The macrolides are a group of closely related compounds characterized by a macrocyclic lactone ring to which various sugars are attached.

Antimicrobial Activity

Erythromycins inhibit protein synthesis by binding to the 50S subunit of bacterial ribosomes. They generally are bacteriostatic and sometimes bactericidal for gram-positive organisms, including most streptococci and corynebacteria. Similar to penicillin, the rate of macrolide-resistant S pneumoniae has increased (15–50%), and recent reports demonstrate increased resistance in group A streptococci in some centers. Erythromycin-resistant pneumococci are resistant to azithromycin and clarithromycin as well. Chlamydia, Mycoplasma, Legionella, and Campylobacter organisms are susceptible.

Pharmacokinetics & Administration

Preparations for oral use include erythromycin base, erythromycin stearate, estolate, and ethyl succinate. Erythromycins are excreted primarily nonrenally; no adjustment is therefore required in kidney disease.

Azithromycin is available for oral and intravenous use; the latter is particularly useful in the treatment of Legionnaire disease.

Clinical Uses

Macrolides are effective in the treatment of infection due to Legionella, Mycoplasma, Ureaplasma, Corynebacterium (including diphtheria), and Chlamydia (including ocular and respiratory infections) organisms. They are useful adjuncts in the treatment of streptococcal and pneumococcal disease in penicillin-allergic patients. Oral erythromycin base is used with neomycin as prophylaxis for colonic surgery. When administered early, erythromycin may shorten the course of Campylobacter enteritis. Erythromycins are effective against certain Bartonella species (bacillary angiomatosis) and Rhodococcus species. In vitro data suggest that macrolides have a direct effect on neutrophil function and the production of cytokines associated with inflammation. Thus, these agents are being evaluated for their anti-inflammatory effects as well. The most well-documented anti-inflammatory benefit associated with the macrolides (azithromycin) is in the prevention of cystic fibrosis exacerbation. A potential link between chlamydial infection and coronary disease was identified, and it was hypothesized that the benefit of macrolides was due to the antichlamydial activity of these agents. However, large subsequent trials have refuted this benefit.

Adverse Effects

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. Hepatitis recurs if the drug is readministered. 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, digoxin, theophylline, calcium channel blockers, and cyclosporine by inhibiting cytochrome P450. An increased risk of cardiac-associated death has been reported with erythromycin, particularly in patients receiving concomitant inhibitors of cytochrome P450 3A4.

Azalides

Antimicrobial Activity

Azalides (azithromycin, clarithromycin, and others) are closely related structurally to the macrolides. They are similar to erythromycin in activity against most organisms and are slightly more active in vitro than erythromycin against H influenzae (azithromycin > clarithromycin > erythromycin). They are also active against Chlamydia trachomatis, Ureaplasma urealyticum, and Haemophilus ducreyi. In addition, these drugs 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, Helicobacter pylori, and Borrelia burgdorferi.

Pharmacokinetics & Administration

Azithromycin and clarithromycin are more acid-stable than erythromycin, concentrate intracellularly and in tissues, and have a long terminal half-life, with high tissue concentrations that persist for days. The elevated tissue levels associated with azithromycin and clarithromycin has been proposed to overcome the high incidence of in vitro resistance seen with pneumococci (30%), but clinical observations have confirmed that in vitro resistance is associated with clinical failure.

Clinical Uses

Azithromycin and clarithromycin are approved for 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 has been estimated to be substantially greater than that associated with infectious complications associated with S pyogenes. While penicillins and cephalosporins are active against F necrophorum, macrolides are predictably inactive. Because of the long half-life, outpatient oral treatment with azithromycin is with once-daily dosing 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 azalides are more expensive than erythromycin; however, the less frequent dosing and improved tolerability make them preferable choices in most patients.

Azithromycin is used as single-dose therapy (1 g) for chlamydial genital infections. While more expensive than 7 days of treatment with doxycycline, the assurance of adequate supervised therapy makes azithromycin preferred therapy in most patients. Azithromycin can also be used as single-dose therapy (1 g) for chancroid, and 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. 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; however, penicillin-resistant strains are often resistant to these agents as well. Azithromycin taken daily for 1 year has been found to decrease the frequency of exacerbations and improved quality of life; however, cochlear toxicity and isolation of azithromycin-resistant bacterial isolates also has been observed. Weekly 1200-mg doses of azithromycin are effective in preventing Mycobacterium 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. Used as prophylaxis, azithromycin (500 mg weekly) is as effective as benzathine penicillin in preventing streptococcal infections in military recruits, and at a dose of 250 mg daily it is adequate as prophylaxis for malaria (although inferior to doxycycline for multidrug-resistant Plasmodium falciparum). Clarithromycin has been used for the therapy of M avium complex infections, usually in combination with other drugs (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 has also been used in combination regimens for the therapy of H pylori infections. When clarithromycin is given with omeprazole and amoxicillin, cure rates in excess of 80–90% have been achieved. The broad use of the macrolides has resulted in increased bacterial resistance. A prospective, randomized trial of healthy volunteers treated with azithromycin or clarithromycin revealed rapid increases in macrolide-resistant streptococci, which continue up to 6 months after the course of therapy. Furthermore, clarithromycin, but not azithromycin, was found to increase the proportion of the more resistant macrolide-lincosamide-streptogramin phenotype resistance.

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 effect on the cytochrome P450 system. Azithromycin is associated with minimal to no drug interactions. Macrolides, particularly clarithromycin and erythromycin, have the potential to prolong QT in patients at risk (concomitant agents known to prolong QT, history of prolonged QT).

Fidaxomycin

Fidaxomycin is a nonabsorbed macrolide approved for the treatment of Clostridium difficile infection. At a dose of 200 mg twice daily for 10 days, fidaxomycin is equal to vancomycin in the treatment of this disease. An advantage of fidaxomycin compared to oral vancomycin is that the macrolide is associated with fewer recurrences as measured by 25 days after treatment conclusion. While the drug 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.