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Comparison of Erythromycin, Clarithromycin, and Azithromycin
Macrolides belong to one of the most commonly used families of antibiotics used to treat infections. Currently available macrolides in common use in the United States are erythromycin and the newer agents clarithromycin and azithromycin. These new macrolides are semisynthetic derivatives of erythromycin, with structural modifications to improve tissue penetration and broaden the spectrum of activity. Structure
Erythromycin, a macrolide derived from Streptomyces erythreus, contains a 14-member macrocyclic lactone ring to which are attached two sugar moieties, desosamine and cladinose. Azithromycin and clarithromycin are semi-synthetic macrolides similar in structure to erythromycin. Clarithromycin differs from erythromycin by the methylation of a hydroxyl group at the 6-position of the lactone ring. Clarithromycin is a 14-member macrolide with a lactone ring attached to two sugar moieties, which confers acid stability and improved antimicrobial and pharmacokinetic properties. A primary metabolite of clarithromycin is the 14-hydroxy epimer that possesses antimicrobial activity, which is thought to have an additive or synergistic action with the parent compound against various microorganisms. Azithromycin is an azalide which differs from erythromycin by the addition of a methyl-substituted nitrogen atom into the lactone ring. These modifications in structure result in better gastrointestinal tolerability and tissue penetration. In addition, there is a decreased risk of interaction with other drugs metabolized by the cytochrome P-450 enzyme system, and increased half-life. Brief history
The first macrolide antibiotic, erythromycin, was isolated in 1952 from products produced by Streptomyces erythreus. In 1991, two semisynthetic derivatives of erythromycin, azithromycin (Zithromax) and clarithromycin (Biaxin), were brought to market. These new agents possess distinct advantages over erythromycin. Mechanism of action
Macrolides inhibits RNA-dependent protein synthesis by reversibly binding to the 50 S ribosomal subunits of susceptible microorganisms. They induce dissociation of peptidyl transfer RNA (tRNA) from the ribosome during the elongation phase. Thus, RNA-dependent protein synthesis is suppressed, and bacterial growth is inhibited. Macrolides are mainly bacteriostatic but can be bacteriocidal depending on bacterial sensitivity and antibiotic concentration. Spectrum of activity
Generally, macrolides are active against gram-positive cocci (mainly staphylococci and streptococci) and bacilli and to a lesser-extent gram-negative cocci. With the exception of Bordetella pertussis, Campylobacter, Chlamydia, Helicobacter, and Legionella species, gram-negative bacilli are generally resistant to the macrolides. Macrolides are also active against mycobacteria, mycoplasma, ureaplasma, spirochetes, and other organisms. The gram-positive activity of clarithromycin is superior to that of erythromycin and azithromycin, especially against Streptococcus pyogenes and Streptococcus pneumoniae. Gram-negative coverage is also increased with clarithromycin compared to erythromycin. Alone, clarithromycin has variable activity against H. influenzae. However, the combination of clarithromycin and its metabolite has good activity. Because of its good distribution, clarithromycin also offers excellent activity against intracellular pathogens such as Legionella and Mycoplasma species. Azithromycin retains the activity of erythromycin against gram-positive organisms but offers increased gram-negative coverage over erythromycin and clarithromycin. It has been demonstrated to be more active than clarithromycin against H. influenzae. However, it has variable activity against the family Enterobacteriaceae. Nonetheless, Salmonella and Shigella species have been shown to be susceptible, as have other diarrheal pathogens such as Yersinia and Campylobacter. Like clarithromycin, azithromycin also has good activity against Legionella and Mycoplasma species. A unique feature of azithromycin is its excellent activity against sexually transmitted pathogens, especially Chlamydia trachomatis. Despite the improvements clarithromycin and azithromycin offer, both these agents demonstrate cross-resistance with erythromycin. FDA approved indications and uses
Erythromycin is indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the following diseases:
Clarithromycin is indicated for the treatment of mild to moderate infections caused by susceptible strains of the designated microorganisms in the following conditions:
Azithromycin is indicated for the treatment of mild to moderate infections caused by susceptible strains of the designated microorganisms in the following conditions:
Pharmacologic properties and dosage
Even though azithromycin and clarithromycin are chemically related to erythromycin and share a common mechanism of action, their pharmacokinetic properties are better than those of erythromycin. The bioavailability of clarithromycin is more than twice that of erythromycin, and the bioavailability of azithromycin is 1.5 times that of erythromycin. This improved absorption is related to increases in acid stability. Erythromycin has a short half-life 1-1.5h and dosing four times daily is generally required. The elimination half-lives of azithromycin and clarithromycin are greater than that of erythromycin, with azithromycin having the longest half-life. The improved pharmacokinetic profile of the newer macrolides is important because these antibiotics exhibit time-dependent bacterial killing activity. Another important difference is that peak serum concentrations of azithromycin are lower than those of the other two agents. This is because azithromycin accumulates to a greater degree in various host cells, which is reflected by its significantly larger volume of distribution. As a consequence, azithromycin has a lower serum area under the curve (AUC). Clarithromycin is acid stable and is well absorbed from the gastrointestinal tract, irrespective of the presence of food. As the best absorbed macrolide, it has a bioavailability of 50%. A steady state is usually achieved after five doses. Clarithromycin concentrates well in tissues. The resultant tissue-serum ratio is greater than that of erythromycin but less than that of azithromycin. Its half-life is 3 to 7 hours, allowing twice daily administration, either orally or intravenously, with similar efficacy. The dosage of clarithromycin is usually 250 to 500 mg orally twice daily for 7 to 14 days. The higher dose of 500 mg twice daily is recommended when H. influenzae is a known or suspected pathogen. Azithromycin is more acid stable than erythromycin. Food decreases absorption of azithromycin capsules, however tablets may be taken without regard to food. The pharmacokinetic profile of azithromycin reflects a rapid and extensive uptake from the circulation into intracellular compartments, followed by slow release. Azithromycin has been shown to penetrate tissues rapidly and extensively. Azithromycin levels in pulmonary macrophages, polymorphonuclear leukocytes, tonsillar tissue, and genital or pelvic tissue remain increased for extended periods, with a mean tissue half-life of 2 to 4 days. Azithromycin is given once daily for five days. A loading dose of 500 mg is given on day 1, followed by 250 mg daily on days 2 through 5. A single oral dose of 1 g is recommended for genital infections with C. trachomatis. Adverse reactions and side effects
The most frequent side effects of oral erythromycin are gastrointestinal and are dose-related. They include nausea, vomiting, abdominal pain, diarrhea and anorexia. Onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment. Symptoms of hepatitis, hepatic dysfunction and/or abnormal liver function test results may occur. Erythromycin has been associated with QT prolongation and ventricular arrhythmias, including ventricular tachycardia and torsades de pointes. Allergic reactions with rash and eosinophilia can occur rarely. A less well-known but nonetheless significant adverse reaction to erythromycin, especially after intravenous administration, is ototoxicity, manifest as tinnitus and/or deafness. Azithromycin and clarithromycin have fewer gastrointestinal side effects than erythromycin. The most frequently side effects with clarithromycin are diarrhea, nausea, abnormal taste, dyspepsia, abdominal discomfort, and headache. The most common side effects with azithromycin are related to the gastrointestinal system: diarrhea, nausea, and abdominal pain. Most of these events are mild or moderate in severity. In clinical trials, the rate of premature discontinuation of therapy with azithromycin and clarithromycin has been less than observed with erythromycin. Drug-drug interactions
Because clarithromycin is metabolized by hepatic cytochrome P450 microsomal enzymes, it, like erythromycin, has the potential to interact with other drugs. However, clarithromycin is less potent P450 inhibitor than erythromycin. Azithromycin is unlikely to interact with drugs metabolized via the hepatic cytochrome P450 enzyme system, and few interactions have been reported clinically. (1) Key differences among drugs
Conclusions
Both azithromycin and clarithromycin have advantages over erythromycin primarily afforded by their improved pharmacokinetic profiles and superior tolerability. Erythromycin, a highly potent agent against gram-positive bacteria, has a number of disadvantages including poor gastric stability, relatively poor potency against respiratory gram-negative pathogens such as Haemophilus influenzae, and a bacteriostatic mode of action. New macrolide antibiotics, clarithromycin and azithromycin, have been developed to overcome these problems. They offer broader antimicrobial spectrum of activity, improved bioavailability and an extended half-life. Azithromycin and clarithromycin have pharmacokinetics that allow shorter dosing schedules because of prolonged tissue levels. Clarithromycin is more acid stable than erythromycin, giving enhanced and more reliable concentrations in serum as well as fewer gastrointestinal side effects. Clarithromycin has been reported to have bactericidal activity against Streptococcus pneumoniae. It is more active than erythromycin against gram-positive cocci. Combination with its 14-hydroxy metabolite enhances its antimicrobial activity. Azithromycin is more active than erythromycin against gram-negative bacteria, showing potentially useful activity against H. influenzae. Azithromycin concentrations in infected tissue have also been shown to be higher than those in noninfected tissue. The high tissue-to-serum level and extended elimination half-life of azithromycin allow for once-daily dosing and short-course therapy. A single dose of azithromycin is effective for genital chlamydial infections. Although both azithromycin and clarithromycin are well tolerated by children, azithromycin has the advantage of shorter treatment regimens and improved tolerance, potentially improving compliance in the treatment of respiratory tract and skin or soft tissue infections. Brief comparison table
References
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