Infectious Disease

Lefamulin: Potential Role of a New Antibiotic in Community Acquired Pneumonia

A novel antibiotic that may play a role in ED management of community acquired pneumonia is lefamulin. What is this medication? How could it fit in the ED paradigm for pneumonia treatment?

Community acquired pneumonia (CAP, or CABP for community acquired bacterial pneumonia) is one of the most commonly encountered diseases in the ED, with >1.2 million visits in the U.S. annually.1 Antibiotics with appropriate coverage for typical and atypical bacterial pathogens have remained the mainstay of treatment, but antibiotic resistance and incidences of side effects with current medications are a concern.

Pharmaceutical companies incentivized to invest in more lucrative drug classes are not producing sufficient new antibiotics, according to the WHO.2 One such novel antibiotic that may play a role in ED management of CABP is lefamulin. What is this medication? How could it fit in the ED paradigm for pneumonia treatment?

Lefamulin: A New Antibiotic with a Novel Mechanism of Action
In 2019, the FDA approved the semi-synthetic pleuromutilin drug, lefamulin, for the treatment of community acquired bacterial pneumonia.3 Lefamulin is active against some of the most common causes of CABP, including multidrug resistant S. pneumoniae, S. aureus, M. pneumonia, H. influenzae with no cross resistance to other classes.4 Lefamulin owes its efficacy to its novel binding mechanism to the bacterial 50S ribosomal subunit.5 Lefamulin is currently in phase IV testing.

The LEAP II trial was a phase III double-blind, double-dummy, parallel-group, noninferiority, randomized controlled trial that compared lefamulin to moxifloxacin in the management of CABP. The primary endpoint was "early clinical response at 96 hours after administration of the first dose" in the intention to treat population. Secondary endpoints included "investigator assessment of clinical response at test of cure" in the modified intention to treat population and in the clinically evaluable population. In both endpoints, lefamulin was shown to be non-inferior to moxifloxacin in the management of community acquired bacterial pneumonia. The incidence of treatment-emergent adverse events was 32.6% with lefamulin and 25% with moxifloxacin, with the majority of these events being nausea, vomiting, and diarrhea and self-reported to be mild or moderate in severity. Both the lefamulin and moxifloxacin groups reported low treatment emergency adverse cardiac and hepatobiliary events. The mean change in QtcF interval was 9.5ms with lefamulin vs 11.6 with moxifloxacin, though one patient discontinued lefamulin due to QT prolongation. Two major limitations of this study are that patients with confirmed or suspected MRSA and patients at risk for cardiac dysfunction and/or having significant hepatic disease were excluded, which limits its generalizability.6 

Community Acquired Bacterial Pneumonia: A Brief Review
The Infectious Disease Society of America and American Thoracic Society updated their clinical practice guidelines for diagnosis and treatment of adults with CAP in August 2019.7 They discussed the best evidence for diagnosis and treatment by separating guidelines into 16 research questions and answers. Question 8 asked, "In the outpatient setting, which antibiotics are recommended for empiric treatment of CAP in adults?" They break this down into recommendations for healthy adults and for adults with comorbidities. For healthy adults, amoxicillin and doxycycline are recommended with "strong recommendation," and macrolides such as azithromycin with "conditional recommendation." For adults with significant comorbidities, combination therapy or monotherapy options were provided. For combination therapy, amoxicillin/clavulanate or a cephalosporin, combined with a macrolide (strong recommendation for combination therapy) or doxycycline (conditional recommendation for combination therapy) were recommended. For monotherapy, a respiratory fluoroquinolone was recommended (strong recommendation). Notable in these recommendations was a downgrading of the recommendation for azithromycin as a monotherapy in uncomplicated outpatient CAP. This was due to increasing levels (>30%) of resistance of S. pneumoniae to macrolides. Reference a local antibiogram for consideration of azithromycin or doxycycline use for CAP. Also notable was the continued strong recommendation towards fluoroquinolone monotherapy.7 Fluoroquinolones first received an FDA black box warning in 2008 for risk of tendonitis and tendon rupture. This warning has been updated multiple times, with risks including aortic dissection and glucose homeostasis dysregulation;8 the 2018 warning regarding aortic dissection was particularly compelling to the EM community. For many, fluoroquinolones have become a "never use" drug. Studies have shown a decline in fluoroquinolone use in the ED in nationally.9

Where Might Lefamulin Fit in the ED Provider Paradigm for CAP Treatment?
Lefamulin is FDA approved and being marketed for use as a single agent for CAP coverage. Its PO formulation may be an option in the future for outpatient prescription. As a new agent, it is not mentioned in the IDSA/ATS guidelines for best practices for CAP treatment; it may be prohibitively expensive for patients (a 5-day course can cost ≥ $1,350), and it may require ID specialist prescription for insurance coverage. Its side effect profile (similar in "serious" adverse effect rate to moxifloxacin in LEAP-2) has been documented through phase III study only, whereas a medication's side effect profile is often refined and better understood after post marketing surveillance. In patients with multiple drug allergies, such as penicillin, cephalosporin, and/or macrolide, there's room to grow in the emergency physician's arsenal for outpatient treatment of CABP. Future study will show if lefamulin plays a role.

Take-Home Points

  • Lefamulin is a new (2019) FDA approved IV and PO medication being marketed for use as a single agent for CAP coverage.
  • IDSA/ATS guidelines for CAP were published in August 2019. Azithromycin's strength of recommendation was downgraded due to increasing resistance. Fluoroquinolones are still a first-line option, though they have fallen out of favor in EM due to an increasingly significant side effect profile.
  • Lefamulin, though expensive, may be an option for CAP, but further knowledge will come with post-marketing surveillance and study.

References

  1. Rui P, Kang K. National Hospital Ambulatory Medical Care Survey: 2017 emergency department summary tables. National Center for Health Statistics. 
  2. Bosely S. Big pharma failing to invest in new antibiotics, says WHO. The Guardian. Published January 17, 2020. Accessed June 1, 2020.
  3. FDA approves new antibiotic to treat community-acquired bacterial pneumonia. U.S. Food and Drug Administration. Published 2019. Accessed May 30, 2020.
  4. Paukner S, Sader HS, Ivezic-Schoenfeld Z, Jones RN. 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):4489‐4495. 
  5. Eyal Z, Matzov D, Krupkin M, et al. A novel pleuromutilin antibacterial compound, its binding mode and selectivity mechanism. Sci Rep. 2016;6:39004. Published 2016 Dec 13. 
  6. Alexander E, Goldberg L, Das AF, 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):1661–1671. 
  7. Metlay JP, Waterer GW, Long AC, 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. 
  8. FDA warns about increased risk of ruptures or tears in the aorta blood. U.S. Food and Drug Administration. Published 2020. Accessed June 5, 2020.
  9. Yarrington M, Anderson D, Dodds Ashley E, et al. Impact of FDA black box warning on fluoroquinolone and alternative antibiotic use in southeastern US hospitals. Infection Control & Hospital Epidemiology. 2019;40(11):1297-1300. 

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