiratory rate ≥ 30 breaths/min, blood pressure <90 mm Hg systolic or ≤60 mm Hg diastolic, and age ≥ 65 years) scores of 0-2; approximately 50% of patients had PORT (Pneumonia Outcomes Research Team) risk class of III, and the remaining patients were more likely to have PORT risk class of II or IV versus V. In patients with atypical pathogens, early clinical response (lefamulin 84.4-96.6%; moxifloxacin 90.3-96.8%) and investigator assessment of clinical response at test of cure (lefamulin 74.1-89.7%; moxifloxacin 74.2-97.1%) were high and similar between arms. Treatment-emergent adverse event rates were similar in the lefamulin (34.1% [31/91]) and moxifloxacin (32.2% [28/87]) groups. Limitations to this analysis include its post hoc nature, the small numbers of patients infected with atypical pathogens, the possibility of PCR-based diagnostic methods to identify non-etiologically relevant pathogens, and the possibility that these findings may not be generalizable to all patients. Lefamulin as short-course empiric monotherapy, including 5-day oral therapy, was well tolerated in adults with community-acquired bacterial pneumonia and demonstrated high clinical response rates against atypical pathogens.

SUBMITTER: Paukner S

PROVIDER: S-EPMC8698636 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Empirical antibiotic coverage for atypical pathogens in community-acquired pneumonia (CAP) has long been debated, mainly because of a lack of epidemiological data. We aimed to assess both testing for atypical pathogens and their prevalence in hospitalized patients with CAP worldwide, especially in relation with disease severity. METHODS:A secondary analysis of the GLIMP database, an international, multicentre, point-prevalence study of adult patients admitted for CAP in 222 hospitals across 6 continents in 2015, was performed. The study evaluated frequency of testing for atypical pathogens, including L. pneumophila, M. pneumoniae, C. pneumoniae, and their prevalence. Risk factors for testing and prevalence for atypical pathogens were assessed through univariate analysis. RESULTS:Among 3702 CAP patients 1250 (33.8%) underwent at least one test for atypical pathogens. Testing varies greatly among countries and its frequency was higher in Europe than elsewhere (46.0% vs. 12.7%, respectively, p?<?0.0001). Detection of L. pneumophila urinary antigen was the most common test performed worldwide (32.0%). Patients with severe CAP were less likely to be tested for both atypical pathogens considered together (30.5% vs. 35.0%, p?=?0.009) and specifically for legionellosis (28.3% vs. 33.5%, p?=?0.003) than the rest of the population. Similarly, L. pneumophila testing was lower in ICU patients. At least one atypical pathogen was isolated in 62 patients (4.7%), including M. pneumoniae (26/251 patients, 10.3%), L. pneumophila (30/1186 patients, 2.5%), and C. pneumoniae (8/228 patients, 3.5%). Patients with CAP due to atypical pathogens were significantly younger, showed less cardiovascular, renal, and metabolic comorbidities in comparison to adult patients hospitalized due to non-atypical pathogen CAP. CONCLUSIONS:Testing for atypical pathogens in patients admitted for CAP in poorly standardized in real life and does not mirror atypical prevalence in different settings. Further evidence on the impact of atypical pathogens, expecially in the low-income countries, is needed to guidelines implementation.

Project description:BackgroundLefamulin, a first-in-class pleuromutilin antibiotic approved for intravenous and oral use in adults with community-acquired bacterial pneumonia (CABP), was noninferior to moxifloxacin in the Lefamulin Evaluation Against Pneumonia (LEAP) 1 intravenous-to-oral switch study and the LEAP 2 oral-only study. Using pooled LEAP 1/2 data, we examined lefamulin efficacy/safety overall and within subgroups of patients presenting with comorbidities typical in CABP management.MethodsIn LEAP 1, adults with CABP were randomized to receive intravenous lefamulin (150 mg every 12 h) for 5‒7 days or moxifloxacin (400 mg every 24 h) for 7 days, with optional intravenous-to-oral switch if predefined improvement criteria were met. In LEAP 2, adults with CABP were randomized to receive oral lefamulin (600 mg every 12 h) for 5 days or moxifloxacin (400 mg every 24 h) for 7 days. Both studies assessed early clinical response (ECR) at 96 ± 24 h after first study drug dose and investigator assessment of clinical response (IACR) at test-of-cure (5‒10 days after last dose). Pooled analyses of the overall population used a 10% noninferiority margin.ResultsLefamulin (n = 646) was noninferior to moxifloxacin (n = 643) for ECR (89.3% vs 90.5%, respectively; difference - 1.1%; 95% CI - 4.4 to 2.2); IACR success rates at test-of-cure were similarly high (≥ 85.0%). High efficacy with both lefamulin and moxifloxacin was also demonstrated across all well-represented patient subgroups, including those with advanced age, diabetes mellitus, a history of cardiovascular diseases (e.g., hypertension, congestive heart failure, or arrhythmia) or chronic lung diseases (e.g., asthma or chronic obstructive pulmonary disease), elevated liver enzymes, or mild-to-moderate renal dysfunction. No new safety signals were identified.ConclusionsLefamulin may provide a valuable intravenous/oral monotherapy alternative to fluoroquinolones or macrolides for empiric treatment of patients with CABP, including cases of patients at risk for poor outcomes due to age or various comorbidities.Trial registrationClinicalTrials.gov LEAP 1 (NCT02559310; Registration Date: 24/09/2015) and LEAP 2 (NCT02813694; Registration Date: 27/06/2016).

Project description:Abstract Background Lefamulin, a first in class pleuromutilin, is being developed as an IV and oral formulation for treating CABP. The second of 2 phase 3 Lefamulin Evaluation Against Pneumonia studies, LEAP 2 (NCT02813694; EudraCT 2015-004782-92) evaluating an oral 5-day regimen, is presented here. LEAP 2 complements the positive results from LEAP 1, an IV-to-oral switch study in patients with PORT Risk Class III-V. Methods In this multicenter, randomized, double-blind, double dummy study, patients with CABP were randomized to oral lefamulin 600 mg q12h for 5 days or moxifloxacin 400 mg q24h for 7 days. Adults with PORT Risk Class II–IV were eligible (?50% were to have PORT Risk Class III or IV). The US FDA primary endpoint was early clinical response (ECR) (96 ± 24 h after first dose) in the intent-to-treat (ITT) population. The EMA coprimary endpoints (FDA secondary endpoints) were investigator assessment of clinical response (IACR) at test of cure (TOC) (5–10 days after last dose) in the modified ITT (mITT) and clinically evaluable (CE) TOC populations. For FDA and EMA endpoints, noninferiority was concluded if the lower limit of the two-sided 95% CI was greater than –10% (Figure 1). Results A total of 738 patients were randomized (n = 370 lefamulin, n = 368 moxifloxacin). Five days of lefamulin was noninferior to 7 days of moxifloxacin for both FDA and EMA primary endpoints (Figure 2). Lefamulin was efficacious regardless of PORT Risk Class (ECR responder rates for PORT II, III, and IV: 91.8% [168/183], 91.0% [132/145], and 85.0% [34/40] for lefamulin; 93.1% [176/189], 90.2% [120/133], and 85.7% [36/42] for moxifloxacin, respectively). Both agents demonstrated similar ECR responder and IACR success rates across baseline CABP pathogens. Rates of serious adverse events (AEs) and AEs leading to discontinuation were low and similar between groups. Most frequently reported AEs were gastrointestinal, the majority of mild severity with few discontinuations. Conclusion Five-day oral lefamulin demonstrated noninferiority for both FDA and EMA efficacy endpoints vs. 7-day oral moxifloxacin. Both agents were safe and generally well tolerated. Lefamulin shows promise as an oral monotherapy with a complete spectrum of antibacterial activity against CABP pathogens. Disclosures E. Alexander, Nabriva: Employee and Shareholder, Salary and Stock Options. L. Goldberg, Nabriva: Employee, Employee Stock Options and Salary. A. Das, Achaogen: Consultant, Consulting fee. Cempra: Consultant, Consulting fee. Contrafect: Consultant, Consulting fee. Paratek: Consultant, Consulting fee. Tetraphase: Consultant, Consulting fee. Wockhardt: Consultant, Consulting fee. Theravance: Consultant, Consulting fee. Zavante: Consultant, Consulting fee. Utility: Consultant, Consulting fee. Former Employee of Nabriva: Employee, Salary. Nabriva: Consultant, Consulting fee. G. J. Moran, Nabriva: Scientific Advisor, Consulting fee. C. Sandrock, Nabriva: Consultant, Consulting fee. L. B. Gasink, Former Employee of Nabriva: Employee, Salary. P. Spera, Nabriva: Employee and Shareholder, Salary. C. Sweeney, Nabriva: Employee, Employee Stock Options and Salary. S. Paukner, Nabriva: Employee and Shareholder, Salary. W. W. Wicha, Nabriva: Employee and Shareholder, Salary. J. Schranz, Nabriva: Employee and Shareholder, Salary.

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Lefamulin in Patients with Community-Acquired Bacterial Pneumonia Caused by Atypical Respiratory Pathogens: Pooled Results from Two Phase 3 Trials.

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