RESUMEN
Lefamulin is a first-in-class systemic pleuromutilin antimicrobial and potent inhibitor of bacterial translation, and the most recent novel antimicrobial approved for the treatment of community-acquired pneumonia (CAP). It exhibits potent antibacterial activity against the most prevalent bacterial pathogens that cause typical and atypical pneumonia and other infectious diseases. Early studies indicate additional anti-inflammatory activity. In this study, we further investigated the immune-modulatory activity of lefamulin in the influenza A/H1N1 acute respiratory distress syndrome (ARDS) model in BALB/c mice. Comparators included azithromycin, an anti-inflammatory antimicrobial, and the antiviral oseltamivir. Lefamulin significantly decreased the total immune cell infiltration, specifically the neutrophils, inflammatory monocytes, CD4+ and CD8+ T-cells, NK cells, and B-cells into the lung by Day 6 at both doses tested compared to the untreated vehicle control group (placebo), whereas azithromycin and oseltamivir did not significantly affect the total immune cell counts at the tested dosing regimens. Bronchioalveolar lavage fluid concentrations of pro-inflammatory cytokines and chemokines including TNF-α, IL-6, IL-12p70, IL-17A, IFN-γ, and GM-CSF were significantly reduced, and MCP-1 concentrations were lowered (not significantly) by lefamulin at the clinically relevant 'low' dose on Day 3 when the viral load peaked. Similar effects were also observed for oseltamivir and azithromycin. Lefamulin also decreased the viral load (TCID50) by half a log10 by Day 6 and showed positive effects on the gross lung pathology and survival. Oseltamivir and lefamulin were efficacious in the suppression of the development of influenza-induced bronchi-interstitial pneumonia, whereas azithromycin did not show reduced pathology at the tested treatment regimen. The observed anti-inflammatory and immune-modulatory activity of lefamulin at the tested treatment regimens highlights a promising secondary pharmacological property of lefamulin. While these results require confirmation in a clinical trial, they indicate that lefamulin may provide an immune-modulatory activity beyond its proven potent antibacterial activity. This additional activity may benefit CAP patients and potentially prevent acute lung injury (ALI) and ARDS.
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Modelos Animales de Enfermedad , Diterpenos , Subtipo H1N1 del Virus de la Influenza A , Ratones Endogámicos BALB C , Infecciones por Orthomyxoviridae , Animales , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Ratones , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/virología , Diterpenos/farmacología , Diterpenos/uso terapéutico , Citocinas/metabolismo , Azitromicina/farmacología , Azitromicina/uso terapéutico , Oseltamivir/farmacología , Oseltamivir/uso terapéutico , Femenino , Pulmón/inmunología , Pulmón/virología , Pulmón/efectos de los fármacos , Pulmón/patología , Antivirales/farmacología , Antivirales/uso terapéutico , Tetrahidronaftalenos/farmacología , Tetrahidronaftalenos/uso terapéutico , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/inmunología , Síndrome de Dificultad Respiratoria/virología , Agentes Inmunomoduladores/farmacología , Agentes Inmunomoduladores/uso terapéutico , Líquido del Lavado Bronquioalveolar/inmunología , Compuestos Policíclicos , TioglicolatosRESUMEN
OBJECTIVES: Lefamulin (Xenleta™), a pleuromutilin antibiotic, was approved for the oral and IV treatment of community-acquired bacterial pneumonia (CABP) in adults in 2019/2020. This study evaluated the in vitro activity of lefamulin and comparators against 19 584 unique bacterial isolates collected from patients with community-acquired respiratory tract infections and hospitalized patients with pneumonia within the global SENTRY Antimicrobial Surveillance Program during 2015-21. METHODS: Isolates were susceptibility tested by the CLSI broth microdilution method, and resistance mechanisms were investigated in isolates with elevated lefamulin MICs. RESULTS: Lefamulin exhibited potent antibacterial activity against the most common and typical CABP pathogens tested, including Streptococcus pneumoniae [MIC50/90, 0.06/0.25 mg/L; 99.9% susceptible (S)], Staphylococcus aureus (MIC50/90, 0.06/0.12 mg/L; 99.6% S), Haemophilus influenzae (MIC50/90, 0.5/2 mg/L; 99.1% S) and Moraxella catarrhalis (MIC50/90, 0.06/0.12 mg/L; 100.0% S). Potent activity was also observed against the less common pneumonia pathogens: ß-haemolytic (MIC50/90 of 0.03/0.06 mg/L) and viridans group Streptococcus spp. (MIC50/90 of 0.06/0.25 mg/L) and Haemophilus parainfluenzae (MIC50/90 of 1/4 mg/L). Lefamulin's activity was not adversely affected by resistance to macrolides, penicillin, tetracyclines, fluoroquinolones and other resistance phenotypes. Non-susceptibility/resistance to lefamulin was rare and primarily determined by ribosomal protection through vga(A) variants in S. aureus, overexpression of AcrAB-TolC efflux pump in H. influenzae or modifications in L3, L4 and 23SrRNA in Streptococcus spp. CONCLUSIONS: Based on the coverage of the most important CABP pathogens and lacking cross-resistance, lefamulin may represent a valuable empirical treatment option for ambulatory and hospitalized patients with CABP, particularly in settings with high prevalence of resistance.
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Infecciones Comunitarias Adquiridas , Diterpenos , Neumonía , Compuestos Policíclicos , Infecciones del Sistema Respiratorio , Tioglicolatos , Humanos , Staphylococcus aureus , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Infecciones del Sistema Respiratorio/microbiología , Bacterias , Neumonía/tratamiento farmacológico , Pruebas de Sensibilidad Microbiana , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Infecciones Comunitarias Adquiridas/microbiología , Haemophilus influenzaeRESUMEN
OBJECTIVES: To determine the phenotypic and genotypic antibiotic susceptibility of Mycoplasma amphoriforme isolates recovered from patients in the UK and Denmark. METHODS: Seven isolates of M. amphoriforme were examined for antimicrobial susceptibility to seven antibiotics using the microbroth dilution assay in line with the CLSI guidelines for mycoplasmas. Each isolate was additionally subjected to WGS to identify resistance-associated mutations. Based on the consensus sequences from the genomic data, PCR primers were designed, and tested, for the amplification of the QRDR within the parC gene. RESULTS: Of the seven isolates investigated, four (57%) were resistant to moxifloxacin (0.5-1â mg/L) and levofloxacin (1-2â mg/L), compared with those that were susceptible (0.03-0.06 and 0.006â mg/L, respectively). Isolate H29 was resistant to five of the seven antibiotics tested: moxifloxacin, 0.5â mg/L; levofloxacin, 2â mg/L; azithromycin, 64â mg/L; erythromycin, 128â mg/L; and clindamycin, 64â mg/L. All isolates were susceptible to tetracycline (0.06â mg/L) and lefamulin (0.001-0.004â mg/L). Mutations from genomic data confirmed the presence of an S89F mutation within the ParC protein among all fluoroquinolone-resistant isolates and an A2059G mutation in the 23S rRNA gene in the macrolide- and lincosamide-resistant isolate H29. CONCLUSIONS: To the best of our knowledge, this is the first time where phenotypic and genotypic resistance data have been paired for M. amphoriforme confirming a correlation between the two. These data suggest the need for focused testing and resistance determination of isolates from high-risk patients given the backdrop of a high prevalence of antimicrobial resistance.
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Antibacterianos , Levofloxacino , Humanos , Moxifloxacino , Pruebas de Sensibilidad Microbiana , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Dinamarca , Reino Unido , Farmacorresistencia BacterianaRESUMEN
WHAT IS THIS SUMMARY ABOUT?: Bacterial pneumonia is an infection of the lung caused by bacteria that is potentially deadly, costly, and affects millions of people worldwide every year. Treatment is becoming more challenging-many current treatments no longer work well because some strains of bacteria that cause pneumonia have become resistant to current antibiotics. Many of the antibiotics that do still work have undesirable side effects. Therefore, new antibiotics that work differently are needed to treat bacterial pneumonia. Lefamulin (brand name, Xenleta®) is an antibiotic that was approved to treat bacterial pneumonia caught outside a hospital (also called community-acquired bacterial pneumonia, or CABP) based on results of two clinical studies. In both studies, participants started treatment with lefamulin before the type of bacteria causing the infection was known. Lefamulin was well tolerated and worked well in 5 to 7 days to kill the bacteria causing the infection and to improve symptoms in almost all participants with CABP. WHAT WERE THE RESULTS?: After the studies were completed, the researchers looked back at what kinds of bacteria were identified from the study participants. Lefamulin worked well to kill bacteria and to improve CABP symptoms for most kinds of infecting bacteria, including bacteria resistant to many current antibiotics. WHAT DO THE RESULTS MEAN?: These results suggest that lefamulin, by itself, provides a much-needed treatment option for CABP that covers most of the key bacteria causing this infection.
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Infecciones Comunitarias Adquiridas , Neumonía Bacteriana , Antibacterianos/administración & dosificación , Bacterias/efectos de los fármacos , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Infecciones Comunitarias Adquiridas/microbiología , Diterpenos , Hospitales , Humanos , Lenguaje , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Bacteriana/microbiología , Compuestos Policíclicos , TioglicolatosRESUMEN
OBJECTIVES: Lefamulin, a pleuromutilin antibiotic approved for community-acquired bacterial pneumonia (CABP), was evaluated for microbiological efficacy in a prespecified pooled analysis of LEAP 1 and 2 phase 3 clinical trial data in patients with CABP. METHODS: In LEAP 1, adults (PORT risk class IIIâV) received intravenous (IV) lefamulin 150 mg every 12 h (q12h) for 5â7 days or moxifloxacin 400 mg every 24 h (q24h) for 7 days, with optional IV-to-oral switch. In LEAP 2, adults (PORT IIâIV) received oral lefamulin 600 mg q12h for 5 days or moxifloxacin 400 mg q24h for 7 days. Primary outcomes were early clinical response (ECR) at 96 ± 24 h after treatment start and investigator assessment of clinical response (IACR) 5â10 days after the last dose. Secondary outcomes included ECR and IACR in patients with a baseline CABP pathogen (detected via culture, urinary antigen testing, serology and/or real-time PCR). RESULTS: Baseline CABP pathogens were detected in 709/1289 patients (55.0%; microbiological intention-to-treat population). The most frequently identified pathogens were Streptococcus pneumoniae (61.9% of patients) and Haemophilus influenzae (29.9%); 25.1% had atypical pathogens and 33.1% had polymicrobial infections. Pathogens were identified most frequently by PCR from sputum, followed by culture from respiratory specimens. In patients with baseline CABP pathogens, ECR rates were 89.3% (lefamulin) and 93.0% (moxifloxacin); IACR success rates were 83.2% and 86.7%, respectively. Results were consistent across CABP pathogens, including drug-resistant isolates and polymicrobial infections. CONCLUSION: Lefamulin is a valuable IV and oral monotherapy option for empirical and directed CABP treatment in adults.
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Coinfección , Infecciones Comunitarias Adquiridas , Neumonía Bacteriana , Adulto , Bacterias , Coinfección/tratamiento farmacológico , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Infecciones Comunitarias Adquiridas/microbiología , Diterpenos , Humanos , Pruebas de Sensibilidad Microbiana , Moxifloxacino/uso terapéutico , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Bacteriana/microbiología , Compuestos Policíclicos , TioglicolatosRESUMEN
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.
RESUMEN
Lefamulin is the first of the pleuromutilin class of antimicrobials to be available for therapeutic use in humans. Minimum inhibitory concentrations of lefamulin were determined by microbroth dilution for 90 characterised clinical isolates (25 Ureaplasma parvum, 25 Ureaplasma urealyticum, and 40 Mycoplasma hominis). All Mycoplasma hominis isolates possessed lefamulin MICs of ≤0.25 mg/L after 48 h (MIC50/90 of 0.06/0.12 mg/L), despite an inherent resistance to macrolides; while Ureaplasma isolates had MICs of ≤2 mg/L after 24 h (MIC50/90 of 0.25/1 mg/L), despite inherent resistance to clindamycin. Two U. urealyticum isolates with additional A2058G mutations of 23S rRNA, and one U. parvum isolate with a R66Q67 deletion (all of which had a combined resistance to macrolides and clindamycin) only showed a 2-fold increase in lefamulin MIC (1-2 mg/L) relative to macrolide-susceptible strains. Lefamulin could be an effective alternative antimicrobial for treating Ureaplasma spp. and Mycoplasma hominis infections irrespective of intrinsic or acquired resistance to macrolides, lincosamides, and ketolides. Based on this potent in vitro activity and the known good, rapid, and homogenous tissue penetration of female and male urogenital tissues and glands, further exploration of clinical efficacy of lefamulin for the treatment of Mycoplasma and Ureaplasma urogenital infections is warranted.
RESUMEN
Several antibiotics demonstrate both antibacterial and anti-inflammatory/immunomodulatory activities and are used to treat inflammatory pulmonary disorders. Lefamulin is a pleuromutilin antibiotic approved to treat community-acquired bacterial pneumonia (CABP). This study evaluated lefamulin anti-inflammatory effects in vivo and in vitro in a lipopolysaccharide-induced lung neutrophilia model in which mouse airways were challenged with intranasal lipopolysaccharide. Lefamulin and comparators azithromycin and dexamethasone were administered 30min before lipopolysaccharide challenge; neutrophil infiltration into BALF and inflammatory mediator induction in lung homogenates were measured 4h postchallenge. Single subcutaneous lefamulin doses (10â140mg/kg) resulted in dose-dependent reductions of BALF neutrophil cell counts, comparable to or more potent than subcutaneous azithromycin (10â100mg/kg) and oral/intraperitoneal dexamethasone (0.5/1mg/kg). Lipopolysaccharide-induced pro-inflammatory cytokine (TNF-α, IL-6, IL-1ß, and GM-CSF), chemokine (CXCL-1, CXCL-2, and CCL-2), and MMP-9 levels were significantly and dose-dependently reduced in mouse lung tissue with lefamulin; effects were comparable to or more potent than with dexamethasone or azithromycin. Pharmacokinetic analyses confirmed exposure-equivalence of 30mg/kg subcutaneous lefamulin in mice to a single clinical lefamulin dose to treat CABP in humans (150mg intravenous/600mg oral). In vitro, neither lefamulin nor azithromycin had any relevant influence on lipopolysaccharide-induced cytokine/chemokine levels in J774.2 mouse macrophage or human peripheral blood mononuclear cell supernatants, nor were any effects observed on IL-8âinduced human neutrophil chemotaxis. These in vitro results suggest that impediment of neutrophil infiltration by lefamulin in vivo may not occur through direct interaction with macrophages or neutrophilic chemotaxis. This is the first study to demonstrate inhibition of neutrophilic lung infiltration and reduction of pro-inflammatory cytokine/chemokine concentrations by clinically relevant lefamulin doses. This anti-inflammatory activity may be beneficial in patients with acute respiratory distress syndrome, cystic fibrosis, or severe inflammation-mediated lung injury, similar to glucocorticoid (eg, dexamethasone) activity. Future lefamulin anti-inflammatory/immunomodulatory activity studies are warranted to further elucidate mechanism of action and evaluate clinical implications.
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Azitromicina , Diterpenos , Compuestos Policíclicos , Tioglicolatos , Animales , Infecciones Comunitarias Adquiridas , Leucocitos Mononucleares , Lipopolisacáridos , RatonesRESUMEN
BACKGROUND: Lefamulin, 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. METHODS: In LEAP 1, adults with CABP were randomized to receive intravenous lefamulin (150 mg every 12 h) for 5â7 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 (5â10 days after last dose). Pooled analyses of the overall population used a 10% noninferiority margin. RESULTS: Lefamulin (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. CONCLUSIONS: Lefamulin 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 REGISTRATION: ClinicalTrials.gov LEAP 1 (NCT02559310; Registration Date: 24/09/2015) and LEAP 2 (NCT02813694; Registration Date: 27/06/2016).
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Antibacterianos/uso terapéutico , Diterpenos/administración & dosificación , Fluoroquinolonas/administración & dosificación , Moxifloxacino/administración & dosificación , Neumonía Bacteriana/tratamiento farmacológico , Compuestos Policíclicos/administración & dosificación , Tioglicolatos/administración & dosificación , Administración Intravenosa , Administración Oral , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Comorbilidad , Diterpenos/efectos adversos , Método Doble Ciego , Femenino , Fluoroquinolonas/efectos adversos , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Moxifloxacino/efectos adversos , Compuestos Policíclicos/efectos adversos , Tioglicolatos/efectos adversos , Estados Unidos , Adulto JovenRESUMEN
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.
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OBJECTIVES: To present results of preclinical studies that supported further development of lefamulin for treating patients with community-acquired bacterial pneumonia (CABP). METHODS: The effect of bovine lung surfactant on the antibacterial activity of lefamulin against Streptococcus pneumoniae and Staphylococcus aureus was determined by broth microdilution assay. In vitro accumulation of lefamulin was evaluated in J774 mouse macrophages. Pharmacokinetics was assessed in female BALB/c (Bagg albino) mice treated with subcutaneous lefamulin (35 or 70 mg/kg). In neutropenic lung infection experiments, BALB/c mice received intraperitoneal cyclophosphamide before challenge with single S. pneumoniae or S. aureus strains; subcutaneous lefamulin (1.25-160 mg/kg) was given twice daily post-infection. Hill models described relationships between AUC/MIC ratios and changes in log10 cfu. RESULTS: Lung surfactant did not significantly increase lefamulin MIC values against test strains. Lefamulin uptake in macrophages was rapid (a plateau was reached in â¼3 h). In mice, distribution of lefamulin [plasma to epithelial lining fluid (ELF)] was rapid, showing an â¼2-fold increase in lefamulin exposure in the ELF during the 5.5 h period. Median plasma AUC/MIC ratios associated with 1 and 2 log10 cfu reductions from baseline were 1.37 and 2.15, respectively, for S. pneumoniae and 2.13 and 6.24 for S. aureus. Corresponding ELF results were 14.0 and 22.0 for S. pneumoniae and 21.7 and 63.9 for S. aureus. CONCLUSIONS: Overall, lefamulin displays desirable pharmacokinetic/pharmacodynamic relationships that are predictive of the clinical effectiveness of lefamulin and other antibacterial agents used to treat CABP.
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Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Diterpenos/farmacocinética , Diterpenos/uso terapéutico , Neutropenia/microbiología , Neumonía Neumocócica/tratamiento farmacológico , Compuestos Policíclicos/farmacocinética , Compuestos Policíclicos/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Tioglicolatos/farmacocinética , Tioglicolatos/uso terapéutico , Animales , Área Bajo la Curva , Bovinos , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Infecciones Comunitarias Adquiridas/microbiología , Ciclofosfamida/administración & dosificación , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Inyecciones Subcutáneas , Pulmón/efectos de los fármacos , Pulmón/microbiología , Macrófagos/efectos de los fármacos , Macrófagos/microbiología , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Neutropenia/inducido químicamente , Staphylococcus aureus/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacos , Tensoactivos/farmacologíaRESUMEN
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.
Asunto(s)
Diterpenos/uso terapéutico , Moxifloxacino/uso terapéutico , Neumonía Bacteriana/tratamiento farmacológico , Compuestos Policíclicos/uso terapéutico , Tioglicolatos/uso terapéutico , Administración Intravenosa , Adulto , Anciano , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Antibacterianos/uso terapéutico , Diterpenos/administración & dosificación , Diterpenos/efectos adversos , Método Doble Ciego , Femenino , Humanos , Linezolid/efectos adversos , Linezolid/uso terapéutico , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Moxifloxacino/administración & dosificación , Moxifloxacino/efectos adversos , Neumonía Bacteriana/metabolismo , Compuestos Policíclicos/administración & dosificación , Compuestos Policíclicos/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Tioglicolatos/administración & dosificación , Tioglicolatos/efectos adversos , PleuromutilinasRESUMEN
Lefamulin, the first semisynthetic pleuromutilin antibacterial for intravenous and oral treatment of community-acquired bacterial pneumonia (CABP), and comparators were evaluated for in vitro activity against a global collection of pathogens commonly causing CABP (n = 8595) from the 2015 and 2016 SENTRY Antimicrobial Surveillance Program. Lefamulin was highly active against the pathogens Streptococcus pneumoniae, including multidrug-resistant and extensively drug-resistant strains (MIC50/90 for total and resistant subsets, 0.06/0.12 µg/ml; 100% inhibited at ≤1 µg/ml), Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA; both MIC50/90, 0.06/0.12 µg/ml; 99.8% and 99.6% inhibited at ≤1 µg/ml, respectively), Haemophilus influenzae (MIC50/90, 0.5/1 µg/ml; 93.8% inhibited at ≤1 µg/ml), and Moraxella catarrhalis (MIC50/90, 0.06/0.12 µg/ml; 100% inhibited at ≤0.25 µg/ml), and its activity was unaffected by resistance to other antibacterial classes.
Asunto(s)
Antibacterianos/uso terapéutico , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Diterpenos/uso terapéutico , Neumonía Bacteriana/tratamiento farmacológico , Compuestos Policíclicos/uso terapéutico , Tioglicolatos/uso terapéutico , Infecciones Comunitarias Adquiridas/microbiología , Infecciones por Haemophilus/tratamiento farmacológico , Haemophilus influenzae/efectos de los fármacos , Humanos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Moraxella catarrhalis/efectos de los fármacos , Infecciones por Moraxellaceae/tratamiento farmacológico , Infecciones Neumocócicas/tratamiento farmacológico , Neumonía Bacteriana/microbiología , Infecciones Estafilocócicas/tratamiento farmacológico , Streptococcus pneumoniae/efectos de los fármacosRESUMEN
This study investigated the molecular mechanisms possibly associated with non-wild-type MICs for lefamulin among staphylococci and streptococci included in the lefamulin surveillance program from 2015 to 2016. A total of 2,919 Staphylococcus aureus, 276 coagulase-negative staphylococci (CoNS), 3,923 Streptococcus pneumoniae, 389 ß-hemolytic, and 178 viridans group streptococci isolates were included in the surveillance studies. Eleven (0.3% of all S. aureus) S. aureus isolates with lefamulin MICs above the staphylococcal epidemiological cutoff (ECOFF) value (>0.25 µg/ml) were selected for this study. Eight (72.7%) S. aureus (lefamulin MIC, 0.5 to 4 µg/ml) isolates carried vga(A or E), one isolate (MIC, 32 µg/ml) carried lsa(E), one isolate (MIC, 16 µg/ml) had an alteration in L4, and one strain (MIC, 0.5 µg/ml) did not carry any of the investigated resistance mechanisms. A total of 14 (5.1% of all CoNS) CoNS isolates had lefamulin MICs (0.5 to >32 µg/ml) above the ECOFF. Similar to S. aureus, 8 (57.1%) CoNS (lefamulin MIC, 1 to 8 µg/ml) isolates carried vga(A or B), while 2 isolates (MIC, 4 to 32 µg/ml) carried cfr High genetic diversity was observed among staphylococci, although 3 S. aureus isolates belonged to sequence type 398 (ST398). Among the 3 Streptococcus agalactiae and 3 viridans group streptococci (0.1% of all streptococci surveyed) isolates selected for additional characterization, all but 1 isolate carried lsa(E). This study documents a low occurrence of surveillance isolates exhibiting a non-wild-type MIC for lefamulin, and among these isolates, vga and lsa(E) prevailed in staphylococci and streptococci, respectively.
Asunto(s)
Antibacterianos/uso terapéutico , Diterpenos/uso terapéutico , Infecciones Neumocócicas/epidemiología , Compuestos Policíclicos/uso terapéutico , Infecciones Estafilocócicas/epidemiología , Staphylococcus aureus/efectos de los fármacos , Streptococcus agalactiae/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacos , Tioglicolatos/uso terapéutico , Transportadoras de Casetes de Unión a ATP/genética , Proteínas Bacterianas/genética , Humanos , Pruebas de Sensibilidad Microbiana , Infecciones Neumocócicas/tratamiento farmacológico , Infecciones Neumocócicas/microbiología , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/aislamiento & purificación , Streptococcus agalactiae/aislamiento & purificación , Streptococcus pneumoniae/aislamiento & purificaciónRESUMEN
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.
Asunto(s)
Antiinfecciosos/farmacología , Chlamydia trachomatis/efectos de los fármacos , Mycoplasma genitalium/efectos de los fármacos , Neisseria gonorrhoeae/efectos de los fármacos , Diterpenos/farmacología , Compuestos Policíclicos , Enfermedades de Transmisión Sexual/microbiología , Tioglicolatos/farmacología , PleuromutilinasRESUMEN
We evaluated the activity of the novel semisynthetic pleuromutilin lefamulin, inhibiting protein synthesis and growth, and the effect of efflux pump inactivation on clinical gonococcal isolates and reference strains (n = 251), including numerous multidrug-resistant and extensively drug-resistant isolates. Lefamulin showed potent activity against all gonococcal isolates, and no significant cross-resistance to other antimicrobials was identified. Further studies of lefamulin are warranted, including in vitro selection and mechanisms of resistance, pharmacokinetics/pharmacodynamics, optimal dosing, and performance in randomized controlled trials.
Asunto(s)
Antibacterianos/farmacología , Diterpenos/farmacología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Neisseria gonorrhoeae/efectos de los fármacos , Tioglicolatos/farmacología , Transportadoras de Casetes de Unión a ATP/metabolismo , Antiportadores/metabolismo , Azitromicina/farmacología , Proteínas Bacterianas/metabolismo , Gonorrea/microbiología , Humanos , Pruebas de Sensibilidad Microbiana , Neisseria gonorrhoeae/aislamiento & purificación , Neisseria gonorrhoeae/fisiología , Compuestos PolicíclicosRESUMEN
Pleuromutilins are antibiotics that selectively inhibit bacterial translation and are semisynthetic derivatives of the naturally occurring tricyclic diterpenoid pleuromutilin, which received its name from the pleuromutilin-producing fungus Pleurotus mutilus Tiamulin and valnemulin are two established derivatives in veterinary medicine for oral and intramuscular administration. As these early pleuromutilin drugs were developed at a time when companies focused on major antibacterial classes, such as the ß-lactams, and resistance was not regarded as an issue, interest in antibiotic research including pleuromutilins was limited. Over the last decade or so, there has been a resurgence in interest to develop this class for human use. This has resulted in a topical derivative, retapamulin, and additional derivatives in clinical development. The most advanced compound is lefamulin, which is in late-stage development for the intravenous and oral treatment of community-acquired bacterial pneumonia and acute bacterial skin infections. Overall, pleuromutilins and, in particular, lefamulin are characterized by potent activity against Gram-positive and fastidious Gram-negative pathogens as well as against mycoplasmas and intracellular organisms, such as Chlamydia spp. and Legionella pneumophila Pleuromutilins are unaffected by resistance to other major antibiotic classes, such as macrolides, fluoroquinolones, tetracyclines, ß-lactam antibiotics, and others. Furthermore, pleuromutilins display very low spontaneous mutation frequencies and slow, stepwise resistance development at sub-MIC in vitro. The potential for resistance development in clinic is predicted to be slow as confirmed by extremely low resistance rates to this class despite the use of pleuromutilins in veterinary medicine for >30 years. Although rare, resistant strains have been identified in human- and livestock-associated environments and as with any antibiotic class, require close monitoring as well as prudent use in veterinary medicine. This review focuses on the structural characteristics, mode of action, antibacterial activity, and resistance development of this potent and novel antibacterial class for systemic use in humans.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Farmacorresistencia Microbiana/genética , Diterpenos/química , Diterpenos/farmacología , Humanos , Pruebas de Sensibilidad Microbiana , Compuestos Policíclicos , Relación Estructura-Actividad , PleuromutilinasRESUMEN
Lefamulin, an investigational pleuromutilin, was tested against a collection of 18 macrolide-susceptible and 42 macrolide-resistant Mycoplasma pneumoniae strains, and the results were compared with those of azithromycin, erythromycin, tetracycline, doxycycline, and moxifloxacin testing. Lefamulin was highly active against all strains tested, with all MICs at ≤0.008 µg/ml. The lefamulin MIC90 (0.002 µg/ml) for macrolide-resistant strains was the lowest among all drugs tested. Minimum bactericidal concentrations were within 2 dilutions of the MIC values, indicating a bactericidal effect.
Asunto(s)
Antibacterianos/farmacología , Macrólidos/farmacología , Mycoplasma pneumoniae/efectos de los fármacos , Azitromicina/farmacología , China , Diterpenos/farmacología , Doxiciclina/farmacología , Farmacorresistencia Bacteriana , Eritromicina/farmacología , Europa (Continente) , Fluoroquinolonas/farmacología , Pruebas de Sensibilidad Microbiana , Moxifloxacino , Compuestos Policíclicos , Estados Unidos , PleuromutilinasRESUMEN
The increasing appearance of pathogenic bacteria with antibiotic resistance is a global threat. Consequently, clinically available potent antibiotics that are active against multidrug resistant pathogens are becoming exceedingly scarce. Ribosomes are a main target for antibiotics, and hence are an objective for novel drug development. Lefamulin, a semi-synthetic pleuromutilin compound highly active against multi-resistant pathogens, is a promising antibiotic currently in phase III trials for the treatment of community-acquired bacterial pneumonia in adults. The crystal structure of the Staphylococcus aureus large ribosomal subunit in complex with lefamulin reveals its protein synthesis inhibition mechanism and the rationale for its potency. In addition, analysis of the bacterial and eukaryotes ribosome structures around the pleuromutilin binding pocket has elucidated the key for the drug's selectivity.