Macrolide & Ketolide Antibiotics Comparison
- Classification of macrolides [Table 1]
- Mechanism of action [Video]
- Spectrum of activity
- Indications and uses [Infographic]
- Side effects
- Drug interactions
- Pharmacologic properties
- Key differences between macrolides
- Brief comparison [Table 2]
Based on "Basic and Clinical Pharmacology"
written by Bertram G. Katzung, MD, PhD
Classification of Macrolides
Table 1. Macrolides classification the basis of their molecular structures.
|Ketolides||• Cethromycin (in clinical development)**
• Modithromycin (in clinical development)**
• Solithromycin (phase 3 clinical trials)
|** Not available in United States|
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.
Ketolides are a new subgroup of macrolide antibiotics designed to overcome bacterial resistance to this class of antibacterial agents. The ketolides are semi-synthetic derivatives. Currently, the only ketolide on the U.S. market is telithromycin sold under the brand name Ketek®.
Mechanism of action
- Macrolides are mainly bacteriostatic.
- Macrolides can be bactericidal depending on bacterial sensitivity and antibiotic concentration.
- Macrolides inhibit bacterial protein synthesis.
Macrolides inhibit RNA-dependent protein synthesis by reversibly binding to the 50S 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.
Chemical structure of ketolides enable these drugs to bind more tightly to ribosomal RNA than the macrolides. As a result telithromycin has increased potency, lower risk of induction of bacterial resistance, and increased activity against macrolide-resistant organisms.
- Macrolide antibiotics have anti-inflammatory activity. They prevent the production of proinflammatory mediators and cytokines3, as well as inhibit migration of neutrophils to sites of inflammation.
- Roxithromycin has stronger anti-inflammatory properties than clarithromycin and azithromycin.
3. Immunomodulatory8Macrolides can:
- Prevent the formation of bacterial biofilm
- Reduce formation of oxygen-free radicals
- Enhance neutrophil apoptosis
- Decrease mucus secretion
- Enhance or reduce activation of the immune system.
Spectrum of activity
- Gram-positive cocci (mainly staphylococci and streptococci)
- Gram-positive bacilli (Listeria monocytogenes, Bacillus anthracis, Corynebacterium species)9
- Some gram-negative cocci and coccobacilli (Neisseria gonorrhoeae, Moraxella catarrhalis, Haemophilus influenzae, Bordetella pertussis, Campylobacter, Helicobacter, and Legionella species)
- Spirochetes (Borrelia recurrentis)
Impotrant differences in antimicrobial activity of macrolides:
- 1. Clarithromycin has superior gram-positive activity11, 12.
- 2. Azithromycin has increased gram-negative coverage10.
- 3. Telithromycin is active against macrolide-resistant Streptococcus pneumoniae.
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. Clarithromycin has strong activity against Mycobacterium leprae and is superior in this respect to erythromycin and azithromycin.
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 and M. catarrhalis. 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 drugs 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.
Telithromycin is active against macrolide-resistant respiratory pathogens, including Streptococcus pneumoniae 7.
Relative activity of macrolides against intra-cellular bacteria 2:
erythromycin = roxithromycin = azithromycin = clarithromycin
azithromycin = clarithomycin > erythromycin = roxithromycin
azithromycin > clarithomycin > erythromycin = roxithromycin
Gram-negative bacilli (e.g. Pseudomonas spp., Enterobacter spp., Escherichia coli ) are generally resistant to the macrolides.
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.
Indications and Uses
Macrolide antibiotics are used for the treatment of the following condirions:
- Streptococcal pharyngitis/tonsillitis.
- Acute bacterial exacerbations of chronic obstructive pulmonary disease due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae.
- Community-acquired pneumonia due to Haemophilus influenzae, Mycoplasma pneumoniae, Streptococcus pneumoniae, or Chlamydia pneumoniae.
- Acute maxillary sinusitis due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae.
- Acute otitis media due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae.
- Skin and skin structure infections caused by Staphylococcus aureus, Streptococcus pyogenes, or Streptococcus agalactiae.
- Disseminated mycobacterial infections due to Mycobacterium avium, or Mycobacterium intracellulare.
- Pertussis (whooping cough) caused by Bordetella pertussis.
- Diphtheria due to Corynebacterium diphtheriae, as an adjunct to antitoxin, to prevent establishment of carriers and to eradicate the organism in carriers.
- Erythrasma due to Corynebacterium minutissimum.
- Intestinal amebiasis caused by Entamoeba histolytica (oral erythromycins only).
- Acute pelvic inflammatory disease caused by Neisseria gonorrhoeae.
- Chlamydia trachomatis infections: conjunctivitis of the newborn, pneumonia of infancy, and urogenital infections (urethritis, cervicitis), including those during pregnancy.
- Nongonococcal urethritis caused by Ureaplasma urealyticum.
- Primary syphilis caused by Treponema pallidum.
- Legionnaires' Disease caused by Legionella pneumophila.
- Orodental infections.
Ketolide antibiotics are developed particularly to treat respiratory tract infections caused by macrolide-resistant organisms.
Telithromycin is indicated for:
- Community-acquired pneumonia (mild to moderate) due to Streptococcus pneumonia, (including Multi-drug resistant Streptococcus pneumoniae), Haemophilus influenzae, Moraxella catarrhalis, Chlamydophila pneumoniae, or Mycoplasma pneumonia.
Gastrointestinal side effects
The most common side effects with macrolides are:
- Abdominal discomfort
Newer macrolides clarithromycin and azithromycin cause significantly less gastrointestinal side effects than erythromycin. According to clinical trials, erythromycin therapy is stopped prematurely more often than with azithromycin or clarithromycin.
Why is erythromycin poorly tolerated?
In the acidic environment of the stomach, erythromycin is degraded to a hemiketal intermediate, a motilin-receptor agonist. Motilin stimulates a G-protein coupled pathway in smooth cells of the gastrointestinal tract leading to contractions.
Arrhythmogenic potency and QT interval prolongation
Erythromycin, clarithromycin, and telithromycin has been associated with QT prolongation. Ventricular arrhythmias, including ventricular tachycardia and torsades de pointes have been reported with erythromycin.
Azithromycin and roxithromycin are less potent at provoking arrhythmia than clarithromycin and erythromycin.
The rank order of arrhythmogenicity potential:
erythromycin > clarithromycin > roxithromycin > azithromycin 4, 5
Other side effects
A less well-known but nonetheless serious adverse reaction to erythromycin, especially after intravenous administration, is ototoxicity, manifesting as tinnitus or hearing loss6. Erythromycin estolate is hepatotoxic and may cause hepatitis.
Telithromycin may cause:
- Exacerbations of myasthenia gravis
- Visual disturbances
- Transient loss of consciousnes
Erythromycin and clarithromycin are metabolized by hepatic cytochrome P450 microsomal enzymes, and have 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.
Ketolide telithromycin is a strong inhibitor of CYP3A4.
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 very 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.
Telithromycin is stable at gastric acid and food does not affect the rate or extent of its absorption. The half-life of telithromycin is about 10 hours. Among macrolides telithromycin is the most highly concentrated in tissue.
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 chemical 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 longer half-life.
Ketolides differ chemically from other macrolides by the absence of α-L-cladinose at position 3 of the erythronolideA ring. Ketolides are very stable, even at pH 1.0.
- Azithromycin and clarithromycin have improved tolerability and fewer gastrointestinal side effects than erythromycin.
- Azithromycin and roxithromycin have much lower potential for interactions than erythromycin and clarithromycin.
- Azithromycin, clarithromycin, and telithromycin have improved pharmacokinetic properties - better bioavailability, better tissue penetration, prolonged half-lives.
- Erythromycin has considerable disadvantages, including poor gastric stability, relatively poor potency against respiratory gram-negative pathogens such as Haemophilus influenzae. Also, erythromycin has the most inconvenient frequent 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.
- Telithromycin is active against macrolide resistant strains of S. pneumonia. However, possible serious hepatotoxicity limits its use.
Table 2. Comparison of main pharmacological properties.
|FDA approval date||April 09, 1959||October 31, 1991||November 1, 1991|
|Fed state affects absorption||Yes||No||No|
|Half-life||1-1.5 hours||3-7 hours||40-60 hours|
|Potential for interactions||High||High||Low|
- Azithromycin (Zithromax) Facts
- Azithromycin vs Clarithromycin head-to-head comparison
- Types of Antibiotics
- Antibiotics for Strep Throat
- Antibiotics for Chlamydia
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Published: May 05, 2007
Last updated: July 04, 2018