The macrolides are bacteriostatic antibiotics with a broad spectrum of activity against many gram-positive bacteria. Currently available macrolides are well tolerated, orally available and widely used to treat mild-to-moderate infections. Several macrolide antibiotics have been linked to liver injury.

Five macrolide antibiotics are currently available for use in the United States: erythromycin, clarithromycin, azithromycin, fidaxomicin and telithromycin, the latter being a related ketolide. Erythromycin was initially isolated in 1952 from Streptomyces erythreus; the other macrolide antibiotics are semisynthetic derivatives. The five macrolide antibiotics have a similar range of activities, being bacteriostatic against many strains of streptococci, staphylococci, clostridia, corynebacteria, listeria, haemophilus sp., moxicella, and Neisseria meningitidis. Clarithromycin and azithromycin are more active than erythromycin against several gram negative bacteria as well as Mycoplasma pneumonia, Helicobacter pylori, Toxoplasma gondii, cryptosporidia and several atypical mycobacteria. Fidaxomicin is not absorbed orally and is used in ten day oral courses to treat Clostridium difficile associated diarrhea. Macrolide antibiotics act by inhibiting protein synthesis of bacteria by binding to the 50S ribosomal element. Resistance occurs by several mechanisms.

Aa low rate of asymptomatic elevation in serum aminotransferase levels that can occur with any of the four orally absorbed macrolide antibiotics, in rates reported to be 1% to 5% of treated patients (depending upon the duration of treatment and intensity of monitoring). These elevations are generally mild-to-moderate in degree, asymptomatic and self-limited and transient in course, rarely requiring dose modification or discontinuation.

More important is clinically apparent liver injury from macrolide antibiotics which has been described for all four of the orally absorbed agents. The liver injury is typically a self-limited cholestatic hepatitis arising within 1 to 3 weeks of starting therapy. Symptoms include fatigue, dark urine and jaundice, often with right upper quadrant pain and fever. The injury is usually self-limited and benign, but in some instances there is prolonged cholestasis and persistence of liver test abnormalities beyond 6 months. in these cases generally shows vanishing bile duct syndrome, or at least, some degree of bile ducts loss. A second form of clinically apparent hepatotoxicity from the macrolide antibiotics is an acute hepatocellular injury that usually arises within days of starting therapy, often with re-exposure. This hepatocellular injury with jaundice can lead to acute liver failure and has an appreciable mortality (either death or need for emergent liver transplantation). This hepatocellular pattern occurs most commonly with telithromycin, but is also described with azithromycin and less commonly with claritheromycin and erythromycin.

Fidaxomicin has little systemic absorption and has not been linked to episodes of clinically apparent liver injury. There is likely to be some degree of cross sensitivity to the hepatic injury among the various macrolide antibiotics, but this has not been well defined.