Ketolides

Ketolides are semisynthetic derivatives of erythromycin in which the cladinose sugar is replaced by a keto group, which improves ribosomal binding and overcomes common macrolide resistance. Telithromycin is the only ketolide that reached routine use; its role has shrunk to almost nothing because of serious toxicity, and it has been withdrawn or restricted in many countries. Solithromycin and cethromycin did not complete licensing.

Mechanism. Binding to two sites on the 23S rRNA of the 50S ribosomal subunit (domains II and V) blocks protein synthesis. Dual binding keeps activity against pneumococci with erm-mediated methylation or mef efflux that are resistant to macrolides.

Pharmacokinetics. About 57 percent oral bioavailability, unaffected by food; half-life about 10 hours; hepatic metabolism with about one third by CYP3A4; high intracellular and lung tissue concentrations. Strong inhibitor of CYP3A4 and CYP2D6.

Spectrum. Streptococcus pneumoniae (including macrolide- and penicillin-resistant strains), Streptococcus pyogenes, H. influenzae, Moraxella, Mycoplasma, Chlamydia, Legionella. Weak against Enterobacterales; no activity against MRSA or Pseudomonas.

• Telithromycin: oral 800 mg tablets; the only ketolide with licensing history.
• Solithromycin and cethromycin: investigational agents without routine clinical availability.

Compared with macrolides, ketolides retain activity against macrolide-resistant pneumococci but carry greater hepatic, visual and neuromuscular toxicity.

Representative regimen (where available). Telithromycin 800 mg orally once daily, for 5 days in community-acquired pneumonia and for 5 to 10 days in other respiratory indications. Reduce to 600 mg daily when creatinine clearance is under 30 mL/min.

Selection. Not first line for any indication. Where a ketolide was once used, alternatives are now preferred: amoxicillin or a respiratory fluoroquinolone for community pneumonia, doxycycline or amoxicillin for sinusitis. Telithromycin has no role in mild infection such as pharyngitis or acute bronchitis. It is not available in most East African settings.

Contraindications. Myasthenia gravis (fatal respiratory failure reported); prior hepatitis or jaundice with telithromycin or a macrolide; congenital or acquired QT prolongation; concurrent simvastatin, lovastatin, atorvastatin, ergot derivatives, pimozide, cisapride; severe renal impairment combined with hepatic impairment.

Serious effects. Acute liver failure and severe hepatitis (the reason for withdrawal in many markets); visual disturbance (blurred vision, difficulty with accommodation, diplopia); syncope and transient loss of consciousness; QT prolongation; exacerbation of myasthenia gravis; C. difficile infection.

Interactions. CYP3A4 and CYP2D6 inhibition raises levels of statins, midazolam, ergotamine, digoxin, theophylline, calcineurin inhibitors, metoprolol and warfarin. Rifampicin and other CYP3A4 inducers lower telithromycin levels sharply.

Monitoring. Liver tests at baseline and with any symptoms; ECG in cardiac disease; stop the drug for jaundice, hepatitis symptoms or visual disturbance. Warn patients not to drive on days when visual disturbance or faintness occurs.

Special groups. Pregnancy and breastfeeding: avoided. Children: not licensed. Older adults: higher risk of QT and hepatic effects. Hepatic impairment: avoided in significant disease.