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Lefamulin: A Novel Oral and Intravenous Pleuromutilin for the Treatment of Community-Acquired Bacterial Pneumonia

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Abstract

Lefamulin is a novel oral and intravenous (IV) pleuromutilin developed as a twice-daily treatment for community-acquired bacterial pneumonia (CABP). It is a semi-synthetic pleuromutilin with a chemical structure that contains a tricyclic core of five-, six-, and eight-membered rings and a 2-(4-amino-2-hydroxycyclohexyl)sulfanylacetate side chain extending from C14 of the tricyclic core. Lefamulin inhibits bacterial protein synthesis by binding to the 50S bacterial ribosomal subunit in the peptidyl transferase center (PTC). The pleuromutilin tricyclic core binds to a pocket close to the A site, while the C14 side chain extends to the P site causing a tightening of the rotational movement in the binding pocket referred to as an induced-fit mechanism. Lefamulin displays broad-spectrum antibacterial activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria as well as against atypical bacteria that commonly cause CABP. Pleuromutilin antibiotics exhibit low rates of resistance development and lack cross-resistance to other antimicrobial classes due to their unique mechanism of action. However, pleuromutilin activity is affected by mutations in 23S rRNA, 50S ribosomal subunit proteins rplC and rplD, ATP-binding cassette (ABC)-F transporter proteins such as vga(A), and the methyltransferase cfr. The pharmacokinetic properties of lefamulin include: volume of distribution (Vd) ranging from 82.9 to 202.8 L, total clearance (CLT) of 19.5 to 21.4 L/h, and terminal elimination half-life (t1/2) of 6.9–13.2 h; protein binding of lefamulin is high and non-linear. The oral bioavailability of lefamulin has been estimated as 24% in fasted subjects and 19% in fed subjects. A single oral dose of lefamulin 600 mg administered in fasted patients achieved a maximum plasma concentration (Cmax) of 1.2–1.5 mg/L with a time of maximum concentration (Tmax) ranging from 0.8 to 1.8 h, and an area under the plasma concentration-time curve from 0 to infinity (AUC0−∞) of 8.5–8.8 mg h/L. The pharmacodynamic parameter predictive of lefamulin efficacy is the free plasma area under the concentration-time curve divided by the minimum inhibitory concentration (fAUC24h/MIC). Lefamulin efficacy has been demonstrated using various animal models including neutropenic murine thigh infection, pneumonia, lung infection, and bacteremia. Lefamulin clinical safety and efficacy was investigated through a Phase II clinical trial of acute bacterial skin and skin structure infection (ABSSSI), as well as two Phase III clinical trials of CABP. The Phase III trials, LEAP 1 and LEAP 2 established non-inferiority of lefamulin to moxifloxacin in both oral and IV formulations in the treatment of CABP. The United States Food and Drug Administration (FDA), European Medicines Agency (EMA), and Health Canada have each approved lefamulin for the treatment of CABP. A Phase II clinical trial has been completed for the treatment of ABSSSI, while the pediatric program is in Phase I. The most common adverse effects of lefamulin include mild-to-moderate gastrointestinal-related events such as nausea and diarrhea. Lefamulin represents a safe and effective option for treating CABP in cases of antimicrobial resistance to first-line therapies, clinical failure, or intolerance/adverse effects to currently used agents. Clinical experience and ongoing clinical investigation will allow clinicians and antimicrobial stewardship programs to optimally use lefamulin in the treatment of CABP.

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Authors and Affiliations

  1. Department of Medical Microbiology and Infectious Diseases, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada

    George G. Zhanel, Heather J. Adam, Alyssa Golden, Frank Schweizer, Michael A. Zhanel, Denice Bay, Philippe Lagacé-Wiens, Andrew Walkty & James A. Karlowsky

  2. College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada

    Christina Deng, Sheryl Zelenitsky & Courtney K. Lawrence

  3. Clinical Microbiology, Diagnostic Services, Shared Health, Winnipeg, MB, Canada

    Heather J. Adam, Philippe Lagacé-Wiens, Andrew Walkty & James A. Karlowsky

  4. Department of Chemistry, Faculty of Science, University of Manitoba, Winnipeg, MB, Canada

    Liam Berry & Frank Schweizer

  5. Department of Medicine, Hamilton Health Sciences, Hamilton, ON, Canada

    Neal Irfan

  6. Department of Medicine, McMaster University, Hamilton, ON, Canada

    Lionel Mandell

  7. Division of Pulmonary, Critical Care, Allergy and Clinical Immunology, The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Joseph P. Lynch III

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  1. George G. Zhanel
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Corresponding author

Correspondence to George G. Zhanel.

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Conflict of interest

Dr. Zhanel has received research grants from Sunovion Pharmaceuticals and Nabriva Therapeutics. No conflicts are declared for Christina Deng, Sheryl Zelenitsky, Courtney K. Lawrence, Heather J. Adam, Alyssa Golden, Rachel Hink, Liam Berry, Frank Schweizer, Michael A. Zhanel, Denice Bay, Philippe Lagacé-Wiens, Andrew Walkty, Lionel Mandell, Joseph P. Lynch III and James A. Karlowsky. Dr. Irfan is part of the Sunovion speaker’s bureau.

Funding statement

The authors are grateful to Sunovion Pharmaceuticals and Nabriva Therapeutics for their assistance with literature retrieval and an unrestricted research grant to aid in funding Christina Deng.

Contribution of authors

George G. Zhanel (involved in design and concept of entire manuscript and drafting all sections, senior and corresponding author), Christina Deng (involved in design and concept of entire manuscript and drafting all sections), Sheryl Zelenitsky (involved in design and concept of entire manuscript and drafting pharmacokinetic and pharmacodynamics sections), Courtney K. Lawrence, (involved in design and concept of entire manuscript and drafting pharmacokinetic and pharmacodynamics sections), Heather J. Adam (involved in design and concept of entire manuscript and drafting microbiology section), Alyssa Golden (involved in design and concept of entire manuscript and drafting mechanisms of action and resistance sections), Liam Berry (involved in design and concept of entire manuscript and drafting chemistry and microbiology sections), Frank Schweizer (involved in design and concept of entire manuscript and drafting chemistry and microbiology sections), Michael A. Zhanel (involved in design and concept of entire manuscript and drafting introduction, mechanisms of action/resistance, chemistry and microbiology sections), Neal Irfan (involved in design and concept of entire manuscript and drafting adverse effects, drug interactions and place in therapy sections), Denice Bay (involved in design and concept of entire manuscript and drafting introduction, mechanisms of action/resistance sections), Philippe Lagacé-Wiens (involved in design and concept of entire manuscript and drafting animal models section), Andrew Walkty (involved in design and concept of entire manuscript and drafting clinical trials, adverse effects and place in therapy sections), Lionel Mandell (involved in design and concept of entire manuscript and drafting clinical trials section), Joseph P. Lynch III (involved in design and concept of entire manuscript and drafting clinical trials and place in therapy sections), and James A. Karlowsky (involved in design and concept of entire manuscript and drafting all sections).

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Zhanel, G.G., Deng, C., Zelenitsky, S. et al. Lefamulin: A Novel Oral and Intravenous Pleuromutilin for the Treatment of Community-Acquired Bacterial Pneumonia. Drugs 81, 233–256 (2021). https://doi.org/10.1007/s40265-020-01443-4

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