Simultaneous assessment of the pharmacokinetics of a pleuromutilin, lefamulin, in plasma, soft tissues and pulmonary epithelial lining fluid

Zeitlinger, Markus; Schwameis, Richard; Burian, Angela; Burian, Bernhard; Matzneller, Peter; Müller, Markus; Wicha, W. W.; Strickmann, Dirk B; Prince, William

doi:10.1093/jac/dkv442

Cited by 59 publications

(59 citation statements)

References 18 publications

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“…The antibacterial spectrum of lefamulin covers the typical Gram-positive and fastidious Gram-negative respiratory pathogens known to cause CABP and atypical pathogens, such as M. pneumoniae (including macrolide-resistant strains), C. pneumoniae, and L. pneumophila (18,19). Pharmacokinetic and pharmacodynamic analyses demonstrated that lefamulin has rapid and predictable penetration into plasma (ϳ1 to 2 g/ml after a single 150-mg intravenous or 600-mg oral dose) (20) and target tissues, such as the epithelial lining fluid in the lung (21), reaching area under the concentration-time curve (AUC):MIC ratios that support the proposed tentative breakpoints of 1 g/ml for S. pneumoniae and 0.5 g/ml for S. aureus (22). This study evaluated the in vitro activity of lefamulin and comparators against a global collection of typical respiratory pathogens that commonly cause CABP, as collected by the SENTRY Antimicrobial Surveillance Program (2015 to 2016).…”

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confidence: 99%

Antibacterial Activity of Lefamulin against Pathogens Most Commonly Causing Community-Acquired Bacterial Pneumonia: SENTRY Antimicrobial Surveillance Program (2015–2016)

Paukner

Gelone²,

Arends

et al. 2019

Antimicrob Agents Chemother

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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 ϭ 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 (MIC 50/90 for total and resistant subsets, 0.06/0.12 g/ml; 100% inhibited at Յ1 g/ml), Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA; both MIC 50/90 , 0.06/0.12 g/ml; 99.8% and 99.6% inhibited at Յ1 g/ml, respectively), Haemophilus influenzae (MIC 50/90 , 0.5/1 g/ml; 93.8% inhibited at Յ1 g/ml), and Moraxella catarrhalis (MIC 50/90 , 0.06/0.12 g/ml; 100% inhibited at Յ0.25 g/ml), and its activity was unaffected by resistance to other antibacterial classes.

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confidence: 99%

Antibacterial Activity of Lefamulin against Pathogens Most Commonly Causing Community-Acquired Bacterial Pneumonia: SENTRY Antimicrobial Surveillance Program (2015–2016)

Paukner

Gelone²,

Arends

et al. 2019

Antimicrob Agents Chemother

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“…and Staphylococcus spp., fastidious Gram-negative organisms, such as Haemophilus influenzae, and atypical respiratory pathogens, including Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila (14)(15)(16). In addition, in healthy human subjects, lefamulin (unbound protein) demonstrated extensive penetration and accumulation in pulmonary epithelial lining fluid, reaching a median total area under the concentration-time curve from 0 to 12 h (AUC 0 -12 ) of 5.78 g · h/ml and a median maximum concentration of drug in serum (C max ) of ϳ0.7 g/ml after a single 150-mg intravenous infusion over 1 h (17). This study evaluated the in vitro activity of lefamulin against specific serotypes of clinical isolates of Streptococcus pneumoniae.…”

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confidence: 99%

In Vitro Activity of Lefamulin Tested against Streptococcus pneumoniae with Defined Serotypes, Including Multidrug-Resistant Isolates Causing Lower Respiratory Tract Infections in the United States

Mendes

Farrell

Flamm

et al. 2016

Antimicrob Agents Chemother

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Lefamulin was evaluated against various Streptococcus pneumoniae serotypes that were collected from adults with lower respiratory tract infections. Lefamulin exhibited MIC 50 and MIC 90 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.

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“…lining fluid, with epithelial lining fluid exposure to lefamulin being 5.7-fold higher than the unbound fraction in plasma [94]. Ιt is 80% protein bound in the serum, has a biologic half-life of 12 hours, and is largely excreted unchanged via the gastrointestinal tract (86%), with the remainder eliminated via the kidneys (14%) [95].…”

Section: Lefamulin Achieves Extensive Penetration and Accumulation Inmentioning

confidence: 99%

Emerging antibiotics for community-acquired pneumonia

Liapikou

Cillóniz

Palomeque

et al. 2019

Expert Opinion on Emerging Drugs

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Introduction: Community-acquired pneumonia is the most common infection leading to hospitalization and death in all age groups, especially in elderly populations. Increasing antibiotic resistance among the common bacterial pathogens associated with community-acquired pneumonia, especially Streptococcus pneumoniae and staphylococci, has made its empirical treatment increasingly problematic, highlighting the need for effective antibiotic therapy. Areas covered: We searched PubMed and ClinicalTrials.gov for English-language reports of phase III clinical trials conducted between 2000 and 2019 concerning the antibiotic treatment of community-acquired pneumonia. We provide a summary of the latest approved drugs for this indication and highlight emerging drugs with a potential indication. Expert opinion: Ceftaroline (a new cephalosporine) and omadacycline (a cycline alternative), either parenterally or orally, are the only two new antibiotics to have been approved by the FDA for the treatment of community-acquired pneumonia in the last five years. Among the antimicrobials in development, Lefamulin (the first pleuromutilin), is currently in phase III development. Among the known antibiotic classes, solithromycin (a macrolide), nemonoxacin (a quinolone), and delafloxacin and zabofloxacin (both fluoroquinolones), have been studied in phase II and III in clinical trials. The availability of these new antibiotics may offer opportunities to improve the empirical treatment for community-acquired pneumonia.

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Simultaneous assessment of the pharmacokinetics of a pleuromutilin, lefamulin, in plasma, soft tissues and pulmonary epithelial lining fluid

Abstract: Lefamulin may be an addition to the therapeutic armamentarium for the treatment of infections. Simultaneous measurements of unbound drug concentration can guide target attainment for future therapeutic trials.

Cited by 59 publications

References 18 publications

Antibacterial Activity of Lefamulin against Pathogens Most Commonly Causing Community-Acquired Bacterial Pneumonia: SENTRY Antimicrobial Surveillance Program (2015–2016)

Antibacterial Activity of Lefamulin against Pathogens Most Commonly Causing Community-Acquired Bacterial Pneumonia: SENTRY Antimicrobial Surveillance Program (2015–2016)

In Vitro Activity of Lefamulin Tested against Streptococcus pneumoniae with Defined Serotypes, Including Multidrug-Resistant Isolates Causing Lower Respiratory Tract Infections in the United States

Emerging antibiotics for community-acquired pneumonia

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