Macrolide Antibiotics Comparison

·         Structure

·         Mechanism of action

·         Spectrum of activity

·         Indications and uses

·         Pharmacologic properties

·         Drug interactions

·         Key differences

·         Conclusions

·         Brief 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.

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. 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.

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.

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. 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. 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:

Mycoplasma pneumoniae:
erythromycin = roxithromycin = azithromycin = clarithromycin

Ureaplasma urealyticum:
azithromycin = clarithomycin > erythromycin = roxithromycin

Legionella pneumophila:
azithromycin > clarithomycin > erythromycin = roxithromycin

Indications and uses

Erythromycin is indicated for:

·         Upper respiratory tract infections of mild to moderate degree caused by Streptococcus pyogenes or Streptococcus pneumoniae.

·         Lower respiratory tract infections of mild to moderate severity caused by Streptococcus pyogenes or Streptococcus pneumoniae.

·         Listeriosis caused by Listeria monocytogenes.

·         Respiratory tract infections due to Mycoplasma pneumoniae.

·         Skin and skin structure infections of mild to moderate severity caused by Streptococcus pyogenes or Staphylococcus aureus (resistant staphylococci may emerge during treatment).

·         Pertussis (whooping cough) caused by Bordetella pertussis. Erythromycin is effective in eliminating the organism from the nasopharynx of infected individuals, rendering them noninfectious.

·         Diphtheria. Infections due to Corynebacterium diphtheriae, as an adjunct to antitoxin, to prevent establishment of carriers and to eradicate the organism in carriers.

·         Erythrasma. In the treatment of infections due to Corynebacterium minutissimum.

·         Intestinal amebiasis caused by Entamoeba histolytica (oral erythromycins only).

·         Acute pelvic inflammatory disease caused by Neisseria gonorrhoeae.

·         Infections caused by Chlamydia trachomatis: conjunctivitis of the newborn, pneumonia of infancy, and urogenital infections during pregnancy. When tetracyclines are contraindicated or not tolerated, erythromycin is indicated for the treatment of uncomplicated urethral, endocervical, or rectal infections in adults due to Chlamydia trachomatis.

·         Nongonococcal urethritis caused by Ureaplasma urealyticum.

·         Primary syphilis caused by Treponema pallidum.

·         Legionnaires' Disease caused by Legionella pneumophila.

Clarithromycin is indicated for:

·         Pharyngitis/Tonsillitis due to Streptococcus pyogenes

·         Acute maxillary sinusitis due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae

·         Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, or Streptococcus pneumoniae

·         Community-Acquired Pneumonia due to Haemophilus influenzae, Mycoplasma pneumoniae, Streptococcus pneumoniae, or Chlamydia pneumoniae

·         Uncomplicated skin and skin structure infections due to Staphylococcus aureus, or Streptococcus pyogenes

·         Disseminated mycobacterial infections due to Mycobacterium avium, or Mycobacterium intracellulare

·         Acute otitis media due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae

Azithromycin is indicated for:

·         Acute bacterial exacerbations of chronic obstructive pulmonary disease due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae.

·         Community-acquired pneumonia of mild severity due to Streptococcus pneumoniae or Haemophilus influenzae

·         Streptococcal pharyngitis/tonsillitis due to Streptococcus pyogenes

·         Uncomplicated skin and skin structure infections due to Staphylococcus aureus, Streptococcus pyogenes, or Streptococcus agalactiae

·         Non-gonococcal urethritis and cervicitis due to Chlamydia trachomatis

·         Disseminated Mycobacterium avium complex Disease

Roxithromycin is indicated for upper and lower respiratory tract infections, skin and soft tissue infections, urogenital infections, and orodental infections.

Pharmacologic properties

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.

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.

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.

Adverse reactions and side effects

The most frequent side effects of oral erythromycin are gastrointestinal and are dose-related. They include nausea, vomiting, abdominal discomfort, 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 or deafness.

Newer macrolides have fewer gastrointestinal side effects than erythromycin. According to clinical trials, therapy with erythromycin is stopped prematurely more often than with azithromycin or clarithromycin.

The most frequent 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 discomfort. Most of these events are mild or moderate in severity.

The most common side effects with roxithromycin include nausea, vomiting, abdominal pain, and diarrhea.

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)

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.

Key differences

·         Azithromycin and clarithromycin have improved tolerability and fewer gastrointestinal side effects than erythromycin.

·         Both azithromycin and roxithromycin have much lower potential for interactions than erythromycin and clarithromycin.

·         Azithromycin and clarithromycin have improved pharmacokinetic properties - better bioavailability, better tissue penetration, prolonged half-lives.

·         Newer macrolides have advantages over erythromycin in dosing regimen.

·         The gram-positive activity of clarithromycin is superior to that of erythromycin and azithromycin.

·         Azithromycin offers increased gram-negative coverage over erythromycin and clarithromycin.

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.

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.