The Medical Letter on Drugs and Therapeutics
Lefamulin (Xenleta) for Community-Acquired Bacterial Pneumonia
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Summary: Lefamulin (Xenleta)
  • A semisynthetic pleuromutilin antibiotic FDA-approved for IV and oral treatment of community-acquired bacterial pneumonia (CABP) in adults.
  • As effective as moxifloxacin in achieving early clinical responses in clinical trials in patients with CABP.
  • Not approved for treatment of CABP caused by MRSA because data establishing clinical efficacy are limited.
  • Not active against Enterobacteriaceae or Pseudomonas aeruginosa.
  • Probability of cross-resistance to beta-lactams, macrolides, fluoroquinolones, tetracyclines, or glycopeptides appears to be low.
  • Metabolized primarily by CYP3A4 and may interact with drugs that are substrates or strong or moderate inhibitors or inducers of CYP3A4.
  • May prolong the QT interval and should not be used with other QT-prolonging drugs, including macrolides or fluoroquinolones, or in patients with ventricular arrhythmias.
  • Should not be used in women who are pregnant. Women of childbearing potential should use effective contraception during lefamulin treatment and for 2 days after the last dose.

Lefamulin (Xenleta – Nabriva), a semisynthetic pleuromutilin antibiotic, has been approved by the FDA for IV and oral treatment of community-acquired bacterial pneumonia (CABP) in adults. It is the first systemic pleuromutilin antibiotic to be approved in the US; retapamulin (Altabax), a 1% topical ointment for treatment of impetigo, was approved in 2007.1

CABP — CABP is a leading cause of hospitalization and death in adults, especially the elderly.2 Causative bacterial pathogens include Streptococcus pneumoniae, Mycoplasma pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Chlamydophila pneumoniae, and Legionella species.

STANDARD TREATMENT — For outpatient treatment of CABP in otherwise healthy adults without recent antibiotic exposure, monotherapy with a macrolide such as azithromycin has been the regimen of choice, but rates of macrolide resistance among S. pneumoniae in parts of the US currently exceed 40%. Doxycycline is a reasonable alternative, but resistance to doxycycline is also increasing among S. pneumoniae. A respiratory fluoroquinolone (levofloxacin or moxifloxacin) is often used for adults with comorbidities or antibiotic exposure during the previous 90 days. These drugs can also be considered for otherwise healthy adults in areas where the rates of pneumococcal resistance to macrolides and doxycycline are ≥25%, but they can cause serious adverse effects.3 Combining a beta-lactam (such as high-dose amoxicillin or cefpodoxime) with a macrolide or doxycycline is another option in areas with high rates of macrolide or doxycycline resistance.4,5

For empiric treatment of CABP in hospitalized patients (not ICU), an antipneumococcal IV beta-lactam (such as ceftriaxone, cefotaxime, ceftaroline, or ampicillin/sulbactam) plus a macrolide (or doxycycline) or monotherapy with an IV respiratory fluoroquinolone (levofloxacin or moxifloxacin) is recommended. Omadacycline, a broad-spectrum IV and oral tetracycline recently approved for treatment of CABP, is an expensive alternative with limited data.6 Addition of vancomycin or linezolid to standard treatment is recommended for patients at increased risk for methicillin-resistant S. aureus (MRSA).

Short-course antibiotic therapy (5-7 days) is as effective as longer-course therapy for treatment of CABP.

MECHANISM OF ACTION — Lefamulin binds to the peptidyl transferase center of the 50S subunit of the bacterial ribosome, inhibiting bacterial protein synthesis. The probability of cross-resistance to beta-lactams, macrolides, fluoroquinolones, tetracyclines, or glycopeptides appears to be low.7

ACTIVITY — Lefamulin is active in vitro and in vivo against S. pneumoniae, H. influenzae, M. pneumoniae, C. pneumoniae, Legionella pneumophila, and methicillin-susceptible strains of S. aureus (MSSA). It has in vitro activity against other streptococcal species, MRSA, Haemophilus parainfluenzae, and M. catarrhalis, but data establishing its clinical efficacy against these pathogens are limited. Lefamulin is also active in vitro against pathogens that cause sexually transmitted infections such as Chlamydia trachomatis, Mycoplasma genitalium, and Neisseria gonorrhoeae.8 It is not active against Enterobacteriaceae or Pseudomonas aeruginosa.

CLINICAL STUDIES — FDA approval of lefamulin for treatment of CABP was based on the results of 2 randomized, double-blind, noninferiority trials (LEAP 1 and LEAP 2) in a total of 1289 adults.

In LEAP 1, patients received IV lefamulin 150 mg every 12 hours or IV moxifloxacin 400 mg every 24 hours. After at least 3 days of IV treatment, patients could be switched to oral therapy (lefamulin 600 mg every 12 hours or moxifloxacin 400 mg every 24 hours). Patients suspected to be infected with MRSA were given adjunctive linezolid if they were in the moxifloxacin group or placebo if they were in the lefamulin group.9 In LEAP 2, summarized in the package insert, patients received oral lefamulin 600 mg every 12 hours for 5 days or oral moxifloxacin 400 mg every 24 hours for 7 days. The results of both trials are summarized in Table 2.

ADVERSE EFFECTS — Infusion-site reactions occurred in 7% of patients treated with IV lefamulin and in 3% of those treated with IV moxifloxacin. Diarrhea was common with oral lefamulin (12% vs 1% with moxifloxacin). Hepatic enzyme elevations, nausea, hypokalemia, insomnia, and headache occurred with both formulations of lefamulin at rates similar to those with moxifloxacin.

Lefamulin can prolong the QT interval. Patients with renal failure or hepatic impairment are at increased risk of QT interval prolongation. The risk of QT interval prolongation may also be increased if higher-than-recommended doses are used or if the drug is infused too rapidly. Use of lefamulin should be avoided in patients with known QT interval prolongation or ventricular arrhythmias, including torsades de pointes, and in those taking Class IA or III antiarrhythmic drugs or other drugs that prolong the QT interval.10 If use of lefamulin cannot be avoided in patients with risk factors for QT interval prolongation, ECG monitoring is recommended during treatment.

Clostridioides difficile-associated diarrhea (CDAD) can occur with use of antibiotics, including lefamulin.

DRUG INTERACTIONS — Lefamulin is metabolized primarily by CYP3A4. Concomitant administration of lefamulin with CYP3A4 or P-glycoprotein (P-gp) inducers or inhibitors could affect serum concentrations of lefamulin and its efficacy (see Table 3). Oral, but not IV, lefamulin significantly increased serum concentrations of the sensitive CYP3A4 substrate midazolam.

PREGNANCY AND LACTATION — No data are available on the use of lefamulin in pregnant women. In animal studies, administration of lefamulin during pregnancy was associated with fetal loss, stillbirth, and decreased fetal body weight and ossification. According to the label, women who could become pregnant should use effective contraception while taking lefamulin and for 2 days after stopping it.

Lefamulin has been detected in the milk of lactating rats. Because it may cause serious adverse effects in the breastfed infant, including QT interval prolongation, mothers who breastfeed should be advised to pump and discard breast milk during lefamulin treatment and for 2 days after taking the last dose.

DOSAGE AND ADMINISTRATION — The FDA-approved dosage of lefamulin for adults with CABP is 600 mg orally every 12 hours for 5 days or 150 mg infused IV over 60 minutes every 12 hours for 5-7 days; patients initially treated with IV lefamulin can be switched to the oral formulation to complete the treatment course.

Lefamulin tablets should be swallowed whole (not crushed or divided) with 6-8 ounces of water at least 1 hour before or 2 hours after a meal. A missed dose of oral lefamulin can be taken if the next dose is not scheduled within 8 hours.

In patients with severe hepatic impairment, the dosage of IV lefamulin should be reduced to 150 mg every 24 hours. Oral lefamulin is not recommended for use in patients with moderate or severe hepatic impairment. No dosage adjustment is needed in patients with renal impairment, including those on hemodialysis.

CONCLUSION — Lefamulin (Xenleta), a new pleuromutilin antibiotic, is effective for IV and oral treatment of adults with community-acquired bacterial pneumonia (CABP), but it can prolong the QT interval, interacts with many other drugs, and should not be used in pregnant women. Older, less expensive antibiotics with a longer history of efficacy and safety are preferred for empiric treatment of CABP.


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