In medical school teaching for most of the last half century, the ascendant antibiotic in our armamentarium has been ß-lactam. This happy marriage between the amide group and a carbonyl group, joined together by a ring, exhibits lethal effects on bacteria by inhibiting cell wall synthesis. The most famous and early member of the family is penicillin, which has been followed in general use by cephems, monobactams, and carbapenems.

These compounds, however, are susceptible to ß-lactamases, a family of hydrolytic enzymes widely manifested by bacteria, conferring antibiotic resistance. While many other antibiotic classes are available, resistance continues to emerge in such common pathogens as Enterococcus and Neisseria. Few new antibiotics are approved by the U.S. Food and Drug Administration (FDA), and over the past decade, these have typically been derivatives of antibiotic classes already in wide use.

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Enter the pleuromutilins and the newest antibiotic utensil in our toolbox, lefamulin (Xenleta).¹ Pleuromutilins are not actually that novel; they were isolated from Pleurotus mutilus mushrooms in the 1950s and adapted for commercial use in the 1970s. The pleuromutilins inhibit ribosomal protein synthesis and bind to the same 50S ribosomal subunit as the amphenicols. Their effects are primarily against Gram-positive organisms, including community-acquired and resistant strains of S. aureus, multidrug-resistant S. pneumoniae, and vancomycin-resistant Enterococcus faecium. Activity is also noted against fastidious Gram-negatives such as Haemophilus spp., Moraxella catarrhalis, Neisseria spp., and Legionella pneumophila, as well as the mycoplasmas, ureaplasmas, and chlamydia. No clinically relevant activity is suspected against anaerobic organisms, eg, Enterococcus faecalis, Enterobacteriaceae, or nonfermenting Gram-negatives such as Acinetobacter baumannii and Pseudomonas aeruginosa.

The pleuromutilin antibiotics tiamulin and valnemulin have been in use in veterinary medicine, such as in pigs and poultry, for decades. For human use, a topical antibiotic, retapamulin, has been available in the United States since 2007 for the treatment of superficial wound and soft-tissue infections like impetigo. Now, lefamulin represents the first pleuromutilin available for intravenous and oral human use, with FDA approval granted in August 2019 by priority review under the Qualified Infectious Disease Product designation.

Clinical Trials

The approval of lefamulin stems from results observed in a pair of Phase III clinical trials, each noninferiority trial testing lefamulin against moxifloxacin: the Lefamulin Evaluation Against Pneumonia (LEAP) trials. LEAP 1 tested lefamulin versus moxifloxacin as intravenous treatment for inpatients, with transition to oral administration based on clinical criteria.² Supplemental treatment with linezolid in the moxifloxacin arm was authorized if methicillin-resistant S. aureus was suspected or confirmed by culture, while the lefamulin arm received matching placebo.

The most conspicuous feature of this trial is the very low acuity of patients enrolled. Most patients fell into Pneumonia Severity Index (PSI/PORT) risk class III, typically recommended for either inpatient or outpatient management depending on patient-specific factors. Clinical trial requirements issued by the FDA necessitate a minimum of 25 percent of trial patients in PORT class IV or V, and the trial population barely clears this regulatory bar. Exclusion criteria were likewise typical for a tightly controlled trial and excluded patients at elevated risk for deterioration such as nursing home residents, patients with immunosuppression, or those undergoing cytotoxic chemotherapy. It is, then, of little surprise the trial met its 10 percent regulatory margin for noninferiority, with 87.3 percent of lefamulin-treated patients classified as responders compared with 90.2 percent of those treated with moxifloxacin ± linezolid.

LEAP 2 performed a similar comparison, except with an entirely oral outpatient regimen. A full peer-reviewed publication detailing these results was not available at the time of this writing, but results are highlighted in two abstracts.^3,4 The trial enrolled patients with milder pneumonia and PORT scores of primarily II and III, and both lefamulin and moxifloxacin monotherapy were similarly efficacious, with response rates around 90 percent. This, again, easily met the regulatory margin for noninferiority.

Treatment-emergent adverse events (TEAEs) were more common in the lefamulin cohort, although few led to discontinuation in these trials. While TEAEs were similar in LEAP 1, diarrhea was observed in 12.2 percent of the lefamulin cohort of LEAP 2 compared with 1.1 percent of those treated with moxifloxacin. Smaller differences were noted with regard to nausea and vomiting in LEAP 2 but were still greater in those treated with lefamulin. No reliable difference in hepatobiliary injury or QT-interval prolongation was reported in either trial.

Caveats

However, it should be clearly recognized these trials and publications are produced in their entirety by the sponsor, Nabriva Therapeutics. The vast majority of authors are either employees of, consultants for, or members of the board of directors for Nabriva. There are clear professional and corporate financial interests tied to conducting the ideal trial leading to approval and to presenting these data in the best possible light. These biases do not imply misconduct nor misleading factual presentation, but they may limit generalizability of the effectiveness and safety profile to real-world use.

Regardless, lefamulin is likely to become an important antibiotic option in human medicine. Its long, effective use in veterinary medicine supports the findings observed in these trials. As with any new antibiotic, stewardship will be critical. While the trade magazine advertisements for Xenleta are likely to surge, our prescribing should not follow suit. The narrow eligibility of these trials, the drug’s use in low-acuity patients, the relative paucity of safety information, and, of course, the drug’s increased cost compared with current generic options all reduce its appropriateness. Antibiotics such as this, with unique mechanisms of action, should be held in reserve for cases in which established resistance limits alternative options. These data portend a welcome advance in our treatment options for otherwise challenging infections but are best restricted to such narrow indications.

The opinions expressed herein are solely those of Dr. Radecki and do not necessarily reflect those of his employer or academic affiliates.

References

1. Veve MP, Wagner JL. Lefamulin: review of a promising novel pleuromutilin antibiotic. Pharmacotherapy. 2018;38(9):935-946.
2. File TM Jr, Goldberg L, Das A, 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 [published online ahead of print Feb. 4, 2019]. Clin Infect Dis.
3. 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 Infect Dis. 2018;5(suppl 1):S761.
4. Alexander E, Goldberg L, Das A, et al. Oral lefamulin demonstrates favorable safety and tolerability in adults with community-acquired bacterial pneumonia in the phase III lefamulin evaluation against pneumonia (LEAP 2) study. In: Proceedings from the 29th European Society of Clinical Microbiology and Infectious Diseases; April 13–16, 2019; Amsterdam, The Netherlands. Abstract O1068.