Macrolides (see table Macrolides Macrolides Macrolides (see table Macrolides) are antibiotics that are primarily bacteriostatic; by binding to the 50S subunit of the ribosome, they inhibit bacterial protein synthesis. Macrolides are relatively... read more ) are antibiotics Overview of Antibacterial Drugs Antibacterial drugs are derived from bacteria or molds or are synthesized de novo. Technically, “antibiotic” refers only to antimicrobials derived from bacteria or molds but is often (including... read more that are primarily bacteriostatic; by binding to the 50S subunit of the ribosome, they inhibit bacterial protein synthesis.
Macrolides are relatively poorly absorbed orally. Fidaxomicin is minimally absorbed and active only locally in the gastrointestinal tract. Food has the following effects on macrolide absorption:
For extended-release clarithromycin, increased absorption
For immediate-release clarithromycin tablet or suspension, no effect
For azithromycin capsules and erythromycin (including base and stearate formulations), decreased absorption
For fidaxomicin, minimal effects
Once absorbed macrolides diffuse well into body fluids, except cerebrospinal fluid, and are concentrated in phagocytes. Excretion is mainly in bile.
Indications for Macrolides
Macrolides are active against
Aerobic and anaerobic gram-positive cocci, except for most enterococci, many Staphylococcus aureus Staphylococcal Infections Staphylococci are gram-positive aerobic organisms. Staphylococcus aureus is the most pathogenic; it typically causes skin infections and sometimes pneumonia, endocarditis, and osteomyelitis... read more strains (especially methicillin-resistant strains), and some Streptococcus pneumoniae Streptococcal Infections Streptococci are gram-positive aerobic organisms that cause many disorders, including pharyngitis, pneumonia, wound and skin infections, sepsis, and endocarditis. Symptoms vary with the organ... read more and S. pyogenes strains
Bacteroides fragilis is resistant. Clarithromycin and azithromycin have enhanced activity against Haemophilus influenzae Haemophilus Infections The gram-negative bacteria Haemophilus species cause numerous mild and serious infections, including bacteremia, meningitis, pneumonia, sinusitis, otitis media, cellulitis, and epiglottitis... read more and activity against Mycobacterium avium complex Nontuberculous Mycobacterial Infections Mycobacteria other than the tubercle bacillus sometimes infect humans. These organisms (called nontuberculous mycobacteria) are commonly present in soil and water and are much less virulent... read more .
Macrolides have been considered the drug of choice for group A streptococcal Streptococcal Infections Streptococci are gram-positive aerobic organisms that cause many disorders, including pharyngitis, pneumonia, wound and skin infections, sepsis, and endocarditis. Symptoms vary with the organ... read more and pneumococcal infections Pneumococcal Infections Streptococcus pneumoniae (pneumococci) are gram-positive, alpha-hemolytic, aerobic, encapsulated diplococci. In the US, pneumococcal infection is a major cause of otitis media, pneumonia, sepsis... read more 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 Some Clinical Uses of Macrolides Macrolides (see table Macrolides) are antibiotics that are primarily bacteriostatic; by binding to the 50S subunit of the ribosome, they inhibit bacterial protein synthesis. Macrolides are relatively... read more ). Macrolides are not used to treat meningitis.
Fidaxomicin has minimal to no activity against gram-negative bacteria but is bactericidal against Clostridioides difficile Clostridioides (formerly Clostridium) difficile–Induced Diarrhea Toxins produced by Clostridioides difficile strains in the gastrointestinal tract cause pseudomembranous colitis, typically after antibiotic use. Symptoms are diarrhea, sometimes bloody, rarely... read more (formerly Clostridium difficile).
Contraindications to 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 (eg, 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.
Use During Pregnancy and Breastfeeding
Animal reproduction studies with erythromycin or azithromycin have not shown risk to the fetus. A higher rate of cardiovascular anomalies has been observed after exposure to erythromycin during early pregnancy than after exposure to penicillin exposure; however, in other studies this increased risk was not observed. Erythromycin is considered safer than azithromycin because clinical use has been much more extensive.
Animal reproduction studies with clarithromycin show some risk. Clarithromycin should not be used in pregnant women except when there is no alternative therapy.
Erythromycin is considered compatible with breastfeeding. Safety of other macrolides during breastfeeding is unknown.
Adverse Effects of Macrolides
Main concerns with macrolides include
Gastrointestinal (GI) disturbances (mainly with erythromycin)
QT-interval prolongation by erythromycin
Inhibition of hepatic metabolism, leading to numerous drug interactions
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.
Dosing Considerations for Macrolides
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:
Warfarin: Further elevation of the prothrombin time/international normalized ratio (PT/INR)
Lovastatin and simvastatin: Rhabdomyolysis
Midazolam and triazolam: Somnolence
Theophylline: Nausea, vomiting, and seizures
Tacrolimus, cyclosporine, and ergot alkaloids: Elevated serum levels of these drugs