Clarithromycin

Clarithromycin is a widely used macrolide antibiotic employed in the management of numerous bacterial infections across respiratory, gastrointestinal, and soft tissue systems. Introduced to clinical practice in 1990, it was synthesised as a semisynthetic derivative of erythromycin and is listed among the World Health Organization’s essential medicines. Its broad antimicrobial utility, coupled with oral and intravenous formulations, has ensured its sustained relevance in both primary and specialised care. Concerns relating to antimicrobial resistance and drug–drug interactions, however, form an important component of contemporary clinical considerations.

Background and Development

Clarithromycin emerged during the 1980s following targeted efforts to produce a macrolide with improved acid stability and better oral bioavailability compared with erythromycin. Chemically identified as 6-O-methylerythromycin, the compound demonstrated enhanced tissue penetration and a broader antimicrobial spectrum. Regulatory approval in 1990 facilitated global adoption, with the drug subsequently made available as a generic preparation.
Its mechanism of action is shared with other macrolides: it inhibits bacterial protein synthesis by binding to 23S ribosomal RNA within the 50S subunit, halting peptide elongation and thereby suppressing bacterial proliferation. In addition to its antibacterial function, clarithromycin has been shown to exert negative allosteric modulation on GABAA_AA​ receptors, a property that later drew investigative interest in neurological contexts such as hypersomnia.

Medical Uses

Clarithromycin is prescribed for a range of community and hospital-acquired infections. Key applications include:

• Respiratory tract infections: Effective in upper and lower respiratory conditions, particularly Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis infections. It is commonly administered for pneumonia, bronchitis, and pharyngitis, including as an alternative to penicillin in streptococcal pharyngitis.
• Helicobacter pylori infection: Frequently used as part of multidrug therapy in the eradication of H. pylori, especially in duodenal ulcer disease.
• Skin and soft tissue infections: Useful in mild to moderate bacterial dermal conditions.
• Atypical and zoonotic infections: Employed in Bartonella-related cat scratch disease, cryptosporidiosis, toxoplasmosis, and Mycobacterium avium complex infections.
• Prophylactic roles: May be administered to individuals at risk of bacterial endocarditis who are unable to take penicillin-based regimens.
• Lyme disease: Occasionally used as a second-line option in specific cases.

Interest has also extended to idiopathic hypersomnia. Research to date remains inconclusive, although clinical guidelines have conditionally supported its use when alternative therapies prove inadequate.

Spectrum of Activity

Clarithromycin displays a broad spectrum of antibacterial activity. Commonly sensitive organisms include:

• Aerobic Gram-positive bacteria: Staphylococcus aureus (non-MRSA), Streptococcus pneumoniae, Streptococcus pyogenes.
• Aerobic Gram-negative bacteria: Haemophilus parainfluenzae, Haemophilus influenzae, Moraxella catarrhalis, Helicobacter species.
• Mycobacteria: Notably Mycobacterium avium complex.
• Atypical bacteria: Chlamydia pneumoniae and Mycoplasma pneumoniae.

Certain organisms remain less reliably covered, and for several species clinical effectiveness has not been sufficiently validated through controlled trials. Rising antimicrobial resistance—particularly macrolide resistance among H. pylori and respiratory pathogens—has led to increased emphasis on susceptibility testing prior to treatment.

Contraindications

Clarithromycin is contraindicated under several clinical circumstances. Individuals with known hypersensitivity to macrolide antibiotics or excipients contained in the formulation should avoid its use. It must not be given to patients with previous drug-induced cholestatic jaundice or hepatic dysfunction associated with macrolide exposure.
Other important contraindications include:

• Electrolyte imbalance: Particularly hypokalaemia, which can predispose to arrhythmias.
• Certain cardiovascular conditions: A history of ventricular arrhythmias, including Torsades de Pointes.
• Concomitant medications: Interactions with cisapride, pimozide, astemizole, terfenadine, ergot alkaloids, ticagrelor, ranolazine, and specific statins render co-administration unsafe. In individuals with renal or hepatic impairment, concomitant colchicine poses a substantial risk of toxicity.

Side Effects

The drug is generally well tolerated but is associated with predictable gastrointestinal disturbances, including nausea, vomiting, abdominal discomfort, and diarrhoea. Headaches and insomnia are also frequently noted. A distinctive metallic or altered taste is a recognised but non-serious reaction.
Less common neurological and psychological symptoms include irritability, hallucinations, dizziness, motion sensitivity, panic attacks, and nightmares. In rare cases, clarithromycin may precipitate ototoxicity, delirium, or mania.
Allergic reactions range from mild rashes to rare anaphylaxis. The suppression of normal flora can predispose patients to oral or vaginal candidiasis.
Liver toxicity, including jaundice and, unusually, cirrhosis, has been documented. Renal complications, particularly in vulnerable groups, may also arise.
Cardiac effects constitute a significant area of concern. Clarithromycin can prolong the QT interval, heightening the risk of serious arrhythmias, especially among patients with underlying cardiac disease or those taking additional QT-prolonging agents. Safety alerts have highlighted increased mortality in certain patient subgroups.

Use in Pregnancy and Breastfeeding

Clarithromycin is not recommended during pregnancy unless no safer alternative exists. Potential foetal risks require that benefits clearly outweigh hazards before use. It remains uncertain whether the drug is excreted in breast milk, prompting caution among lactating mothers.

Drug Interactions

The inhibition of CYP3A4 by clarithromycin underscores many of its most clinically relevant interactions. Elevated serum levels of co-administered drugs may result in toxicity, while reduced metabolism of others may diminish therapeutic effect. Important interactions include:

• Colchicine: Risk of severe or fatal toxicity due to increased systemic concentration.
• Statins metabolised by CYP3A4: Increased incidence of rhabdomyolysis, mandating avoidance with agents such as simvastatin and lovastatin.
• Calcium-channel blockers: Potential for hypotension, bradycardia, kidney failure, and lactic acidosis.
• Carbamazepine: Elevated drug levels leading to diplopia, ataxia, nausea, and hyponatraemia.
• HIV medications: Variable effects requiring careful dose adjustments; levels of zidovudine may be reduced.

Pharmacology and Mechanism

By binding to the 50S ribosomal subunit, clarithromycin disrupts peptide chain formation, halting bacterial protein synthesis. The result is bacteriostatic activity, although bactericidal effects may occur at higher concentrations against selected organisms.
Its additional neuropharmacological action on GABAA_AA​ receptors has provided an explanatory basis for experimental exploration of its wakefulness-promoting potential, though this remains outside mainstream therapeutic use.