Macrolide Antibiotics Comparison
Macrolides are one of the most commonly used families of antibiotics. Currently available macrolides are erythromycin and the newer agents clarithromycin, azithromycin, roxithromycin, dirithromycin, and telithromycin.
The first macrolide antibiotic, erythromycin, was isolated in 1952 from products produced by Streptomyces erythreus. In 1991, two semisynthetic derivatives of erythromycin, azithromycin and clarithromycin, were brought to market. Roxithromycin was first introduced by German pharmaceutical company Hoechst Uclaf in 1987, however, it is not available in U.S.
Erythromycin, a macrolide derived from Streptomyces erythreus, contains a 14-member macrocyclic lactone ring to which are attached two sugar moieties, desosamine and cladinose. In the acidic environment of the stomach, it is rapidly degraded to the 8,9-anhydro-6,9- hemiketal and then to the 6,9,9,12-spiroketal form.
Azithromycin, clarithromycin, and roxithromycin are semi-synthetic macrolides similar in structure to erythromycin.
Clarithromycin (6-O-methyl-erythromycin) has the same macrolide, 14-membered lactone ring as erythromycin. The only difference is that at the 6-position a methoxy group replaces the hydroxyl group. 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 (9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin), a 15-membered ring macrolide, is an azalide which differs from erythromycin by the addition of a methyl-substituted nitrogen atom into the lactone ring.
Roxithromycin is a semi-synthetic 14-membered ring macrolide antibiotic in which the erythronolide A lactone ring has been modified to prevent inactivation by gastric acid.
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.
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.
Macrolide antibiotics have anti-inflammatory activity, which likely depends on their ability to prevent the production of proinflammatory mediators and cytokines3. Roxithromycin has stronger anti-inflammatory properties than clarithromycin and azithromycin.
Spectrum of activity
Generally, macrolides are active against gram-positive cocci (mainly staphylococci and streptococci) and bacilli, and to 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.
But why are macrolides NOT very effective against Gram-negative bacteria? They have large hydrophobic molecules and cannot penetrate both the inner and outer membranes of Gram-negative bacteria.
Erythromycin has activity against gram-positive cocci and some gram-negative organisms (eg. B.pertussis, M. pneumoniae, L. pneumophilia).
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. Azithromycin is 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. Its unique feature is an excellent activity against sexually transmitted pathogens, especially Chlamydia trachomatis.
Despite the improvements clarithromycin and azithromycin offer, both these agents demonstrate cross-resistance with erythromycin.
Roxithromycin has some expanded activity spectrum compared with erythromycin. It has improved activity against Moraxella catarrhalis, Haemophilus species, Pasteurella species, and other atypical mycobacteria.
Relative activity of macrolides against intra-cellular bacteria 2:
Indications and uses
Erythromycin is indicated for:
Clarithromycin is indicated for:
Azithromycin is indicated for:
Roxithromycin is indicated for upper and lower respiratory tract infections, skin and soft tissue infections, urogenital infections, and orodental infections.
Even though azithromycin, clarithromycin, and roxithromycin are chemically related to erythromycin and share a common mechanism of action, their pharmacokinetic properties are better than those of erythromycin.
Unlike the other macrolides, clarithromycin has an active metabolite, 14-hydroxy (OH)-clarithromycin.
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 erythromycin and clarithromycin. 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). On the other hand, azithromycin achieves vey high tissue concentrations.
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.
Azithromycin is more acid stable than erythromycin. 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. Its 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.
Roxithromycin is also more acid-stable than erythromycin, and achieves higher serum concentrations. It has good oral availability, which is independent of food. A half-life is about 12 hours.
Gastrointestinal side effects
The most common side effects with macrolides are nausea, vomiting, abdominal discomfort, and diarrhea.
Newer macrolides clarithromycin and azithromycin cause significantly less gastrointestinal side effects (nausea, vomiting, abdominal discomfort, and diarrhea) than erythromycin. According to clinical trials, therapy with erythromycin is stopped prematurely more often than with azithromycin or clarithromycin.
Why is erythromycin poorly tolerated?
Arrhythmogenic potency and QT interval prolongation
Erythromycin has been associated with QT prolongation and ventricular arrhythmias, including ventricular tachycardia and torsades de pointes.
Azithromycin and roxithromycin are less potent at provoking arrhythmia than clarithromycin and erythromycin.
The rank order of arrhythmogenicity potential:
Other side effects
A less well-known but nonetheless significant adverse reaction to erythromycin, especially after intravenous administration, is ototoxicity, manifest as tinnitus or deafness.
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)
Roxithromycin is not metabolized extensively. It is predominantly cleared unchanged in the bile or metabolised by non-CYP450 mechanisms. So, it has a low potential for drug interactions.
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.
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 allow for once-daily dosing and short-course therapy.
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 Macrolide Comparison
Published: May 05, 2007