Clarithromycin

Abstract

Clarithromycin is a broad spectrum macrolide antibacterial agent active in vitro and effective in vivo against the major pathogens responsible for respiratory tract infections in immunocompetent patients. It is highly active in vitro against pathogens causing atypical pneumonia (Chlamydia pneumoniae, Mycoplasma pneumoniae and Legionella spp.) and has similar activity to other macrolides against Staphylococcus aureus, Streptococcus pyogenes, Moraxella catarrhalis and Streptococcus pneumoniae. Haemophilus influenzae is susceptible or intermediately susceptible to clarithromycin alone, but activity is enhanced when the parent drug and metabolite are combined in vitro. Absorption of clarithromycin is unaffected by food. More than half of an oral dose is systemically available as the parent drug and the active 14-hydroxy metabolite. Pharmacokinetics are nonlinear, with plasma concentrations increasing in more than proportion to the dosage. First-pass metabolism results in the rapid appearance of the active metabolite 14-hydroxy-tiarithromycin in plasma. Clarithromycin and its active metabolite are found in greater concentrations in the tissues and fluids of the respiratory tract than in plasma. Dosage adjustments are required for patients with severe renal failure, but not for elderly patients or those with hepatic impairment. Drug interactions related to the cytochrome P450 system may occur with clarithromycin use. In addition to the standard immediate-release formulation for administration twice daily, a modified-release formulation of clarithromycin is now available for use once daily. In dosages of 500 to 1000 mg/day for 5 to 14 days, clarithromycin was as effective in the treatment of community-acquired upper and lower respiratory tract infections in hospital and community settings as β-lactam agents (with or without a β-lactamase inhibitor), cephalosporins and most other macrolides. Clarithromycin was similar in efficacy to azithromycin in comparative studies and is as effective as and better tolerated than erythromycin. Adverse events are primarily gastrointestinal in nature, but result in fewer withdrawals from therapy than are seen with erythromycin. Clarithromycin provides similar clinical and bacteriological efficacy to that seen with β-lactam agents, cephalosporins and other macrolides. It offers a cost-saving alternative to intravenous erythromycin use in US hospitals and is available in both once-daily and twice-daily formulations. The spectrum of activity of clarithromycin against common and emerging respiratory tract pathogens may make it suitable for use in the community as empirical therapy of respiratory tract infections in both children and adults. The activity of clarithromycin against most respiratory pathogens in vitro is similar to that of other macrolides. Streptococcus pyogenes isolates showed excellent susceptibility to clarithromycin. Clarithromycin is very active against pathogens causing atypical pneumonia (Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella pneumophila) and against Moraxella catarrhalis. The only characterised resistance pattern results in cross-resistance between macrolides, as seen in strains of Staphylococcus aureus and Streptococcus pyogenes. Isolates that are susceptible to erythromycin or penicillin are also susceptible to clarithromycin. Haemophilus influenzae is susceptible or intermediately susceptible to clarithromycin alone. The combination of the parent drug and metabolite shows at least additive if not synergistic activity, such that Haemophilus influenzae is susceptible in vitro to the combination. 14-Hydroxy-clarithromycin was also active against L pneumophila isolates. In vitro studies in blood show that clarithromycin is active against bacteria both intra-and extracellularly. Postantibiotic effects may occur with some species and bactericidal effects are seen with H. influenzae, Streptococcus pneumoniae, and possibly M. catarrhalis. In addition to its antimicrobial effects, clarithromycin appears to improve immune function and improves the viscoelastic properties of mucus and sputum. Absorption of clarithromycin is unaffected by food, oral bioavailability of the parent drug is 52 to 55% and first-pass metabolism produces the active 14-hydroxy metabolite. Pharmacokinetics are nonlinear as a result of hepatic elimination, with capacity-limited formation of the active 14-hydroxy metabolite occurring at doses >600mg. Total body clearance decreases and the elimination half-life increases with increasing dose, whereas plasma concentrations and the area under the plasma concentration-time curve (AUC) increase more than proportionately with increases in the dose. However, once steady-state is reached, no accumulation occurs with additional doses administered. Clarithromycin is not extensively protein bound but has a volume of distribution of 191 to 306L. Concentrations of the drug in respiratory tract tissues and fluids greatly exceed those in plasma. Furthermore, tissue concentrations of both clarithromycin and 14-hydroxy-clarithromycin exceed the MICs for most respiratory pathogens. About 40% of the drug is removed from the body in the faeces and ≈53% in the urine. Reductions in clarithromycin clearance seen in elderly patients and those with hepatic disease were well tolerated and do not appear to require dosage adjustments. In patients with renal failure, however, plasma concentrations and AUC values of the parent drug and active metabolite increase markedly, necessitating dosage reductions in patients with creatinine clearance (CL_CR) values of ≤30 ml/min (≤1.8 L/h). Clarithromycin is found in breastmilk of nursing mothers treated with the drug. A modified-release formulation of clarithromycin has been developed to allow administration...