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The macrolides (see Table 10: Bacteria and Antibacterial Drugs: Macrolides ) are primarily bacteriostatic; by binding to the 50S subunit of the ribosome, they inhibit bacterial protein synthesis.
Pharmacology:
Azithromycin , clarithromycin , dirithromycin , and erythromycin are relatively poorly absorbed orally. Azithromycin and erythromycin can also be given parenterally. Dirithromycin is a pro-drug that is converted during intestinal absorption. Food increases absorption of dirithromycin and the extended-release formulation of clarithromycin , does not affect that of clarithromycin , and decreases that of azithromycin capsules and erythromycin (including the base and stearate) preparations. All macrolides diffuse well into body fluids except CSF and are concentrated in phagocytes. Excretion is mainly in bile. No dosage adjustment is required for azithromycin and dirithromycin in patients with renal insufficiency.
Indications:
These drugs are active against aerobic and anaerobic gram-positive cocci; however, most enterococci, many Staphylococcus
aureus strains (especially methicillin-resistant), and some Streptococcus pneumoniae and S. pyogenes strains are resistant. Macrolides also are active against Mycoplasma
pneumoniae
, Chlamydia trachomatis
, Chlamydophila pneumoniae
, Legionella sp, Corynebacterium diphtheriae
, Campylobacter
, Treponema pallidum
, Propionibacterium acnes, and Borrelia burgdorferi. Bacteroides fragilis are resistant. Clarithromycin and azithromycin have enhanced activity against Haemophilus influenzae and activity against Mycobacterium avium complex.
Macrolides have been considered the drug of choice in group A streptococcal and pneumococcal infections when penicillin cannot be used. However, pneumococci with reduced penicillin sensitivity are often resistant to macrolides. Erythromycin is used for uncomplicated skin infections. Macrolides are the drugs of choice in infection due to M. pneumoniae
, Legionella, or Bordetella pertussis and in C. diphtheriae carriers. Because of their activity 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 are used for symptomatic cat-scratch disease (Bartonella henselae) and bacillary angiomatosis and peliosis hepatis in patients with AIDS (B. henselae and B. quintana). Azithromycin also is used with other drugs for cerebral toxoplasmosis and babesiosis. Oral erythromycin has been used with an oral aminoglycoside for bowel preparation before GI tract surgery. Clarithromycin and azithromycin are essential in multidrug regimens for M.
avium complex. Azithromycin is also used for C. trachomatis urethritis and cervicitis. Topical erythromycin is used for acne. Macrolides are not used for meningitis.
Toxicity:
Erythromycin commonly causes dose-related GI disturbances, including nausea, vomiting, abdominal cramps, and diarrhea; disturbances are less common with clarithromycin and azithromycin . 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 administration, primarily in adults, but can occur earlier if the drug has been given previously. Erythromycin is not given IM because of severe pain; it may cause phlebitis or pain when used IV. Hypersensitivity reactions are rare.
Erythromycin has numerous drug interactions because it inhibits hepatic metabolism through the cytochrome P-450 system. Erythromycin causes QT interval prolongation and predisposes to ventricular tachyarrhythmia, especially in women and in patients with known prolongation of QT interval or electrolyte abnormalities or those taking an additional drug that may lengthen the QT interval. Erythromycin and clarithromycin can further elevate the PT/INR when taken with warfarin ; they can cause rhabdomyolysis with lovastatin and simvastatin ; somnolence with midazolam and triazolam ; nausea, vomiting, and seizures with theophylline ; and elevated serum levels of tacrolimus , cyclosporine , and ergot alkaloids. Azithromycin has the least tendency to cause drug interactions.
Telithromycin
Telithromycin is a ketolide antibiotic. Ketolides are chemically related to macrolides and inhibit bacterial ribosomal protein synthesis without inducing macrolide, clindamycin , or streptogramin resistance. Telithromycin is active against erythromycin -susceptible staphylococci and streptococci and multidrug-resistant S. pneumoniae. Telithromycin is also active against erythromycin -susceptible enterococci, B. pertussis
, H. influenzae
, Helicobacter pylori
, Moraxella catarrhalis
, M. pneumoniae
, C. pneumoniae
, Legionella sp, Prevotella sp, and Peptostreptococcus sp. Telithromycin is rapidly absorbed orally with or without food and most is metabolized in the liver. Telithromycin is used in adults to treat community-acquired pneumonia, acute bacterial sinusitis, and acute bacterial exacerbation of COPD.
Diarrhea, nausea, vomiting, and dizziness are the most common adverse effects. Prolongation of the QT interval, exacerbation of myasthenia gravis, hyperbilirubinemia, elevation of liver enzymes, and visual disturbances are less common. Cross-sensitivity with macrolides can occur. Telithromycin inhibits cytochrome P3A4, increasing levels of digoxin , ergot alkaloids, benzodiazepines, metoprolol , statins, cisapride , pimozide , sirolimus , and tacrolimus . Cytochrome P3A4 inducers such as rifampin , phenytoin , carbamazepine , and phenobarbital decrease levels of telithromycin ; the P3A4 inhibitors itraconazole and ketoconazole increase levels of telithromycin . Telithromycin decreases absorption of sotalol .
Last full review/revision November 2005
Content last modified November 2005
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