Skip to main content
SpringerLink
Log in

Leave it to Lefamulin: A Pleuromutilin Treatment Option in Community-Acquired Bacterial Pneumonia

  • Review Article
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Lefamulin (BC-3781) is the first systemic pleuromutilin antibiotic found to be safe and effective in the treatment of community-acquired bacterial pneumonia (CABP) in humans. This novel antibiotic was developed to combat the increasing incidence of bacterial resistance to current therapies. As the first semisynthetic pleuromutilin for systemic use in humans, lefamulin has demonstrated efficacy against the most common bacteria responsible for CABP, including strains exhibiting resistance to macrolides, fluoroquinolones, tetracyclines, vancomycin, and beta-lactams. In vitro studies have demonstrated efficacy against Staphylococcus aureus, beta-hemolytic and viridans group streptococci, coagulase-negative staphylococci, Enterococcus faecium, Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumophilia, and Moraxella catarrhalis at MIC values lower than those of currently available therapies. Two phase III trials (LEAP-1 and LEAP-2) have demonstrated similar findings, meeting non-inferiority criteria for CABP with a minimal side-effect profile. Pharmacokinetic and pharmacodynamic evaluations have shown sufficient drug levels in plasma, subcutaneous adipose tissue, skeletal muscle, and epithelial lining fluid, warranting further investigation for other clinical uses. Lefamulin was approved by the United States Food and Drug Administration (FDA) on 19 August 2019 for the treatment of CABP.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Global Health Estimates 2016: deaths by cause, age, sex, by country and by region, 2000–2016. Geneva, World Health Organization. 2018. Accessed 12 Sep 2019.

  2. Rui P, Kang K, Ashman JJ. National hospital ambulatory medical care survey: 2016 emergency department summary tables. 2016. https://www.cdc.gov/nchs/data/ahcd/nhamcs_emergency/2016_ed_web_tables.pdf.

  3. Center for disease control and prevention: national vital statistics reports, Vol. 67, No. 5, July 26, 2018. Table I–12. https://www.cdc.gov/nchs/data/nvsr/nvsr67/nvsr67_05_tables.pdf.

  4. Cilloniz C, Martin I, Garcia C, San Jose A, Torres A. Microbial etiology of pneumonia: epidemiology, diagnosis, and resistance patterns. Int J Mol Sci. 2016; 17(12): 2120. (Published online 2016 Dec 16). https://doi.org/10.3390/ijms17122120.

    Article  Google Scholar 

  5. ​Ventola CL. The antibiotic resistance crisis: part 1: causes and threats. Pharm Ther. 2015;40(4):277–83.

    Google Scholar 

  6. American Thoracic Society: Top 20 Pneumonia Facts 2018. https://www.thoracic.org/patients/patient-resources/resources/top-pneumonia-facts.pdf. Accessed 6 Jun 2019.

  7. National Center for Biotechnology Information. PubChem Database. Tiamulin, CID=443604, https://pubchem.ncbi.nlm.nih.gov/compound/Tiamulin. Accessed 8 Jun 2019.

  8. Parish L, Parish J. Retapamulin: a new topical antibiotic for the treatment of uncomplicated skin infections. Drugs Today (Barc). 2008;44(2):91–102. https://doi.org/10.1358/dot.2008.44.2.1153446.

    Article  CAS  PubMed  Google Scholar 

  9. Sader H, Paukner S, Ivezic-Schoenfeld Z, Biedenbach D, Schmitz F, Jones R. Antimicrobial activity of the novel pleuromutilin antibiotic BC-3781 against organisms responsible for community acquired respiratory tract infections (CARTIs). J Antimicrob Chemother. 2012;67(5):1170–5. https://doi.org/10.1093/jac/dks001(Epub 2012 Jan 27).

    Article  CAS  PubMed  Google Scholar 

  10. Eyal Z, Matzov D, Krupkin M, et al. A novel pleuromutilin antibacterial compound, its binding mode and selectivity mechanism. Sci Rep. 2016;6:39004. https://doi.org/10.1038/srep39004. (Published 2016 Dec 13).

  11. Rodvold KA. Introduction: lefamulin and pharmacokinetic/pharmacodynamic rationale to support the dose selection of lefamulin. J Antimicrob Chemother. 2019;74(Supplement_3):iii2–iii4. https://doi.org/10.1093/jac/dkz084.

    Article  Google Scholar 

  12. Paukner S, Sader H, Ivezic-Schoenfeld Z, Biedenbach D, Jones R. Antimicrobial activity of the pleuromutilin antibiotic BC-3781 against bacterial pathogens isolated in the SENTRY antimicrobial surveillance program in 2010. Antimicrob Agents Chemother. 2013;57(9):4489–95. https://doi.org/10.1128/AAC.00358-13(Epub 2013 Jul 8).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mendes R, Paukner S, Doyle T, et al. Low prevalence of gram-positive isolates showing elevated MIC results during the SENTRY surveillance program for 2015-2016 and characterization of resistance mechanisms. Antimicrob Agens Chemother. 2019;63(4):e02158-18. https://doi.org/10.1128/AAC.02158-18(Epub 2019 Jan 22).

    Article  Google Scholar 

  14. Rubino C, Xue B, Bhavnani S, et al. Population pharmacokinetic analysis for BC-3781 using phase 2 data from patients with acute bacterial skin and skin structure infections. Antimicrob Agents Chemother. 2015;59(1):282–8. https://doi.org/10.1128/AAC.02033-13(Epub 2014 Oct 27).

    Article  CAS  PubMed  Google Scholar 

  15. Zeitlinger M, Schwameis R, Burian A, et al. Simultaneous assessment of the pharmacokinetics of a pleuromutilin, lefamulin, in plasma, soft tissues and pulmonary epithelial lining fluid. J Antimicrob Chemother. 2016;71:1022–6. https://doi.org/10.1093/jac/dkv442.

    Article  CAS  PubMed  Google Scholar 

  16. Bhavnani S, Zhang L, Hammel J, et al. Pharmacokinetic/pharmacodynamics target attainment analysis to support intravenous and oral lefamulin dose selection for the treatment of patients with community acquired bacterial pneumonia. J Antimicrob Chemother. 2019;74(Supplement_3):iii35–iii41. https://doi.org/10.1093/jac/dkz089.

    Article  Google Scholar 

  17. Xenleta (lefamulin) [prescribing information]. King of Prussia, PA: Nabriva Therapeutics US, Inc. 2019.

  18. Mendes R, Farrell D, Flamm R, et al. 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. Antimicrob Agents Chemother. 2016;60(7):4407–4411. https://doi.org/10.1128/aac.00627-16. (Published 2016 Jun 20).

    Article  CAS  Google Scholar 

  19. ​Wicha W, Craig W, Andes D. In vivo pharmacodynamics of lefamulin, the first systemic pleuromutilin for human use, in a neutropenic murine thigh infection model. J Antimicrob Chemother. 2019;74(Supplement_3):iii5–iii10. https://doi.org/10.1093/jac/dkz085.

    Article  Google Scholar 

  20. ​Wicha W, Strickmann D, Paukner S. Pharmacokinetics/pharmacodynamics of lefamulin in a neutropenic murine pneumonia model with Staphylococcus aureus and Streptococcus pneumoniae. J Antimicrob Chemother. 2019;74(Supplement_3):iii11–iii18. https://doi.org/10.1093/jac/dkz086.

    Article  Google Scholar 

  21. ​File T, Goldberg L, Das A, et al. Efficacy and safety of IV-to-oral lefamulin, a pleuromutilin antibiotic, for treatment of community-acquired bacterial pneumonia: the phase 3 LEAP 1 trial. Clin Infect Dis. 2019. https://doi.org/10.1093/cid/ciz090. [Epub ahead of print].

    Article  Google Scholar 

  22. ​Alexander E, et al. Abstract LB6. Presented at: IDWeek. 2018. San Francisco.

  23. ​Prince W, Ivezic-Schoenfeld Z, Lell C, et al. Phase II clinical study of BC-3781, a pleuromutilin antibiotic, in treatment of patients with acute bacterial skin and skin structure infections. Antimicrob Agents Chemother. 2013;57(5):2087–94. https://doi.org/10.1128/AAC.02106-12(Epub 2013 Feb 19).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Moxifloxacin. In: Lexi-Drugs [database online]. Hudson, Ohio: Wolters-Kluwer Health.2019. Accessed 15 Sep 2019.

  25. Linezolid. In: Lexi-Drugs [database online]. Hudson, Ohio: Wolters-Kluwer Health. 2019. Accessed 15 Sep 2019.

  26. Metlay J, Waterer G, Long A, et al. Diagnosis and treatment of adults with community-acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019;200(7):e45–e67. https://doi.org/10.1164/rccm.201908-1581st.

    Article  Google Scholar 

  27. Metersky ML, Ma A, Houck PM, Bratzler DW. Antibiotics for bacteremic pneumonia: Improved outcomes with macrolides but not fluoroquinolones. Chest. 2007;131:466.

    Article  CAS  Google Scholar 

  28. Paukner S, Gruss A, Jensen J. In vitro activity of lefamulin against sexually transmitted bacterial pathogens. Antimicrob Agents Chemother. 2018;6:25. https://doi.org/10.1128/aac.02380-17. (Print 2018 May).

  29. Jacobsson S, Paukner S, Golparian D, Jensen JS, Unemo M. In vitro activity of the novel pleuromutilin lefamulin (BC-3781) and effect of efflux pump inactivation on multidrug-resistant and extensively drug-resistant neisseria gonorrhoeae. Antimicrob Agents Chemother. 2017;61(11):e01497-17. https://doi.org/10.1128/aac.01497-17. (Published 2017 Oct 24).

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacy Practice, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, 1718 Pine Street, Abilene, TX, 79601, USA

    Young Ran Lee & Katy Louise Jacobs

Authors
  1. Young Ran Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katy Louise Jacobs
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Young Ran Lee.

Ethics declarations

Funding

No funding was received for the preparation of this article.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, Y.R., Jacobs, K.L. Leave it to Lefamulin: A Pleuromutilin Treatment Option in Community-Acquired Bacterial Pneumonia. Drugs 79, 1867–1876 (2019). https://doi.org/10.1007/s40265-019-01219-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40265-019-01219-5

Search

Navigation