Skip to main content
Log in

Clinical Pharmacokinetics and Pharmacodynamics of Lefamulin

  • Review Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Lefamulin (Xenleta) has been approved by the US FDA for the treatment of community-acquired bacterial pneumonia (CABP). It may be taken intravenously or orally and has activity against a broad range of pulmonary pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydophila pneumonia, as well as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Lefamulin has an adverse effect profile that is similar to other antimicrobial agents commonly used to treat CABP. Despite these promising features, the use of lefamulin remains limited in clinical practice. However, given the rise of antibiotic-resistant organisms, this may soon change. This review examines what is known about the pharmacokinetics and pharmacodynamics of lefamulin and looks ahead to its potential applications in clinical practice, including the treatment of sexually transmitted infections such as multidrug-resistant Mycoplasma genitalium, as well as its role as a synergistic agent used in combination with other antimicrobials in the treatment of drug-resistant organisms.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Novak R. Are pleuromutilin antibiotics finally fit for human use? Ann N Y Acad Sci. 2011;1241:71–81.

    CAS  PubMed  Google Scholar 

  2. Sader HS, Biedenbach DJ, Paukner S, Ivezic-Schoenfeld Z, Jones RN. Antimicrobial activity of the investigational pleuromutilin compound BC-3781 tested against Gram-positive organisms commonly associated with acute bacterial skin and skin structure infections. Antimicrob Agents Chemother. 2012;56(3):1619–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Sader HS, Paukner S, Ivezic-Schoenfeld Z, Biedenbach DJ, Schmitz FJ, Jones RN. 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.

    CAS  PubMed  Google Scholar 

  4. Perez F, Salata RA, Bonomo RA. Current and novel antibiotics against resistant Gram-positive bacteria. Infect Drug Resist. 2008;1:27–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Paukner S, Riedl R. Pleuromutilins: potent drugs for resistant bugs-mode of action and resistance. Cold Spring Harb Perspect Med. 2017;7(1):a027110.

    PubMed  PubMed Central  Google Scholar 

  6. Prince WT, Ivezic-Schoenfeld Z, Lell C, Tack KJ, Novak R, Obermayr F, 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Blondeau J. Gram-negative superbugs: inappropriate antimicrobial therapy and mortality. Expert Rev Clin Pharmacol. 2013;6(4):347–9.

    CAS  PubMed  Google Scholar 

  8. Williams DH, Bardsley B. The Vancomycin Group of antibiotics and the fight against resistant bacteria. Angew Chem Int Ed Engl. 1999;38(9):1172–93.

    PubMed  Google Scholar 

  9. Shang R, Wang J, Guo W, Liang J. Efficient antibacterial agents: a review of the synthesis, biological evaluation and mechanism of pleuromutilin derivatives. Curr Top Med Chem. 2013;13(24):3013–25.

    CAS  PubMed  Google Scholar 

  10. Mendes RE, Farrell DJ, Flamm RK, Talbot GH, Ivezic-Schoenfeld Z, Paukner S, 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):4407–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Paukner S, Gelone SP, Arends SJR, Flamm RK, Sader HS. Antibacterial activity of lefamulin against pathogens most commonly causing community-acquired bacterial pneumonia: SENTRY Antimicrobial Surveillance Program (2015–2016). Antimicrob Agents Chemother. 2019;63(4):e02161-e2218.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Waites KB, Crabb DM, Duffy LB, Jensen JS, Liu Y, Paukner S. In vitro activities of lefamulin and other antimicrobial agents against macrolide-susceptible and macrolide-resistant Mycoplasma pneumoniae from the United States, Europe, and China. Antimicrob Agents Chemother. 2017;61(2):e02008-e2016.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Wu S, Zheng Y, Guo Y, Yin D, Zhu D, Hu F. Activity of lefamulin against the common respiratory pathogens isolated from mainland china during 2017–2019. Front Microbiol. 2020;11:578824.

    PubMed  PubMed Central  Google Scholar 

  14. Felix TM, Karpa K. Lefamulin (Xenleta) for the treatment of community-acquired bacterial pneumonia. Am Fam Physician. 2020;102(6):373–4.

    PubMed  Google Scholar 

  15. Rubino CM, Xue B, Bhavnani SM, Prince WT, Ivezic-Schoenfeld Z, Wicha WW, et al. Population pharmacokinetic analyses 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.

    CAS  PubMed  Google Scholar 

  16. Griffith RS. Introduction to vancomycin. Rev Infect Dis. 1981;3(Suppl):S200–4.

    PubMed  Google Scholar 

  17. Griffith RS. Vancomycin use—an historical review. J Antimicrob Chemother. 1984;14(Suppl D):1–5.

    CAS  PubMed  Google Scholar 

  18. Elting LS, Rubenstein EB, Kurtin D, Rolston KV, Fangtang J, Martin CG, et al. Mississippi mud in the 1990s: risks and outcomes of vancomycin-associated toxicity in general oncology practice. Cancer. 1998;83(12):2597–607.

    CAS  PubMed  Google Scholar 

  19. Grupper M, Nicolau DP. Obesity and skin and soft tissue infections: how to optimize antimicrobial usage for prevention and treatment? Curr Opin Infect Dis. 2017;30(2):180–91.

    PubMed  Google Scholar 

  20. Yu J, Zhou Z, Owens KH, Ritchie TK, Ragueneau-Majlessi I. What can be learned from recent new drug applications? A systematic review of drug interaction data for drugs approved by the U.S. FDA in 2015. Drug Metab Dispos. 2017;45(1):86–108.

    CAS  PubMed  Google Scholar 

  21. Wicha WW, Strickmann DB, Paukner S. Pharmacokinetics/pharmacodynamics of lefamulin in a neutropenic murine pneumonia model with Staphylococcus aureus and Streptococcus pneumoniae. J Antimicrob Chemother. 2019;74(Suppl 3):iii11–8.

  22. Zeitlinger M, Schwameis R, Burian A, Burian B, Matzneller P, Müller M, 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(4):1022–6.

    CAS  PubMed  Google Scholar 

  23. Busse D, Schaeftlein A, Solms A, Ilia L, Michelet R, Zeitlinger M, et al. Which analysis approach is adequate to leverage clinical microdialysis data? A quantitative comparison to investigate exposure and reponse exemplified by levofloxacin. Pharm Res. 2021;38(3):381–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Busse D, Simon P, Michelet R, Ehmann L, Mehner F, Dorn C, et al. Quantification of microdialysis related variability in humans: clinical trial design recommendations. Eur J Pharm Sci. 2021;157:105607.

    CAS  PubMed  Google Scholar 

  25. Zhang L, Wicha WW, Bhavnani SM, Rubino CM. Prediction of lefamulin epithelial lining fluid penetration after intravenous and oral administration using phase 1 data and population pharmacokinetics methods. J Antimicrob Chemother. 2019;74(Suppl 3):iii27–34.

  26. Wicha WW, Prince WT, Lell C, Heilmayer W, Gelone SP. Pharmacokinetics and tolerability of lefamulin following intravenous and oral dosing. J Antimicrob Chemother. 2019;74(Suppl 3):iii19–26.

  27. Wicha WW, Marbury TC, Dowell JA, Crandon JL, Leister C, Ermer J, et al. Pharmacokinetics and safety of lefamulin after single intravenous dose administration in subjects with impaired renal function and those requiring hemodialysis. Pharmacotherapy. 2021;41(5):451–6.

    CAS  PubMed  Google Scholar 

  28. Wicha WW, Marbury TC, Dowell JA, Crandon JL, Leister C, Ermer J, et al. Pharmacokinetics and safety of lefamulin after single intravenous dose administration in subjects with impaired hepatic function. Pharmacotherapy. 2021;41(5):457–62.

    CAS  PubMed  Google Scholar 

  29. Wicha WW, Craig WA, 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(Suppl 3):iii5–10.

  30. File TM, Goldberg L, Das A, Sweeney C, Saviski J, Gelone SP, et al. Efficacy and safety of intravenous-to-oral lefamulin, a pleuromutilin antibiotic, for the treatment of community-acquired bacterial pneumonia: the phase III lefamulin evaluation against pneumonia (LEAP 1) trial. Clin Infect Dis. 2019;69(11):1856–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Alexander E, Goldberg L, Das AF, Moran GJ, Sandrock C, Gasink LB, et al. Oral lefamulin vs moxifloxacin for early clinical response among adults with community-acquired bacterial pneumonia: the LEAP 2 randomized clinical trial. JAMA. 2019;322(17):1661–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Lodise T, Colman S, Stein DS, Fitts D, Goldberg L, Alexander E, et al. Post hoc assessment of time to clinical response among adults hospitalized with community-acquired bacterial pneumonia who received either lefamulin or moxifloxacin in 2 phase III randomized, double-blind, double-dummy clinical trials. Open Forum Infect Dis. 2020;7(5):ofaa145.

  33. Zhanel GG, Deng C, Zelenitsky S, Lawrence CK, Adam HJ, Golden A, et al. Lefamulin: a novel oral and intravenous pleuromutilin for the treatment of community-acquired bacterial pneumonia. Drugs. 2021;81(2):233–56.

    CAS  PubMed  Google Scholar 

  34. Wang H, Charles CV. A review of newly approved antibiotic treatment for community-acquired bacterial pneumonia: lefamulin. Sr Care Pharm. 2020;35(8):349–54.

    PubMed  Google Scholar 

  35. Eraikhuemen N, Julien D, Kelly A, Lindsay T, Lazaridis D. Treatment of community-acquired pneumonia: a focus on lefamulin. Infect Dis Ther. 2021;10(1):149–63.

    PubMed  PubMed Central  Google Scholar 

  36. Tang HJ, Lai CC, Chao CM. The clinical efficacy of lefamulin in the treatment of elderly patients with community-acquired bacterial pneumonia. J Thorac Dis. 2020;12(8):4588–90.

    PubMed  PubMed Central  Google Scholar 

  37. Sheam MM, Syed SB, Nain Z, Tang SS, Paul DK, Ahmed KR, et al. Community-acquired pneumonia: aetiology, antibiotic resistance and prospects of phage therapy. J Chemother. 2020;32(8):395–410.

    CAS  PubMed  Google Scholar 

  38. Powell D, Donato A. In community-acquired bacterial pneumonia, lefamulin was noninferior to moxifloxacin at 96 h after the first dose. Ann Intern Med. 2020;172(4):JC22.

    PubMed  Google Scholar 

  39. Mercuro NJ, Veve MP. Clinical utility of lefamulin: if not now, when? Curr Infect Dis Rep. 2020;22(9):25.

    PubMed  PubMed Central  Google Scholar 

  40. Rodvold KA. Introduction: lefamulin and pharmacokinetic/pharmacodynamic rationale to support the dose selection of lefamulin. J Antimicrob Chemother. 2019;74(Suppl 3):iii2–4.

  41. Perry W, Golan Y. Therapeutic potential of lefamulin in the treatment of community-acquired pneumonia. Future Microbiol. 2019;14:927–39.

    CAS  PubMed  Google Scholar 

  42. Amaya-Villar R, Garnacho-Montero J. How should we treat acinetobacter pneumonia? Curr Opin Crit Care. 2019;25(5):465–72.

    PubMed  Google Scholar 

  43. Pujol M, Delgado O, Puigventós F, Corzo JE, Cercenado E, Martínez JA. Evaluation of new antimicrobials for the hospital formulary. Policies restricting antibiotic use in hospitals. Enferm Infecc Microbiol Clin. 2013;31(Suppl 4):45–50.

    PubMed  Google Scholar 

  44. Schiff GD, Galanter WL, Duhig J, Koronkowski MJ, Lodolce AE, Pontikes P, et al. A prescription for improving drug formulary decision making. PLoS Med. 2012;9(5):1–7.

    PubMed  Google Scholar 

  45. Karlowsky JA, Lob SH, Young K, Motyl MR, Sahm DF. Activity of imipenem-relebactam against multidrug-resistant Pseudomonas aeruginosa from the United States—SMART 2015–2017. Diagn Microbiol Infect Dis. 2019;95(2):212–5.

    CAS  PubMed  Google Scholar 

  46. Tooke CL, Hinchliffe P, Lang PA, Mulholland AJ, Brem J, Schofield CJ, et al. Molecular basis of class A β-lactamase inhibition by relebactam. Antimicrob Agents Chemother. 2019;63(10):e00564-e619.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Leone S, Damiani G, Pezone I, Kelly ME, Cascella M, Alfieri A, et al. New antimicrobial options for the management of complicated intra-abdominal infections. Eur J Clin Microbiol Infect Dis. 2019;38(5):819–27.

    CAS  PubMed  Google Scholar 

  48. Kollef MH, Betthauser KD. New antibiotics for community-acquired pneumonia. Curr Opin Infect Dis. 2019;32(2):169–75.

    PubMed  Google Scholar 

  49. Andersson N, Allard A, Lidgren Y, Boman J, Nylander E. Are urogenital symptoms caused by sexually transmitted infections and colonizing bacteria? J Low Genit Tract Dis. 2021;25(3):232–5.

    PubMed  Google Scholar 

  50. Bras-Cachinho J, Lanotte P, Mereghetti L, Le Brun C. Mycoplasma genitalium: prevalence of macrolide and fluoroquinolone resistance at the University Hospital of Tours, and check of the S-DiaMGRes® (Diagenode Diagnostics) [in French]. Ann Biol Clin (Paris). 2021;79(2):151–7.

    PubMed  Google Scholar 

  51. Herrmann B, Malm K. Comparison between Abbott m2000 RealTime and Alinity m STI systems for detection of Chlamydia trachomatis, Neisseria gonorrhoeae, and Mycoplasma genitalium. Eur J Clin Microbiol Infect Dis. 2021. https://doi.org/10.1007/s10096-020-04135-9 ((Epub 15 Mar 2021)).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Muñoz Santa A, Aramburu Arnuelos J, Bernet Sánchez A, Bellés Bellés A. Mycoplasma genitalium: analysis of mutations associated with macrolide resistance in Lleida, Spain. Enferm Infecc Microbiol Clin (Engl, Ed). 2021. https://doi.org/10.1016/j.eimc.2021.02.004 ((Epub 23 Mar 2021)).

    Article  Google Scholar 

  53. Sell J, Nasir M, Courchesne C. Urethritis: rapid evidence review. Am Fam Physician. 2021;103(9):553–8.

    PubMed  Google Scholar 

  54. Fernández-Huerta M, Serra-Pladevall J, Pumarola T, Pich OQ, Espasa M. Comment on: lower mgpB diversity in macrolide-resistant Mycoplasma genitalium infecting men visiting two sexually transmitted infection clinics in Montpellier, France. J Antimicrob Chemother. 2021;76(6):1649–50.

    PubMed  Google Scholar 

  55. Le Roy C, Touati A, Balcon C, Garraud J, Molina JM, Berçot B, et al. Identification of 16S rRNA mutations in Mycoplasma genitalium potentially associated with tetracycline resistance in vivo but not selected in vitro in M. genitalium and Chlamydia trachomatis. J Antimicrob Chemother. 2021;76(5):1150–4.

    PubMed  Google Scholar 

  56. Shedko ED, Khayrullina GA, Goloveshkina EN, Akimkin VG. Clinical evaluation of commercial PCR assays for antimicrobal resistance in Mycoplasma genitalium and estimation of resistance-mediated mutation prevalence in Moscow and Moscow region. Eur J Clin Microbiol Infect Dis. 2021;40(7):1413–8.

    CAS  PubMed  Google Scholar 

  57. Paukner S, Gruss A, Jensen JS. In vitro activity of lefamulin against sexually transmitted bacterial pathogens. Antimicrob Agents Chemother. 2018;62(5):e02380-e2417.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Jacobsson S, Paukner S, Golparian D, Jensen JS, Unemo M. 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):e01497-1517.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Tyrrell JM, Aboklaish AF, Walsh TR, Vaara T, Vaara M. The polymyxin derivative NAB739 is synergistic with several antibiotics against polymyxin-resistant strains of Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii. Peptides. 2019;112:149–53.

    CAS  PubMed  Google Scholar 

  60. Zieliński M, Park J, Sleno B, Berghuis AM. Structural and functional insights into esterase-mediated macrolide resistance. Nat Commun. 2021;12(1):1732.

    PubMed  PubMed Central  Google Scholar 

  61. Lee H, Choi YY, Sohn YJ, Kim YK, Han MS, Yun KW, et al. Clinical efficacy of doxycycline for treatment of macrolide-resistant. Antibiotics (Basel). 2021;10(2):192.

    PubMed  PubMed Central  Google Scholar 

  62. Lee YR, Jacobs KL. Leave it to lefamulin: a pleuromutilin treatment option in community-acquired bacterial pneumonia. Drugs. 2019;79(17):1867–76.

    CAS  PubMed  Google Scholar 

  63. Dillon C, Guarascio AJ, Covvey JR. Lefamulin: a promising new pleuromutilin antibiotic in the pipeline. Expert Rev Anti Infect Ther. 2019;17(1):5–15.

    CAS  PubMed  Google Scholar 

  64. Årdal C, Røttingen JA. Open source drug discovery in practice: a case study. PLoS Negl Trop Dis. 2012;6(9):e1827.

    PubMed  PubMed Central  Google Scholar 

  65. File TM, Alexander E, Goldberg L, et al. Lefamulin efficacy and safety in a pooled phase 3 clinical trial population with community-acquired bacterial pneumonia and common clinical comorbidities. BMC Pulm Med. 2021;21(1):154.

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Matthew William McCarthy.

Ethics declarations

Funding

Research funding was received from the National Institutes of Health.

Conflict of interest

Matthew McCarthy reports no conflicts of interest.

Ethics Approval

Not applicable.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Availability of Data and Material

Not applicable.

Code Availability

Not applicable.

Author Contributions

Not applicable.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

McCarthy, M.W. Clinical Pharmacokinetics and Pharmacodynamics of Lefamulin. Clin Pharmacokinet 60, 1387–1394 (2021). https://doi.org/10.1007/s40262-021-01056-4

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-021-01056-4

Navigation