Clinical Review & Education
From The Medical Letter on Drugs and Therapeutics
Lefamulin (Xenleta) for Community-Acquired
Bacterial Pneumonia
Lefamulin (Xenleta – Nabriva), a semisynthetic pleuromutilin
antibiotic, has been approved by the FDA for IV and oral treat-
ment of community-acquired bacterial pneumonia (CABP) in
adults. It is the first systemic
pleuromutilin antibiotic to be
Related article page 1661
approved in the US; retapamu-
lin (Altabax), a 1% topical ointment for treatment of impetigo,
was approved in 2007.1
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.
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 cur-
rently exceed 40%. Doxycycline is a reasonable alternative, but re-
sistance to doxycycline is also increasing among S. pneumoniae.
A respiratory fluoroquinolone (levofloxacin or moxifloxacin) is of-
ten used for adults with comorbidities or antibiotic exposure dur-
ing 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 ⱖ25%, but they can
cause serious adverse effects.3 Combining a beta-lactam (such
as high-dose amoxicillin or cefpodoxime) with a macrolide or doxy-
cycline is another option in areas with high rates of macrolide or
doxycycline resistance.4,5
For empirical treatment of CABP in hospitalized patients
(not ICU), an antipneumococcal IV beta-lactam (such as ceftriax-
one, cefotaxime, ceftaroline, or ampicillin/sulbactam) plus a mac-
rolide (or doxycycline) or monotherapy with an IV respiratory fluo-
roquinolone (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 stan-
dard 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 treat-
ment of CABP.
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
Lefamulin is active in vitro and in vivo against S. pneumoniae,
H. influenzae, M. pneumoniae, C. pneumoniae, Legionella pneumo-
phila, 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 establish-
jama.com
© 2019 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by a University of Massachusetts Amherst User on 11/05/2019
ing its clinical efficacy against these pathogens are limited. Lefamu-
lin is also active in vitro against pathogens that cause sexually trans-
mitted infections such as Chlamydia trachomatis, Mycoplasma
genitalium, and Neisseria gonorrhoeae.8 It is not active against
Enterobacteriaceae or Pseudomonas aeruginosa.
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 1.
Infusion-site reactions occurred in 7% of patients treated with
IV lefamulin and in 3% of those treated with IV moxifloxacin. Diar-
rhea was common with oral lefamulin (12% vs 1% with moxifloxa-
cin). 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 fail-
ure or hepatic impairment are at increased risk of QT interval pro-
longation. 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
Table 1. Lefamulin Clinical Trial Results
Early Clinical
Regimen Response, %a
LEAP 1 (n = 551)b
Lefamulin 150 mg IV q 12 h × ≥3 dc 87.3d
e,f
Moxifloxacin 400 mg IV q 24 h × ≥3 d 90.2
LEAP 2 (n = 738)g
Lefamulin 600 mg PO q 12 h × 5 d 90.8d
Moxifloxacin 400 mg PO q 24 h × 7 d 90.8
a
The primary endpoint. At 72-120 hours after the first dose. Response was
defined as survival, improvement in at least 2 symptoms (cough, sputum
production, chest pain, dyspnea), no worsening of any symptom, and
avoidance of any non-study antibacterial medication for CABP.
b
File TM, et al. Clin Infect Dis. February 4, 2019.
c
Patients could be switched to 600 mg PO q 12 h to complete treatment.
d
Noninferior to moxifloxacin.
e
Patients could be switched to 400 mg PO q 24 h to complete treatment.
f
Linezolid was added in patients suspected to be infected with MRSA.
g
Summarized in the package insert.
(Reprinted) JAMA November 5, 2019 Volume 322, Number 17 1709
 Clinical Review & Education From The Medical Letter on Drugs and Therapeutics

Table 2. Lefamulin Drug Interactions

IV Formulation
P-gp inducers or strong or moderate CYP3A4 inducersa • Can decrease lefamulin serum concentrations and possibly its efficacy
• Avoid concurrent use
Drugs that prolong the QT intervalb • Avoid concurrent use
Oral Formulation
P-gp inducers or strong or moderate CYP3A4 inducersa • Can decrease lefamulin serum concentrations and possibly its efficacy
• Avoid concurrent use
P-gp inhibitors or strong CYP3A4 inhibitorsa • Can increase lefamulin serum concentrations
• Avoid concurrent use
P-gp inhibitors or moderate CYP3A4 inhibitorsa • Can increase lefamulin serum concentrations
• Monitor for adverse effects
Sensitive CYP3A4 substrates that prolong the QT interval • Can increase serum concentrations of CYP3A4 substrates and the risk of QT
(such as pimozide)b interval prolongation
• Avoid concurrent use
Sensitive CYP3A4 substrates that do not prolong the QT intervalc • Can increase serum concentrations of CYP3A4 substratesd
• Monitor for adverse effects
Drugs that prolong the QT intervalb • Avoid concurrent use
c
Abbreviation: P-gp, P-glycoprotein. Such as midazolam, alprazolam, diltiazem, verapamil, simvastatin, and
a
Inhibitors and inducers of CYP enzymes and P-glycoprotein. Med Lett Drugs vardenafil.
d
Ther. March 12, 2019. Oral lefamulin increased the AUC and Cmax of midazolam by 200% and
b
Such as Class IA and III antiarrhythmics, macrolides, and fluoroquinolones. 100%, respectively.
Woosley RL, et al. QT drugs list.

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 recom-
mended during treatment.
Clostridioides difficile-associated diarrhea (CDAD) can occur with
use of antibiotics, including lefamulin.
Lefamulin is metabolized primarily by CYP3A4. Concomitant ad-
ministration of lefamulin with CYP3A4 or P-glycoprotein (P-gp)
inducers or inhibitors could affect serum concentrations of lefamu-
lin and its efficacy (see Table 2). Oral, but not IV, lefamulin signifi-
cantly increased serum concentrations of the sensitive CYP3A4
substrate midazolam.
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 be-
come 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. Be-
cause 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 treat-
ment and for 2 days after taking the last dose.
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 lefamu-
lin 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.
Lefamulin (Xenleta), a new pleuromutilin antibiotic, is effec-
tive for IV and oral treatment of adults with community-acquired bac-
terial pneumonia (CABP), but it can prolong the QT interval, inter-
acts with many other drugs, and should not be used in pregnant
women. Older, less expensive antibiotics with a longer history of ef-
ficacy and safety are preferred for empirical treatment of CABP.

ARTICLE INFORMATION
Editors: Mark Abramowicz, MD, President; Gianna
Zuccotti, MD, MPH, Vice President and Executive
Editor; Jean-Marie Pflomm, PharmD, Editor in Chief
Once a month, The Medical Letter provides a
previously published article to JAMA to be
republished.
Previous Publication: The entire article and
reference list were published in The Medical Letter
on Drugs and Therapeutics. September 23, 2019;61
(1581):145-148. It is reprinted here with permission
from ©The Medical Letter Inc.
About The Medical Letter: The Medical Letter is a
nonprofit organization that publishes biweekly new
drug evaluations and treatment recommendations.
The Medical Letter does not sell advertising or
receive any commercial support. Financial
support comes primarily from sales of
subscriptions, books, software, continuing
education materials, and licenses.
For a free trial subscription to The Medical Letter, go
to www.medicalletter.org/tmlj. The Medical Letter—
Essential to your practice.

1710 JAMA November 5, 2019 Volume 322, Number 17 (Reprinted) jama.com

© 2019 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a University of Massachusetts Amherst User on 11/05/2019