The U.S. Food and Drug Administration (FDA) has recently granted approval of the new antibiotic lefamulin to Nabriva Therapeutics, for the treatment of community-acquired bacterial pneumonia (CABP), following favorable results from two phase 3 clinical trials that demonstrated comparable rates of clinical success to moxifloxacin with or without linezolid.1–3 CABP is a common cause of morbidity and mortality among adults worldwide and continues to pose a threat to public health with the increasing appearance of antibiotic resistant bacteria. The addition of lefamulin as a treatment option for CABP represents a significant breakthrough in global efforts to address antimicrobial resistance.
On August 19th 2019, the FDA announced the approval of both oral and intravenous (IV) lefamulin for the treatment of CABP in adults.1 Lefamulin is a pleuromutilin antibiotic, designed to inhibit protein synthesis by selectively binding to bacterial ribosomes.4 Pleuromutilins were discovered as natural product antibiotics in 1950, with retapamulin being the first derivative available in clinical use for humans as a topical treatment.5 Their distinctive mechanism of action and highly conserved ribosomal target reduces the likelihood for the development of resistant bacteria, and cross-resistance with other classes of antibiotics such as beta-lactams, macrolides, fluoroquinolones and tetracyclines.6,7
CABP is a lower respiratory tract bacterial infection acquired anywhere other than in acute or long-term care settings and is a major cause of morbidity and mortality worldwide. The Global Burden of Disease Study reported that lower respiratory tract infections were the second biggest cause of deaths in 2013, with an incidence rate of 1.5-14 cases per 1,000 person-years.8 Director of the FDA’s Office of Antimicrobial Products, Edward Cox commented, “for managing this serious disease, it is important for physicians and patients to have treatment options. This approval reinforces our ongoing commitment to address the treatment of infectious diseases by facilitating the development of new antibiotics.”1
Two pivotal phase 3 studies demonstrated the clinical efficacy and safety of IV and oral lefamulin in the treatment of a total of 1,289 adults with CABP. In the LEAP1 study, patients were randomized to receive 5-7 days of IV lefamulin or 7 days of IV moxifloxacin. After 6 doses, patients could be switched to an oral drug if the improvement criteria were met. If methicillin-resistant Staphylococcus aureus was suspected, linezolid or placebo was added to moxifloxacin or lefamulin, respectively. Results showed that lefamulin was comparable to the efficacy of moxifloxacin, with or without linezolid in reaching both the FDA and the European Medicine Agency primary endpoints. Lefamulin was also generally safe and well-tolerated.3 More recently, the LEAP2 study compared 5 days of oral lefamulin to 7 days of oral moxifloxacin. Both agents demonstrated similar clinical efficacy and rates of adverse events suggesting a favorable safety profile.2
Lefamulin received the FDA’s Qualified Infectious Disease Product and Fast Track designation highlighting the agency’s initiative to combat antibiotic resistance.1 Nabriva Therapeutics has also stated that they will continue to develop this antibiotic for pediatric use and expand its indications beyond CABP for the treatment of other conditions such as acute bacterial skin and skin structure infections, sexually transmitted infections, ventilator-associated bacterial pneumonia, osteomyelitis, and prosthetic joint infections.9
1. Commissioner O of the. FDA approves new antibiotic to treat community-acquired bacterial pneumonia. FDA. (Accessed September 18, 2019, at http://www.fda.gov/news-events/press-announcements/fda-approves-new-antibiotic-treat-community-acquired-bacterial-pneumonia. Published September 11, 2019)
2. Alexander E, Goldberg L, Das A, et al. LB6. Oral Lefamulin Is Safe and Effective in the Treatment of Adults With Community-Acquired Bacterial Pneumonia (CABP): Results of Lefamulin Evaluation Against Pneumonia (LEAP 2) Study. Open Forum Infectious Diseases. 2018;5(suppl_1):S761-S761.
3. File TM, Goldberg L, Das A, 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. Clinical Infectious Diseases. February 2019.
4. Eyal Z, Matzov D, Krupkin M, et al. A novel pleuromutilin antibacterial compound, its binding mode and selectivity mechanism. Scientific Reports. 2016;6:39004.
5. Drug Approval Package: Altabax (Retapamulin) NDA #022055. (Accessed September 20, 2019, at https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022055s000TOC.cfm)
6. Sader HS, Paukner S, Ivezic-Schoenfeld Z, et al. 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):1170-1175.
7. Paukner S, Riedl R. Pleuromutilins: Potent Drugs for Resistant Bugs—Mode of Action and Resistance. Cold Spring Harb Perspect Med. 2017;7(1).
8. Global, regional, and national age–sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. The Lancet. 2015;385(9963):117-171.
9. Novel Antibiotics | Lefamulin | Nabriva.com. (Accessed September 20, 2019, at https://www.nabriva.com/pipeline-research.)