Macrolides

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.

Macrolides (except fidaxomicin) 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 species

• Corynebacterium diphtheriae

• Campylobacter species

• Treponema pallidum

• Cutibacterium acnes (formerly Propionibacterium acnes)

• Borrelia burgdorferi

Bacteroides fragilisis resistant. Clarithromycin and azithromycin have enhanced activity againstHaemophilus influenzae and activity against Mycobacterium avium complex.

Macrolides have been considered the antibiotics 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 macrolide resistance among S. pyogenes varies globally. Because macrolides are active against atypical respiratory pathogens, they are often used empirically for lower respiratory tract infections, but another antibiotic 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 againstClostridioides difficile (formerly Clostridium difficile). It is used exclusively for C. difficile infection because there is minimal systemic absorption.

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 medications. This effect is most likely due to inhibition of metabolism of these medications byerythromycin and clarithromycin.

Clinical Calculators

QT Interval Correction (EKG)

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 toerythromycin 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.

Available animal studies with fidaxomicin have not shown signs of teratogenicity.Fidaxomicin has minimal systemic absorption, therefore risk of adverse effect to a fetus or breastfeeding infant should be relatively low.

Main concerns with macrolides include

• Gastrointestinal (GI) disturbances (mainly with erythromycin)

• QT-interval prolongation

• 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 medication with food may help decrease GI disturbances.Erythromycinmay 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 iferythromycin 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 should be avoided in neonates unless no other options are available because of the risk for infantilehypertrophic pyloric stenosis. This risk is less with other macrolides.

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 medication that may prolong the QT interval.

Clarithromycin and azithromycin may also cause QT-interval prolongation but are less likely to cause arrhythmias.

Jaundice and arrhythmias are not reported with fidaxomicin. Because of minimal systemic absorption, there is very little chance of toxicity to any other organ system outside the GI tract.

For azithromycin, no dosage adjustment is required for renal insufficiency.

Erythromycin and, to some extent, clarithromycin interact with numerous medications because they inhibit hepatic metabolism via the cytochrome P-450 (CYP450) system.Azithromycin is the least likely to interact with other medications.

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 medications

Fidaxomicin does not have clinically significant interactions with commonly prescribed medications.