Macrolides (see Table: Macrolides) are antibiotics that are primarily bacteriostatic; by binding to the 50S subunit of the ribosome, they inhibit bacterial protein synthesis.
Except for telithromycin (see Telithromycin), macrolides are relatively poorly absorbed orally. Fidaxomicin is minimally absorbed and active only locally in the GI tract. Food has the following effects on macrolide absorption:
Once absorbed macrolides diffuse well into body fluids, except CSF, and are concentrated in phagocytes. Excretion is mainly in bile.
Macrolides are active against
Aerobic and anaerobic gram-positive cocci, except for most enterococci, many Staphylococcus aureus strains (especially methicillin-resistant strains), and some Streptococcus pneumoniae and S. pyogenes strains
Bacteroides fragilis is resistant. Clarithromycin and azithromycin have enhanced activity against Haemophilus influenzae and activity against Mycobacterium avium complex.
Macrolides have been considered the drug of choice for group A streptococcal and pneumococcal infections when penicillin cannot be used. However, pneumococci with reduced penicillin sensitivity are often resistant to macrolides, and in some communities, up to 20% of S. pyogenes are macrolide-resistant. Because they are active against atypical respiratory pathogens, they are often used empirically for lower respiratory tract infections, but another drug is often necessary to cover macrolide-resistant pneumococci. Macrolides have other clinical uses (see Table: Some Clinical Uses of Macrolides). Macrolides are not used to treat meningitis.
Fidaxomicin has minimal to no activity against gram-negative bacteria but is bactericidal against Clostridium difficile.
Some Clinical Uses of Macrolides
Macrolides are contraindicated in patients who have had an allergic reaction to them.
Concomitant administration of macrolides with astemizole, cisapride, pimozide, or terfenadine is contraindicated because potentially fatal cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, torsades de pointes) may occur when clarithromycin or erythromycin is given with these drugs. This effect is most likely due to inhibition of metabolism of these drugs by erythromycin and clarithromycin.
Erythromycin and azithromycin are in pregnancy category B (animal studies show no risk and human evidence is incomplete, or animal studies show risk but human studies do not). Erythromycin is considered safer because clinical use has been much more extensive.
Clarithromycin is in category C (animal studies show some risk, evidence in human studies is inadequate, but clinical benefit sometimes outweighs risk).
Erythromycin is considered compatible with breastfeeding. Safety of other macrolides during breastfeeding is unknown.
Main concerns include
Erythromycin commonly causes dose-related GI disturbances, including nausea, vomiting, abdominal cramps, and diarrhea; disturbances are less common with clarithromycin and azithromycin. Taking the drug with food may help decrease GI disturbances. Erythromycin may cause dose-related tinnitus, dizziness, and reversible hearing loss. Cholestatic jaundice occurs most commonly with erythromycin estolate. Jaundice usually appears after 10 days of use, primarily in adults but can occur earlier if the drug has been given previously. Erythromycin is not given IM because it causes severe pain; when given IV, it may cause phlebitis or pain. Hypersensitivity reactions are rare.
Erythromycin causes QT-interval prolongation and predisposes to ventricular tachyarrhythmia, especially in women, in patients who have QT-interval prolongation or electrolyte abnormalities, and in patients taking another drug that may prolong the QT interval.
For azithromycin, no dosage adjustment is required for renal insufficiency.
Erythromycin and, to some extent, clarithromycin interact with numerous drugs because they inhibit hepatic metabolism via the cytochrome P-450 (CYP450) system. Azithromycin is the least likely to interact with other drugs. Interactions may occur when erythromycin or clarithromycin is taken with the following: