e1-04: Erythromycin Group (Macrolides)

The macrolides are a group of closely related compounds characterized by a macrocyclic lactone ring with various sugars attached. Representative antibiotics include erythromycin, azithromycin, clarithromycin, and fidaxomicin.

Erythromycins inhibit protein synthesis by binding to the 50S subunit of bacterial ribosomes. While they are generally bacteriostatic, they can be bactericidal for certain organisms. Similar to penicillin, the rate of macrolide-resistant S pneumoniae is high (25–35%), and increased regional resistance in group A streptococci has been intermittently reported. Erythromycin-resistant pneumococci are resistant to azithromycin and clarithromycin as well. Chlamydia, Mycoplasma, Legionella, and Campylobacter organisms are susceptible.

Preparations for oral use include erythromycin base, erythromycin stearate, estolate, and ethyl succinate. Erythromycins are excreted primarily nonrenally therefore, no adjustment is required in kidney dysfunction. Azithromycin is available for oral and intravenous use. Clarithromycin is only available as an oral preparation in the United States, but an intravenous preparation is available outside of the United States.

Macrolides are effective in the treatment of infection due to Legionella, Mycoplasma, Ureaplasma, Corynebacterium (including diphtheria), Chlamydia, and Chlamydophila (including ocular and respiratory infections) organisms. They are useful alternatives in the treatment of certain patients with a serious penicillin allergy. When administered early, erythromycin may shorten the course of Campylobacter enteritis. Erythromycins are effective against certain Bartonella species (bacillary angiomatosis) and Rhodococcus species. Clarithromycin, in combination with proton pump inhibitors, is useful in the treatment of Helicobacter pylori. Treatment of atypical mycobacteria infections, particularly Mycobacterium avium complex, whenever possible, should include azithromycin or clarithromycin in combination therapy.

These agents are also sometimes used for their anti-inflammatory action. In vitro data suggest that macrolides have a direct effect on neutrophil function and the production of cytokines associated with inflammation. The most well-documented non-antibacterial benefit associated with the macrolides (azithromycin) is in the prevention of cystic fibrosis exacerbation. Evidence does not support a benefit of macrolides due to their antichlamydial activity in the setting of coronary artery disease.

Nausea, vomiting, and diarrhea may occur after oral or intravenous intake. Erythromycins—particularly the estolate—can produce acute cholestatic hepatitis (fever, jaundice, impaired liver function), probably as a hypersensitivity reaction. Reversible auditory impairment occurs with large prolonged dosing, particularly in patients with impaired kidney or liver function. Clarithromycin and erythromycin have been associated with prolongation of the QT interval and torsades de pointes, more commonly in women. Erythromycins (and clarithromycin) can increase the effects of oral anticoagulants, colchicine, digoxin, theophylline, calcium channel blockers, and cyclosporine by inhibiting cytochrome P450. An increased risk of cardiac-associated death has been reported with clarithromycin and erythromycin, particularly in patients receiving concomitant inhibitors of cytochrome P450 3A4. Considering the substantially improved safety and minimal drug interactions with azithromycin, this agent should be preferentially used over either clarithromycin or erythromycin.

Antimicrobial Activity

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.

Clinical Uses

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. The less frequent dosing and improved tolerability of azithromycin makes it a preferable choice over erythromycin or clarithromycin 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 as monotherapy in mild cases of community-acquired pneumonia or in combination with beta-lactams for comorbid patients with community-acquired pneumonia. The Infectious Diseases Society of America recommends azithromycin monotherapy only in areas with pneumococcal resistance rates less than 25%. 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 with long-term therapy. 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. 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.

Adverse Effects

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). The FDA has warned against using clarithromycin in patients with heart disease based on increased cardiac-related adverse events or mortality.

Fidaxomicin is a nonabsorbed macrolide approved for the treatment of C difficile infection. At a dose of 200 mg twice daily for 10 days, fidaxomicin is equal to vancomycin in the treatment of this disease. However, fidaxomicin has been associated with fewer recurrences of C difficile infection compared to oral vancomycin. While the medication offers an important advance in the treatment of C difficile infection, its considerable acquisition cost is a barrier to its use in most patients with this disease. The most common adverse events reported in clinical trials include nausea and vomiting.