Macrolides (see Table 12: Bacteria and Antibacterial Drugs: Macrolides) are primarily bacteriostatic; by binding to the 50S subunit of the ribosome, they inhibit bacterial protein synthesis.

Pharmacology

Dirithromycin is a prodrug that is converted to its active form during intestinal absorption. Except for telithromycin, macrolides are relatively poorly absorbed orally. Food has the following effects on absorption:

• For dirithromycin and 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

All macrolides diffuse well into body fluids, except CSF, and are concentrated in phagocytes. Excretion is mainly in bile.

Indications

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
• Mycoplasma pneumoniae
• Chlamydia trachomatis
• Chlamydophila pneumoniae
• Legionella sp
• Corynebacterium diphtheriae
• Campylobacter sp
• Treponema pallidum
• Propionibacterium acnes
• Borrelia burgdorferi

Table 12
Macrolides Drug Route Azithromycin Oral or parenteral Clarithromycin Oral Dirithromycin Oral Erythromycin Oral or parenteral Telithromycin Oral

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 13: Bacteria and Antibacterial Drugs: Some Clinical Uses of Macrolides). Macrolides are not used to treat meningitis.

Table 13
Some Clinical Uses of Macrolides Drug Indication Comments Macrolides Infection due to Mycoplasma pneumoniae, Legionella sp, or Bordetella pertussis Eradication of Corynebacterium diphtheriae in carriers Drugs of choice   Symptomatic cat-scratch disease (Bartonella henselae) —   Bacillary angiomatosis and peliosis hepatis in patients with AIDS (involving B. henselae or B. quintana) — Azithromycin Cerebral toxoplasmosis Used with other drugs   Babesiosis Used with other drugs   Chlamydia trachomatis urethritis and cervicitis   Clarithromycin and azithromycin Mycobacterium avium complex Part of a multidrug regimen Erythromycin Uncomplicated skin infections —   Acne Topical use   Bowel preparation before GI tract surgery Taken orally and used with an oral aminoglycoside

Contraindications

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. Postmarketing surveillance has reported cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, torsades de pointes) when clarithromycin or erythromycin was coadministered with astemizole, cisapride, pimozide, or terfenadine; this effect was most likely due to inhibition of metabolism of these drugs by erythromycin and clarithromycin. Deaths have been reported.

Use During Pregnancy and Breastfeeding

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.

Adverse Effects

Main concerns include

• 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 azithromycin and dirithromycin, 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 are taken with the following:

• Warfarin: Further elevation of the 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

Telithromycin

Telithromycin is a ketolide antibiotic. Ketolides are chemically related to macrolides and inhibit bacterial ribosomal protein synthesis without inducing resistance to macrolides, clindamycin, or streptogramins.

Telithromycin is rapidly absorbed orally with or without food and is metabolized primarily in the liver.

Indications

Telithromycin is active against erythromycin-susceptible staphylococci and streptococci and multidrug-resistant S. pneumoniae. Telithromycin is also active against erythromycin-susceptible enterococci, Bordetella pertussis, H. influenzae, Helicobacter pylori, Moraxella catarrhalis, M. pneumoniae, C. pneumoniae, and Legionella, Prevotella, and Peptostreptococcus spp. Because of safety concerns, telithromycin is recommended only for the treatment of adults ≥ 18 yr with community acquired mild to moderate pneumonia due to the following:

• S. pneumoniae (including multidrug-resistant strains, ie, penicillin-resistant S. pneumoniae; isolates resistant to ≥ 2 of the following: penicillin, 2nd-generation cephalosporins [eg, cefuroxime], macrolides, tetracyclines, trimethoprim/sulfamethoxazole)
• H. influenzae
• M. catarrhalis
• C. pneumoniae
• M. pneumoniae

Contraindications

Contraindications include

• Previous allergic reaction to telithromycin or any macrolide
• Previous hepatitis or jaundice after taking telithromycin or a macrolide
• Concurrent use of pimozide or cisapride because of cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, torsades de pointes)
• Myasthenia gravis because telithromycin may exacerbate symptoms and fatal respiratory failure has occurred in patients with this disorder

Use During Pregnancy and Breastfeeding

Telithromycin is in pregnancy category C because animal studies show some risk, evidence in human studies is inadequate, but clinical benefit sometimes outweighs risk.

Safety of telithromycin during breastfeeding is unknown.

Adverse Effects

Adverse effects include

• GI disturbances
• QT-interval prolongation
• Severe hepatitis

Diarrhea, nausea, vomiting, and dizziness are the most common adverse effects. Prolongation of the QT interval, hyperbilirubinemia, elevation of liver enzymes, transient loss of consciousness (sometimes associated with vagal syndrome), and visual disturbances (particularly a slowed ability to accommodate and to release accommodation) are less common. Severe hepatotoxicity, which may be fatal and may require liver transplantation, may occur.

Cross-sensitivity with macrolides can occur.

Dosing Considerations

Telithromycin inhibits cytochrome P-450 (CYP450) 3A4, increasing levels of the following drugs:

• Digoxin: Digoxin side effects or serum levels should be monitored.
• Ergot alkaloids: Concomitant use should be avoided.
• Benzodiazepines: Concomitant use requires caution.
• Metoprolol: Concomitant use in patients with heart failure requires caution.
• Statins: Concomitant use of simvastatin, lovastatin, or atorvastatin (but not pravastatin or fluvastatin) should be avoided.
• Cisapride: Concomitant use is contraindicated.
• Pimozide: Concomitant use is contraindicated.
• Sirolimus
• Tacrolimus

CYP3A4 inducers such as rifampin, phenytoin, carbamazepine, and phenobarbital decrease levels of telithromycin; the CYP3A4 inhibitors itraconazole and ketoconazole increase levels of telithromycin. Telithromycin decreases absorption of sotalol.

Last full review/revision July 2009 by Matthew E. Levison, MD