Lefamulin. Comment on: "Novel Antibiotics for Multidrug-Resistant Gram-Positive Microorganisms. Microorganisms, 2019, 7, 270".
ABSTRACT: On 18 August 2019, an article was published in Microorganisms presenting novel, approved anti-Gram-positive antibiotics. On 19 August 2019, the U.S. Food and Drug Administration announced the approval of lefamulin, a representative of a new class of antibiotics, the pleuromutilins, for the treatment of adult community-acquired bacterial pneumonia. We present a brief description of lefamulin.
Project description:The pleuromutilin antibiotic lefamulin demonstrated in vitro activity against the most relevant bacterial pathogens causing sexually transmitted infections (STI), including Chlamydia trachomatis (MIC50/90, 0.02/0.04 mg/liter; n = 15), susceptible and multidrug-resistant Mycoplasma genitalium (MIC range, 0.002 to 0.063 mg/liter; n = 6), and susceptible and resistant Neisseria gonorrhoeae (MIC50/90, 0.12/0.5 mg/liter; n = 25). The results suggest that lefamulin could be a promising first-line antibiotic for the treatment of STI, particularly in populations with high rates of resistance to standard-of-care antibiotics.
Project description:OBJECTIVES:To explore the pharmacokinetics (PK) of oral and intravenous (iv) lefamulin after single and multiple doses, and the effect of food on bioavailability. METHODS:Lefamulin PK was examined in four studies. In Study 1, PK was assessed in patients with acute bacterial skin and skin structure infections who received repeated iv lefamulin q12h (150 mg). In Study 2, a four-period crossover study, healthy subjects received a single dose of oral lefamulin [immediate-release (IR) tablet, 1 × 600 mg] in a fasted and fed state, oral lefamulin (capsule, 3 × 200 mg) in a fasted state, and iv lefamulin in a fasted state. In Study 3, a three-period crossover study, healthy males received a single oral lefamulin dose (IR) in the following states: fasted, fasted followed by a high-calorie meal 1 h post-dose, and fed. Study 4 had two parts; in part A, healthy males received a single lefamulin dose (IR) in a fasted and fed state; in part B, subjects received repeated doses of lefamulin (IR, q12h) or placebo. Adverse events (AEs) were recorded in each study. RESULTS:Single and repeated dosing of iv and oral lefamulin resulted in comparable exposure. Intravenous and oral lefamulin (given fasted or with a meal 1 h post-dose) resulted in bioequivalence. Bioequivalence was not established between oral lefamulin in the fed state and iv or oral administration in the fasted state. All AEs were mild or moderate in severity, no serious AEs were reported, and no participant discontinued because of an AE. CONCLUSIONS:The PK of lefamulin supports successful switch from iv to oral therapy; lefamulin was generally well tolerated.
Project description:BACKGROUND:Lefamulin, a pleuromutilin antibiotic, is active against pathogens commonly causing community-acquired bacterial pneumonia (CABP). The Lefamulin Evaluation Against Pneumonia (LEAP 1) study was a global noninferiority trial to evaluate the efficacy and safety of lefamulin for the treatment of CABP. METHODS:In this double-blind study, adults with CABP of Pneumonia Outcomes Research Team risk class ?III were randomized 1:1 to receive lefamulin at 150 mg intravenously (IV) every 12 hours or moxifloxacin at 400 mg IV every 24 hours. After 6 doses, patients could be switched to an oral study drug if prespecified improvement criteria were met. If methicillin-resistant Staphylococcus aureus was suspected, either linezolid or placebo was added to moxifloxacin or lefamulin, respectively. The US Food and Drug Administration primary endpoint was an early clinical response (ECR) 96 ± 24 hours after the first dose of the study drug in the intent-to-treat (ITT) population (noninferiority margin, 12.5%). The European Medicines Agency co-primary endpoints were an investigator assessment of clinical response (IACR) 5-10 days after the last dose of the study drug in the modified ITT (mITT) and clinically evaluable (CE) populations (noninferiority margin, 10%). RESULTS:There were 551 patients randomized (n = 276 lefamulin; n = 275 moxifloxacin). Lefamulin was noninferior to moxifloxacin for ECR (87.3% vs 90.2%, respectively; difference -2.9%, 95% confidence interval [CI] g -8.5 to 2.8) and IACR (mITT, 81.7% vs 84.2%, respectively; difference -2.6%, 95% CI -8.9 to 3.9; CE, 86.9% vs 89.4%, respectively; difference -2.5%, 95% CI -8.4 to 3.4). Rates of study drug discontinuation due to treatment-emergent adverse events were 2.9% for lefamulin and 4.4% for moxifloxacin. CONCLUSIONS:Lefamulin was noninferior to moxifloxacin for the primary efficacy endpoints and was generally safe and well tolerated. CLINICAL TRIALS REGISTRATION:NCT02559310.
Project description: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 ?]). 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 ?]) and 89.7% and 93.6%, respectively, in the clinically evaluable population (difference, -3.9% [1-sided 97.5% CI, -8.2% to ?]) 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.
Project description:AbstractBackgroundLefamulin, 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.MethodsIn 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).ResultsA total of 738 patients were randomized ( = 370 lefamulin, = 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.ConclusionFive-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 , Nabriva: Employee and Shareholder, Salary and Stock Options. , Nabriva: Employee, Employee Stock Options and Salary. , 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. , Nabriva: Scientific Advisor, Consulting fee. , Nabriva: Consultant, Consulting fee. , Former Employee of Nabriva: Employee, Salary. , Nabriva: Employee and Shareholder, Salary. , Nabriva: Employee, Employee Stock Options and Salary. , Nabriva: Employee and Shareholder, Salary. , Nabriva: Employee and Shareholder, Salary. , Nabriva: Employee and Shareholder, Salary.
Project description:OBJECTIVES:Lefamulin is a semi-synthetic intravenous and oral pleuromutilin antibiotic with activity against pathogens commonly associated with community-acquired bacterial pneumonia. Using data from two Phase 1 studies, a population pharmacokinetics (PPK) model for lefamulin in plasma and epithelial lining fluid (ELF) was constructed. METHODS:Plasma pharmacokinetic (PK) data from a crossover, bioavailability, food-effect study and plasma and ELF PK data from a tissue penetration study in normal healthy volunteers were used to construct a PPK model for lefamulin. Model development involved refinement of a previous PPK model for intravenous and oral administration, followed by application of the model to plasma and ELF data from the tissue penetration study. The ELF penetration ratio of lefamulin was determined using model-based simulations. RESULTS:The PPK analysis data set contained 1103 plasma and 12 ELF lefamulin concentrations from 32 subjects. A three-compartment model with non-linear protein binding and two parallel absorption processes provided precise and unbiased estimated plasma concentration-time profiles. The absorption rate was slower and bioavailability was decreased after a high-fat/high-calorie meal. ELF data were well described using first-order rate constants into and out of the ELF compartment. The median predicted lefamulin total-drug ELF AUC0-24/free-drug plasma AUC0-24 ratio was ∼5:1 after intravenous or oral administration. CONCLUSIONS:The final PPK model allowed precise characterization of plasma and ELF exposures after intravenous and oral administration. The high ELF penetration ratio suggests that the penetration of lefamulin into the effect site is rapid and extensive, irrespective of route of administration.
Project description:Lefamulin was evaluated against various Streptococcus pneumoniae serotypes that were collected from adults with lower respiratory tract infections. Lefamulin exhibited MIC50 and MIC90 values of 0.12 and 0.25 ?g/ml, respectively, against the entire collection (n = 822). Similar results were obtained for lefamulin against each of the most common serotypes as well as against multidrug-resistant isolates and strains that are nonsusceptible to ceftriaxone or erythromycin. These data support the clinical development of lefamulin for the treatment of community-acquired respiratory tract infections.
Project description:Time to clinical response, a proxy for hospital "discharge readiness," was compared between CABP inpatients who received lefamulin or moxifloxacin in the Lefamulin Evaluation Against Pneumonia (LEAP) trials. The analysis included 926 inpatients. A short and comparable median time to clinical response (4 days) was observed in both treatment groups.
Project description:Background:Interest in patient-reported outcomes (PROs) as part of benefit-risk assessment for new drug approvals is increasing. Lefamulin is the first intravenous (IV) and oral pleuromutilin antibiotic for treatment of adults with community-acquired bacterial pneumonia (CABP). Assessment of health-related quality of life (HRQoL) was prospectively incorporated in its CABP trials (Lefamulin Evaluation Against Pneumonia [LEAP] 1 and 2) via the 12-Item Short-Form Survey (SF-12), a widely used PRO that measures general health status in 8 domains. Methods:HRQoL was evaluated by SF-12 at baseline and test of cure (TOC; 5-10 days after the last study drug dose) in patients who received lefamulin or moxifloxacin in LEAP 1 (IV/oral treatment) and LEAP 2 (oral-only treatment). SF-12 outcomes included the 8 domains, physical component and mental component summary scores, and the Short-Form Six-Dimension health utility score. Results:Analysis included 1215 patients (lefamulin: n = 607; moxifloxacin: n = 608). At baseline, all mean SF-12 scores in both treatment groups were well below the United States reference mean. Clinically meaningful and significant improvements from baseline to TOC were observed in all SF-12 scores. No significant differences in mean score improvements from baseline to TOC between treatment groups were observed. SF-12 score improvements at TOC across predefined subgroups were comparable between treatment groups. Conclusions:Results indicate that adults with CABP experienced comparable HRQoL improvements with lefamulin relative to moxifloxacin, and treatment with either agent resulted in returns to population norm HRQoL levels. These data suggest that lefamulin is a potential alternative to moxifloxacin for treatment of adults with CABP.
Project description:OBJECTIVES:Lefamulin is a semi-synthetic intravenous (iv) and oral pleuromutilin antibiotic active against community-acquired bacterial pneumonia (CABP) pathogens. Pharmacokinetic/pharmacodynamic (PK/PD) target attainment analyses were carried out to evaluate lefamulin 150 mg iv q12h and 600 mg orally q12h under fed and fasted conditions for the treatment of patients with CABP. METHODS:The analyses undertaken used a population PK model based on Phase 1 PK data, non-clinical PK/PD targets for efficacy and in vitro surveillance data for Streptococcus pneumoniae (SP) and Staphylococcus aureus (SA), and Monte Carlo simulation. Percentage probabilities of PK/PD target attainment by MIC on day 1 were determined using median total-drug epithelial lining fluid (ELF) and free-drug plasma AUC:MIC ratio targets associated with 1 and 2 log10 cfu reductions from baseline. RESULTS:Percentage probabilities of attaining the total-drug ELF AUC:MIC ratio target for a 1 log10 cfu reduction from baseline for SP were ≥99.2% at the MIC90 of 0.12 mg/L and 96.7%, 82.1% and 96.3% for iv and oral dosing regimens under fed and fasted conditions, respectively, at the MIC99 of 0.25 mg/L. Percentage probabilities of attaining the free-drug plasma AUC:MIC target for the same endpoint at the SP MIC99 were 100% for each regimen. For the SA MIC90 of 0.12 mg/L and AUC:MIC ratio targets for the same endpoint, percentage probabilities were 92.7%-100% for iv and oral dosing regimens. CONCLUSIONS:These data provide support for lefamulin 150 mg iv q12h and 600 mg orally q12h for the treatment of patients with CABP and suggest that doses may not need to be taken under fasted conditions.