Azalides (azithromycin, clarithromycin, and others) are structurally closely related to the macrolides. They are similar to erythromycin in activity against most organisms with slightly more activity in vitro against H influenzae (azithromycin > clarithromycin > erythromycin) than erythromycin. They are also active against Chlamydia trachomatis, Ureaplasma urealyticum, and Haemophilus ducreyi. In addition, these medications have in vitro activity against a number of unusual pathogens, including atypical mycobacteria (Mycobacterium avium-intracellulare, Mycobacterium chelonei, Mycobacterium fortuitum, Mycobacterium marinum), Toxoplasma gondii, Campylobacter jejuni, H pylori, and Borrelia burgdorferi.
Pharmacokinetics & Administration
Azithromycin and clarithromycin are more acid-stable than erythromycin, concentrating intracellularly and within tissues. Azithromycin, in particular, has a long terminal half-life, with high tissue concentrations that persist for days. While elevated tissue levels associated with azithromycin and clarithromycin has been proposed to overcome the high incidence of in vitro resistance seen with pneumococci (30%), in vitro resistance has been associated with clinical failure.
Azithromycin and clarithromycin are approved for the treatment of streptococcal pharyngitis, uncomplicated skin infections, and acute bacterial exacerbations of chronic bronchitis. When prescribing these agents in the treatment of pharyngitis in young adults, caution should be used due to the increased risk for Fusobacterium necrophorum, the etiologic agent in Lemierre syndrome. Morbidity and mortality in this patient population have been estimated to be substantially greater than that associated with infectious complications associated with S pyogenes. While penicillins and cephalosporins are active against Fusobacterium necrophorum, macrolides are predictably inactive.
Because of the long half-life, outpatient oral treatment with azithromycin can be administered once daily for a total of 5 days (500 mg on day 1 and then 250 mg on days 2–5). Clarithromycin is usually administered in a dosage of 250–500 mg orally twice daily, although an extended-release formulation that is given as a single daily 1000-mg dose is approved for acute sinusitis and acute exacerbation of chronic bronchitis. While azithromycin is associated with increased acquisition cost compared with erythromycin, the less frequent dosing and improved tolerability make it a preferable choice in most patients.
Azithromycin is used as single-dose therapy (1 g) for chlamydial genital infections. The assurance of adequate supervised therapy makes azithromycin preferred therapy over longer course doxycycline in most patients for this specific indication. Azithromycin is used as single-dose therapy (1 g) for chancroid; a single dose of 1 g is as efficacious as 7 days of doxycycline for nongonococcal urethritis in men and incubating syphilis. A single dose of azithromycin (20 mg/kg, maximum dose of 1 g) is effective in treating trachoma and substantially reduces disease burden in endemic areas. While effective in the treatment of trachoma, mass distribution has been associated with increased circulation of macrolide-resistant S pneumoniae. A 1-g dose of azithromycin is also effective therapy for severe cholera. The spectrum of activity of the macrolides—particularly their atypical coverage—results in their usefulness in mild to moderate cases of community-acquired pneumonia. Azithromycin taken daily for 1 year has been found to decrease the frequency of exacerbations of chronic obstructive pulmonary disease and improved quality of life; however, cochlear toxicity and isolation of azithromycin-resistant bacterial isolates also have been observed. Similarly, early administration of azithromycin in young children with recurrent severe lower respiratory tract infections has been associated with a decreased likelihood of severe lower respiratory tract infection. Azithromycin is not useful for acute exacerbations of asthma. Weekly 1200-mg doses of azithromycin are effective in preventing M avium complex infections in HIV-positive patients, and doses of 500 mg daily are useful in M avium complex pulmonary infections in non–HIV-positive patients. Azithromycin is effective in the treatment of dysentery caused by multidrug-resistant Shigella and Campylobacter organisms.
Clarithromycin has been used for the therapy of M avium complex infections, usually in combination with other medications (eg, rifabutin and ethambutol), and can be given daily (500 mg twice daily) or three times weekly (1000 mg) as intermittent therapy. Oral clarithromycin (500 mg twice daily for 6 months), in combination with other agents, is effective therapy for disseminated M chelonei infections. Clarithromycin is part of first-line treatment of H pylori infections as part of bismuth quadruple therapy or concomitant therapy consisting of a proton pump inhibitor, clarithromycin, amoxicillin, and metronidazole. A prospective, randomized trial of healthy volunteers treated with azithromycin or clarithromycin revealed a rapid increase in colonization with macrolide-resistant streptococci, which continued up to 6 months after therapy.
Adverse effects of azithromycin and clarithromycin are similar to those of erythromycin, but upper gastrointestinal upset, the major side effect, occurs less often with the azalides. Hepatic enzyme elevations and reversible cochlear toxicity have been reported. Clarithromycin is similar to erythromycin in its inhibition of the cytochrome P450 system. Drug interactions between clarithromycin and calcium channel blockers as well as between clarithromycin and statins are associated with increased 30-day risk of hospitalization with acute kidney injury. Azithromycin is associated with minimal to no drug interactions. Macrolides prolong QT in patients at risk (eg, patients receiving concomitant agents known to prolong QT, history of prolonged QT). While some studies suggest an increased rate of death associated with cardiovascular causes, others refute this risk. Nonetheless, the FDA has warned against using clarithromycin in patients with heart disease based on increased cardiac-related adverse events or mortality.