Lefabac

Approved Indication:

• Community-Acquired Bacterial Pneumonia (CABP) in adults, caused by susceptible strains of the following organisms:
• Streptococcus pneumoniae
• Staphylococcus aureus (methicillin-susceptible strains only)
• Haemophilus influenzae
• Legionella pneumophila
• Mycoplasma pneumoniae
• Chlamydophila pneumoniae

Clinically Accepted (Off-label) Uses:

• Under investigation for acute bacterial skin and skin structure infections (ABSSSI), including infections caused by drug-resistant gram-positive organisms.
• May be considered in patients intolerant to macrolides, fluoroquinolones, or beta-lactams in select respiratory infections.

Dosage Forms:

• Oral Tablets: Lefamulin acetate equivalent to 600 mg of lefamulin, every 12 hours for 5 days.
• IV Injection: Lefamulin acetate equivalent to 150 mg of lefamulin, administered every 12 hours over 60 minutes for 5 to 7 days.

Route of Administration: Oral or intravenous (IV)

Recommended Regimens for Adults with CABP:

Transition:
Patients may start with IV and switch to oral formulation once clinically stable to complete the course.

Special Populations:

• Renal Impairment:
• No dosage adjustment required, including for patients with end-stage renal disease or on dialysis.
• Hepatic Impairment:
• Mild (Child-Pugh A): No adjustment
• Moderate (Child-Pugh B): Avoid IV formulation; use oral with caution
• Severe (Child-Pugh C): Use not recommended
• Geriatric Patients: No dosage adjustment necessary.
• Pediatric Patients: Safety and efficacy not established for patients <18 years.

Lefamulin is a semi-synthetic pleuromutilin antibiotic that selectively binds to the peptidyl transferase center (PTC) of the 50S subunit of bacterial ribosomes. This unique binding site inhibits the formation of peptide bonds during translation, thereby blocking bacterial protein synthesis. Lefamulin’s mechanism results in bacteriostatic or bactericidal activity, depending on the organism and drug concentration. Its selective affinity for bacterial ribosomes limits its activity on human mitochondrial or cytoplasmic ribosomes, contributing to its favorable safety profile. It is effective against key respiratory pathogens, including multi-drug resistant strains.

• Absorption (Oral):
  Bioavailability ~25%; food may delay absorption but does not reduce overall exposure.
• Distribution:
• Highly distributed in pulmonary tissue and epithelial lining fluid.
• Plasma protein binding ~95%.
• Metabolism:
• Primarily metabolized in the liver via CYP3A4.
• Elimination:
• ~77% excreted in feces
• ~10% excreted in urine
• Half-life:
• Approximately 10 hours
• Steady-State:
  Achieved within 2 to 3 days with twice-daily dosing.

• Pregnancy:
• Not assigned a specific FDA pregnancy category.
• Animal studies showed embryo-fetal toxicity at high doses.
• Use during pregnancy only if the potential benefit justifies the potential risk.
• Lactation:
• It is unknown whether lefamulin is excreted in human breast milk.
• Because of the potential for serious adverse effects in nursing infants, caution is advised.
• Consider temporary discontinuation of breastfeeding during treatment.
• Contraceptive Warning:
• May reduce the effectiveness of hormonal contraceptives.
• Recommend using alternative (non-hormonal) contraception during treatment and for 2 days after the last dose.

• Class: Antibacterial Agent
• Subclass: Pleuromutilin Antibiotic

• Known hypersensitivity to lefamulin or any of its components
• Co-administration with strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin)
• Patients with known QT interval prolongation
• Concomitant use with other QT-prolonging agents

• QT Interval Prolongation:
  Can cause life-threatening arrhythmias; avoid in patients with congenital long QT syndrome, bradyarrhythmias, or electrolyte abnormalities.
• Hepatic Impairment:
  IV formulation should not be used in moderate to severe hepatic impairment.
• Clostridioides difficile–associated diarrhea (CDAD):
  Can occur with almost all antibacterial agents; monitor for persistent or severe diarrhea.
• CYP3A4 Drug Interactions:
  Avoid strong inducers or inhibitors. Monitor closely with moderate CYP3A4 modulators.
• Allergic Reactions:
  Risk of hypersensitivity, including anaphylaxis and angioedema.

Common Adverse Effects (≥2%):

• Diarrhea
• Nausea
• Vomiting
• Liver enzyme elevations (ALT, AST)
• Injection site reactions (with IV use)

Less Common (<2%):

• Headache
• Dizziness
• Hypokalemia
• Rash
• QT prolongation

Serious Adverse Effects:

• QT interval prolongation and potential torsades de pointes
• Hepatotoxicity, especially in patients with liver disease
• Severe hypersensitivity reactions
• CDAD

Onset:
Most side effects occur during the first few days of therapy and resolve upon discontinuation.

• Strong CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine):
  ↓ Lefamulin levels — contraindicated
• Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin):
  ↑ Lefamulin exposure — use with caution
• QT-prolonging drugs (e.g., amiodarone, sotalol, fluoroquinolones):
  ↑ Risk of arrhythmias — avoid co-administration
• Hormonal contraceptives:
  May be less effective — recommend non-hormonal contraception

Enzyme involvement:

• Substrate of CYP3A4
• Inhibitor of P-glycoprotein (P-gp)

• FDA Approval (2019):
  Approved for CABP in adults based on results from LEAP 1 and LEAP 2 clinical trials.
• IDSA/ATS Guidelines:
  Recognize lefamulin as a suitable alternative for outpatient or inpatient management of CABP, especially in patients allergic to beta-lactams or macrolides.
• EMA Approval:
  Approved for use in the European Union with similar indications and restrictions.
• Ongoing Research:
  Studying use in ABSSSI and infections caused by multi-drug resistant gram-positive organisms.

Oral Tablets:

• Store at 20°C to 25°C (68°F to 77°F)
• Allowable range: 15°C to 30°C (59°F to 86°F)
• Protect from moisture and heat
• Store in original container; keep tightly closed

IV Injection:

• Store vials at 2°C to 8°C (36°F to 46°F)
• Do not freeze
• Protect from light
• After dilution:
• Stable up to 6 hours at room temperature or
• 24 hours under refrigeration (2°C to 8°C)