Macrolides are a class of antibiotics known as broad-spectrum antibiotics that are used to treat a wide range of bacterial infections. Macrolides are derived from Streptomyces species. They have a common macrolytic lactone ring to which one or more sugars are attached. They are different from one another in their chemical substitutions on structures of various carbon atoms and the amino and neutral sugars.
Macrolides are one of the oldest classes of antibiotics. Macrolide antibiotics have been regarded among the best-tolerated antibiotics for almost 50 years. The first member of the class, Erythromycin was discovered in 1952. Newer macrolides, azithromycin, clarithromycin and dithromycin are semi-synthetic macrolides similar in structure to erythromycin. These agents have been developed to overcome the problems associated with erythromycin. The newer macrolide antibiotics offer the advantage of fewer adverse gastrointestinal effects than erythromycin and dosing regimens of only once or twice a day. The newer macrolides also have a broader spectrum of antibacterial activity than erythromycin. The newest generation of macrolides, the ketolides, whose clinical use is in its early stage, are characterized by improved activity against some of the resistant strains.
Macrolides advantages and disadvantages
Macrolides disadvantages:
The newer Macrolides advantages:
Mechanism of actionThe mechanism of action of the macrolides is inhibition of bacterial protein synthesis by binding reversibly to the subunit 50S of the bacterial ribosome, thereby inhibiting translocation of peptidyl-tRNA. This action is mainly bacteriostatic (inhibition the growth and reproduction of bacteria), but can also be bactericidal in high concentrations. Macrolides tend to accumulate within leukocytes, and are therefore actually transported into the site of infection.
Macrolides bind to the large ribosomal subunit in the vicinity of the peptidyl transferase center and cause cell growth arrest due to inhibition of protein synthesis.
Macrolides spectrum of antibacterial activity
Macrolides have activity against many gram-positive bacteria (excluding enterococci and methicillin-resistant Staphylococcus aureus), and have variable activity against respiratory gram-negative pathogens, Mycobacterium avium infections, gonorrhea. Macrolide antibiotics are noted for their intracellular accumulation and activity against intracellular pathogens such as Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella spp. Apart from antimicrobial activities, macrolides can modify host cell functions.
Clarithromycin and azithromycin have similar spectrum to erythromycin but increased activity against Hemophilus, Mycobacterium avium intracellulare, and toxoplasma. Azithromycin has increased gram-negative activity, while clarithromycin has increased gram-positive activity.
Spectrum of activity:
Conditions treated with MacrolidesMacrolide antibiotics have antibacterial activity against gram-positive bacteria, some gram-negative bacteria and intracellular pathogens. The spectrum of antibacterial activity combined with excellent intracellular and tissue penetration has led to the extensive use of this class of drugs in respiratory disease. Macrolide antibiotics also have demonstrated anti-inflammatory properties in various in vitro and in vivo model systems.
Macrolides are used to treat:
This group of antibiotics has been widely used in children for their antibacterial effects against diseases such as diphtheria, pertussis, Mycoplasma pneumonia, Chlamydia pneumonia and Legionella.
Side effects
The macrolides are well-tolerated agents. The commonest side effects are gastro-intestinal disturbances (nausea, vomiting, diarrhea, dyspepsia, abdominal pain and cramps). Side effects are more common and severe with erythromycin therapy. Azithromycin and clarithromycin have fewer gastrointestinal side effects than erythromycin.
Allergic reactions, headache, taste disturbance, eosinophilia, reversible hearing loss, and hepatotoxicity are an infrequent occurrence with all the macrolides. Macrolides should be avoided in severe liver disease due to increased risk of hepatotoxicity and altered handling. Macrolide are contraindicated if there is a history of hypersensitivity.
Erythromycin is considered safe in pregnancy and breast feeding. Clarithromycin is safe in breast feeding (pregnancy category C). The evidence for safety of azithromycin is lacking, and use is therefore inadvisable unless benefit is considered to outweigh potential harm.
Drug interactions
Macrolides are divided into 3 groups for likely occurrence of drug-drug interactions:
Macrolides are one of the oldest classes of antibiotics. Macrolide antibiotics have been regarded among the best-tolerated antibiotics for almost 50 years. The first member of the class, Erythromycin was discovered in 1952. Newer macrolides, azithromycin, clarithromycin and dithromycin are semi-synthetic macrolides similar in structure to erythromycin. These agents have been developed to overcome the problems associated with erythromycin. The newer macrolide antibiotics offer the advantage of fewer adverse gastrointestinal effects than erythromycin and dosing regimens of only once or twice a day. The newer macrolides also have a broader spectrum of antibacterial activity than erythromycin. The newest generation of macrolides, the ketolides, whose clinical use is in its early stage, are characterized by improved activity against some of the resistant strains.
Macrolides advantages and disadvantages
Macrolides disadvantages:
- severe allergic skin reactions
- cardiac arrhythmias
- many drug interactions including prolonging INR
- macrolide resistance is reported for 20%30% of Streptococcus pneumoniae
The newer Macrolides advantages:
- broad antibacterial spectrum
- simple to use, convenient dosing regimens - daily or twice daily dosing regimen
- side-effect profiles (low incidence of gastrointestinal side effects). One of the most important features of the macrolide class is the excellent safety profile allowing the drug to be used broadly across all age groups
- macrolide antibiotics, as a group, are generally safe in pregnancy
- excellent tissue and intracellular penetration
- enhanced acid stabilities
Mechanism of actionThe mechanism of action of the macrolides is inhibition of bacterial protein synthesis by binding reversibly to the subunit 50S of the bacterial ribosome, thereby inhibiting translocation of peptidyl-tRNA. This action is mainly bacteriostatic (inhibition the growth and reproduction of bacteria), but can also be bactericidal in high concentrations. Macrolides tend to accumulate within leukocytes, and are therefore actually transported into the site of infection.
Macrolides bind to the large ribosomal subunit in the vicinity of the peptidyl transferase center and cause cell growth arrest due to inhibition of protein synthesis.
Macrolides spectrum of antibacterial activity
Macrolides have activity against many gram-positive bacteria (excluding enterococci and methicillin-resistant Staphylococcus aureus), and have variable activity against respiratory gram-negative pathogens, Mycobacterium avium infections, gonorrhea. Macrolide antibiotics are noted for their intracellular accumulation and activity against intracellular pathogens such as Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella spp. Apart from antimicrobial activities, macrolides can modify host cell functions.
Clarithromycin and azithromycin have similar spectrum to erythromycin but increased activity against Hemophilus, Mycobacterium avium intracellulare, and toxoplasma. Azithromycin has increased gram-negative activity, while clarithromycin has increased gram-positive activity.
Spectrum of activity:
- Gram-positive aerobes (Methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (only PSSP), Group and viridans streptococci, Bacillus sp., Corynebacterium sp.). Erythromycin and clarithromycin display the best activity (clarithromycin>erythromycin>azithromycin).
- Gram-negative aerobes (H. influenzae, M. catarrhalis, Neisseria sp.). Newer macrolides (clarithromycin and azithromycin) have enhanced activity (azithromycin>clarithromycin>erythromycin).
- Anaerobes. Activity against upper airway anaerobes.
- Atypical bacteria. All macrolides have excellent activity against atypical bacteria including: Legionella pneumophila - DOC, Chlamydia sp., Mycoplasma sp., Ureaplasma urealyticum.
- Other bacteria. Mycobacterium avium complex (MAC Ц only A and C), Treponema pallidum, Campylobacter, Borrelia, Bordetella, Brucella, Pasteurella.
Conditions treated with MacrolidesMacrolide antibiotics have antibacterial activity against gram-positive bacteria, some gram-negative bacteria and intracellular pathogens. The spectrum of antibacterial activity combined with excellent intracellular and tissue penetration has led to the extensive use of this class of drugs in respiratory disease. Macrolide antibiotics also have demonstrated anti-inflammatory properties in various in vitro and in vivo model systems.
Macrolides are used to treat:
- Respiratory tract infections (sinusitis, pharyngitis, lower respiratory tract infections)
- Skin and soft tissue infections
- Sexually transmitted diseases
- Cervicitis, urethritis
- Mycobacterial infections
- H.pylori infections (clarithromycin, as part of triple therapy)
This group of antibiotics has been widely used in children for their antibacterial effects against diseases such as diphtheria, pertussis, Mycoplasma pneumonia, Chlamydia pneumonia and Legionella.
Side effects
The macrolides are well-tolerated agents. The commonest side effects are gastro-intestinal disturbances (nausea, vomiting, diarrhea, dyspepsia, abdominal pain and cramps). Side effects are more common and severe with erythromycin therapy. Azithromycin and clarithromycin have fewer gastrointestinal side effects than erythromycin.
Allergic reactions, headache, taste disturbance, eosinophilia, reversible hearing loss, and hepatotoxicity are an infrequent occurrence with all the macrolides. Macrolides should be avoided in severe liver disease due to increased risk of hepatotoxicity and altered handling. Macrolide are contraindicated if there is a history of hypersensitivity.
Erythromycin is considered safe in pregnancy and breast feeding. Clarithromycin is safe in breast feeding (pregnancy category C). The evidence for safety of azithromycin is lacking, and use is therefore inadvisable unless benefit is considered to outweigh potential harm.
Drug interactions
Macrolides are divided into 3 groups for likely occurrence of drug-drug interactions:
- group 1 (e.g. erythromycin) are frequently involved
- group 2 (e.g. clarithromycin) are less commonly involved
- group 3 (e.g. azithromycin, dirithromycin) drug interactions have not been described
- anticoagulants
- astemizole
- bromocriptine
- carbamazepine
- cisapride
- cyclosporine
- digoxin
- disopyramide
- ergot alkaloids
- methylprednisolone
- terfenadine
- theophylline and related compounds
- triazolam
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