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RESEARCH LETTER
Year : 2021  |  Volume : 38  |  Issue : 3  |  Page : 300-301  

Lefamulin, a recently approved novel antibacterial agent to fight against community-acquired bacterial pneumonia


1 Department of Pharmacology, Burdwan Medical College, Burdwan, West Bengal, India
2 Department of Pharmacology, Midnapore Medical College, Midnapore, West Bengal, India
3 Department of Pharmacology, Diamond Harbour Government Medical College, Diamond Harbour, West Bengal, India
4 Independent Scholer, Barasat, Kolkata, India

Date of Submission16-Feb-2020
Date of Acceptance25-Apr-2020
Date of Web Publication30-Apr-2021

Correspondence Address:
Dwaipayan Sarathi Chakraborty
Department of Pharmacology, Diamond Harbour Government Medical College, Diamond Harbour, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/lungindia.lungindia_93_20

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How to cite this article:
Choudhury S, Bala M, Chakraborty DS, Lahiry S. Lefamulin, a recently approved novel antibacterial agent to fight against community-acquired bacterial pneumonia. Lung India 2021;38:300-1

How to cite this URL:
Choudhury S, Bala M, Chakraborty DS, Lahiry S. Lefamulin, a recently approved novel antibacterial agent to fight against community-acquired bacterial pneumonia. Lung India [serial online] 2021 [cited 2021 May 8];38:300-1. Available from: https://www.lungindia.com/text.asp?2021/38/3/300/315313



Sir,

Community-acquired bacterial pneumonia (CABP), a potentially serious respiratory infection, is a leading cause of hospitalization worldwide, and despite antibiotic treatment, it is still a relevant cause of death.[1] Streptococcus pneumoniae is the most commonly isolated pathogen associated with CABP; other common pathogens include Haemophilus influenzae,  Moraxella More Details catarrhalis, and Staphylococcus aureus along with atypical pathogens like Chlamydophila pneumoniae, Legionella pneumophila, and Mycoplasma pneumonia. Currently, India accounts for 23% of the global pneumonia burden and 36% of the World Health Organization regional burden. Reported incidence rate of CABP in India is nearly 4 million cases/year.[2]

Current recommendations for the treatment of CABP mainly focus on initiation of empirical antibiotic therapies. The American Thoracic Society and Infectious Diseases Society of America clinical guideline on the diagnosis and treatment of adults with community-acquired pneumonia recommend usage of beta-lactam, macrolide, and fluoroquinolones more commonly according to severity, comorbidities.[3] However, newer class of drug is need of the hour due to the continued presence of resistance, re-emergence of previous pathogens in addition to new ones, high rate of treatment failure, and adverse reactions of the existing molecules.

In this regard, Lefamulin is a novel first-in-class, systemic, semi-synthetic pleuromutilin antibiotic designed to inhibit the synthesis of bacterial protein. It was approved by the Food and Drug Administration (FDA) on August 19, 2019, to treat adult patients with CABP. The drug is designed to be given either intravenously (150 mg twice daily for 5–7 days) or orally (600 mg twice daily for 5 days). It has high oral bioavailability with a biologic half-life of 12 h and is largely excreted via the gastrointestinal tract (86%) in its unchanged form.[4]

Lefamulin inhibits translation by binding to the A- and P-site of the peptidyl transferase center of the 50S subunit of the bacterial ribosome via four H-bonds and other interactions resulting in an “induced fit.” It selectively inhibits bacterial ribosomal translation but does not affect eukaryotic ribosomal translation. This unique mechanism of action has been associated with a low probability of cross-resistance to other antimicrobials.[5] The antibacterial spectrum of lefamulin covers both typical Gram-positive and fastidious Gram-negative respiratory pathogens and atypical pathogens. The SENTRY Antimicrobial Surveillance Program demonstrated potent antimicrobial activity for lefamulin against acute bacterial skin and skin structure infection and CABP.[1]

Of late, two multicenter, randomized, double-blind, double-dummy, Phase 3 trials – lefamulin evaluation against pneumonia (LEAP 1 and LEAP 2) – evaluated lefamulin as monotherapy for the treatment of adult patients with CABP. LEAP 1 evaluated the safety and efficacy of intravenous lefamulin (150 mg) twice daily versus intravenous moxifloxacin (400 mg) once daily (with or without linezolid) in 551 adults with moderate-to-severe CABP (Pneumonia Patient Outcomes Research Team [PORT] Risk Class III), with the option of switching to oral administration. Lefamulin was non-inferior to moxifloxacin for early clinical response ([ECR] 87.3% vs. 90.2%, respectively; difference −2.9%, 95% confidence interval [CI] −8.5–2.8) and investigator assessment of clinical response ([IACR] modified intention to treat [mITT], 81.7% vs. 84.2%, respectively; difference −2.6%, 95% CI −8.9–3.9; clinically evaluable (CE), 86.9% vs. 89.4%, respectively; difference −2.5%, 95% CI −8.4–3.4).[6]

LEAP 2 compared the safety and efficacy of 600 mg of oral lefamulin twice daily for 5 days versus 400 mg of oral moxifloxacin once daily for 7 days in 738 adult patients with moderate CABP (PORT Risk Class II–IV). The FDA primary endpoint was ECR at 96 h after the first dose, whereas the secondary endpoints were IACR at the test of cure. ECR rates were 90.8% with lefamulin and 90.8% with moxifloxacin (difference, 0.1% [one-sided 97.5% CI: −4.4% to ∞]). Rates of IACR success were 87.5% with lefamulin and 89.1% with moxifloxacin in the mITT population (difference, −1.6% [one-sided 97.5% CI: −6.3% to ∞]) and 89.7% and 93.6%, respectively, in the clinically evaluable population (difference, −3.9% [one-sided 97.5% CI: −8.2% to ∞]) at the test of cure. Both the clinical trials met efficacy endpoints for noninferiority and provided evidence that lefamulin was generally well tolerated [Table 1]. Few commonly encountered adverse effects were mainly diarrhea, nausea, and elevation liver enzymes.[7] In conclusion, this drug promises to be a new hope in treating CABP in future due to its unique features such as new class of molecule with novel mechanism, complete spectrum of coverage, well-tolerated profile, excellent pharmacological parameters with mild food interaction, no loading dose, no dose adjustment, and convenience of use in both hospital or community settings due to the availability of parental and oral preparations and short course of monotherapy. Although high cost would prohibit large-scale usage, expanded data on safety/efficacy is still required.
Table 1: Efficacy results (% responders) in LEAP 1 & 2 comparing FDA vs EMA primary end-points

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Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Paukner S, Gelone SP, Arends SJ, 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:e02161-18.  Back to cited text no. 1
    
2.
Nayar S, Hasan A, Waghray P, Ramananthan S, Ahdal J, Jain R. Management of communityacquired bacterial pneumonia in adults: Limitations of current antibiotics and future therapies. Lung India 2019;36:525-33  Back to cited text no. 2
    
3.
Metlay JP, Waterer GW, Long AC, Anzueto A, Brozek J, Crothers K. Diagnosis and Treatment of Adults with Community-acquired Pneumonia. Am J Respir Crit Care Med 2019;200:e45–e67.  Back to cited text no. 3
    
4.
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;59:282-8.  Back to cited text no. 4
    
5.
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:e02008-16.  Back to cited text no. 5
    
6.
File TM Jr., Goldberg L, Das A, Sweeney C, Saviski J, Gelone SP, 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;69:1856-67.  Back to cited text no. 6
    
7.
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;322:1661-71.  Back to cited text no. 7
    



 
 
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