Pleuromutilin Antibiotic (Community-Acquired Pneumonia) Pregnancy: Avoid — insufficient human data. Animal studies show foetal toxicity. Use only if no safer alternative available for CABP in pregnancy; amoxicillin-clavulanate + macrolide preferred. Specialist ID/obstetric input.

Lefamulin

Brand names: Xenleta

Adult dose

Dose: IV: 150 mg every 12 hours for 5–7 days. Oral: 600 mg every 12 hours for 5 days

Route: Intravenous (infuse over 60 minutes) or Oral

Frequency: Every 12 hours

Max: 300 mg/day (IV); 1200 mg/day (oral)

Community-acquired bacterial pneumonia (CABP) in adults. IV initiation followed by optional oral step-down. Oral bioavailability ~25% — lower than IV (dose is higher for oral). Active against atypical pathogens (Mycoplasma, Legionella, Chlamydophila) and MRSA. QTc prolongation requires ECG. Source: BNF 90; MHRA SPC Xenleta.

Paediatric dose

Dose: Not licensed under 18 years N/A/kg

Route: N/A

Frequency: N/A

Max: N/A

Not licensed for paediatric pneumonia.

Dose adjustments

Renal

No dose adjustment for oral formulation. IV: eGFR <30 mL/min: use oral if possible (IV formulation cyclodextrin vehicle accumulates); if IV necessary, dose adjust and monitor.

Hepatic

Moderate hepatic impairment (Child-Pugh B): IV — reduce to 150 mg every 24h. Oral — no adjustment. Severe (Child-Pugh C): not recommended.

Paediatric weight-based calculator

Patient weight (kg)

Not licensed for paediatric pneumonia.

Clinical pearls

First pleuromutilin for human systemic use: pleuromutilins were previously only used in veterinary medicine (tiamulin, valnemulin). Lefamulin is the first human-licensed pleuromutilin. Novel mechanism: binds the 50S ribosomal subunit at peptidyl transferase centre (PTC) — unique site distinct from macrolides, lincosamides, oxazolidinones. No cross-resistance with any current antibiotic class.
LEAP trials (NEJM 2019): lefamulin non-inferior to moxifloxacin (with or without linezolid for MRSA) for CABP (early clinical response 87.3% vs 90.2%). Particularly valuable for CABP when fluoroquinolones are contraindicated (tendinopathy, QTc, MRSA concern). Covers all CABP pathogens including MRSA and atypicals.
MRSA pneumonia coverage — key differentiator: unlike most CAP antibiotics (beta-lactams, macrolides), lefamulin has activity against MRSA in pneumonia. Particularly relevant for post-influenza staphylococcal pneumonia. Not approved for MRSA SSTI — only CABP.
QTc monitoring required: mean QTc prolongation of 11–13 ms. ECG before initiating. Do not start if QTc >500 ms. Avoid concurrent QTc-prolonging drugs (fluoroquinolones, azithromycin, antipsychotics). Repeat ECG at 48h if any concern.
Short course — 5 days: 5-day course for oral non-severe CABP equivalent to standard 7-day fluoroquinolone courses. Shorter duration reduces side effects and resistance selection pressure. IV can be switched to oral within 24–48h of clinical improvement. Source: BNF 90; File et al. NEJM 2019 (LEAP-1/LEAP-2); MHRA SPC Xenleta.

Contraindications

QTc >500 ms at baseline
Concurrent QTc-prolonging drugs — additive risk
MAO inhibitors — dopaminergic risk (lefamulin has weak MAO-like activity)
Severe hepatic impairment (Child-Pugh C)

Side effects

Injection site reactions, nausea, diarrhoea (most common with IV)
QTc prolongation (mean 11–13 ms increase — ECG required)
Elevated liver transaminases
Insomnia, headache
Taste disturbance

Interactions

Strong CYP3A4 inhibitors (clarithromycin, itraconazole): increase lefamulin AUC 2–3 fold — dose reduce or avoid
Strong CYP3A4 inducers (rifampicin): reduce lefamulin — avoid
QTc-prolonging drugs (azithromycin, fluoroquinolones, antipsychotics): additive QTc prolongation — avoid or ECG monitor
P-gp inhibitors/inducers: affect lefamulin transport

Monitoring

ECG at baseline and at 48h (QTc monitoring)
Clinical response at 72h (temperature, oxygenation, CRP — CURB-65 or PSI reassessment)
LFTs at baseline and end of treatment
Liver function (hepatic dose adjustment in Child-Pugh B IV)
Electrolytes (potassium, magnesium — hypokalaemia increases QTc risk)

Reference: BNFc; BNF 90; File et al. NEJM 2019 (LEAP-1); Paukner et al. NEJM 2019 (LEAP-2); MHRA SPC Xenleta. Verify against your local formulary and the latest BNF before prescribing.

Curated clinical cross-links plus same-class fallbacks.

Calculators

Pathways