Azithromycin (Zithromax)

Zithromax®, Zithromax® Z-Pak®, Zithromax® Tri-Pak™ | Zmax™

Classification:
Antiinfective Agents

• Macrolides

Description: Azithromycin is a semisynthetic antibiotic belonging to the macrolide subgroup of azalides and is similar in structure to erythromycin. Although azithromycin is significantly more expensive, it can be dosed once daily and produces less GI intolerance than does erythromycin. An apparent advantage over erythromycin is that azithromycin reaches higher intracellular concentrations, thus increasing its efficacy and duration of action. These advantages are demonstrated in studies that show that single doses of azithromycin are effective for the treatment of STDs due to chlamydia and gonorrhea. While azithromycin has been studied in regimens for H. pylori eradication and some studies show efficacy, the azithromycin-containing regimens have not been as effective as regimens containing clarithromycin in terms of eradication rates; macrolide cross-resistance is also an issue. Azithromycin was initially approved by the FDA in November 1991. An oral suspension was introduced in April 1995 and, in late 1995, was approved for treatment of pediatric otitis media and pharyngitis. In mid-1996, azithromycin was approved for Mycobacterium avium complex (MAC) prophylaxis in patients with advanced HIV disease. An intravenous dosage form is also available for initial treatment of community-acquired pneumonia (CAP) and pelvic inflammatory disease. The oral suspension was subsequently approved for community-acquired pneumonia in children in May 2002. On January 15, 2004, Zithromax® was approved as a 3-day treatment for acute bacterial sinusitis. An extended-release oral suspension (Zmax™) was approved June 10, 2005 for treatment of acute bacterial sinusitis and CAP as a single dose. Phase III clinical trials for an ophthalmic formulation, AzaSite™ (azithromycin 1%), report that ophthalmic azithromycin is as effective as ophthalmic tobramycin for bacterial conjunctivitis.

Mechanism of Action: Azithromycin inhibits protein synthesis in bacterial cells by binding to the 50 S subunit of bacterial ribosomes. Action is generally bacteriostatic but can be bactericidal in high concentrations or against susceptible organisms. Azithromycin is more active against gram-negative organisms but has less activity against streptococci and staphylococci than does erythromycin. In addition to chlamydial infections, it is also useful for treating mild to moderate upper respiratory infections and mild community-acquired pneumonia. It is not clear if azithromycin, like erythromycin, is effective in the treatment of diabetic gastroparesis.

Azithromycin is generally active against organisms that are usually susceptible to erythromycin. These include gram-positive organisms, such as Staphylococcus aureus, Streptococcus agalactiae, S. pyogenes, and S. pneumoniae, and gram-negative Haemophilus influenzae and Moraxella catarrhalis. Chlamydia trachomatis is also susceptible to azithromycin. Other organisms that have shown in vitro susceptibility include streptococci (Groups C, F, G), Streptococcus viridans group, Bordetella pertussis, Campylobacter jejuni, Haemophilus ducreyi, Legionella pneumophilia, Bacteroides bivius, Clostridium perfringens, Peptostreptococcus species, Mycoplasma pneumoniae, Treponema pallidum, and Ureaplasma urealyticum. The excellent tissue penetration and very low MIC of azithromycin against Borrelia burgdorferi (the causative agent of Lyme disease) suggest it may be highly useful in treating this serious disease. Clinicians are advised to consult susceptibility data at the institution in which they practice to determine azithromycin’s activity.

Pharmacokinetics: Azithromycin is administered orally and intravenously. Following oral administration, absorption of azithromycin is rapid. The absolute bioavailability of azithromycin capsules (no longer commercially available) is 38%. According to the manufacturer, the azithromycin 250 mg tablets are bioequivalent to the azithromycin 250 mg capsules in the fasted state. Food increases the mean serum concentration (Cmax) of azithromycin tablets and immediate-release oral suspension by about 23% and 56%, respectively; however, the AUC remains unchanged. In clinical trials with pediatric patients, azithromycin immediate-release oral suspension was routinely administered following a low-fat breakfast. After administration of the extended-release (ER) oral suspension, the mean Cmax and AUC of azithromycin were lower by 57% and 17%, respectively, compared to azithromycin immediate-release oral suspension. The bioavailability of azithromycin from the ER oral suspension relative to the immediate-release oral suspension was 83%. Therefore, the ER oral suspension is not bioequivalent and is not interchangeable with the immediate-release oral suspension. Administration of the ER oral suspension with a high-fat meal increases azithromycin mean Cmax by 115% and mean AUC by 23% compared to administration in the fasting state; a standard meal increased the Cmax by 119% and the mean AUC by 12% compared to the fasted state. Per the manufacturer, both azithromycin tablets and the immediate-release oral suspension may be taken with or without food. The extended-release oral suspension should be taken on an empty stomach, 1 hour before or 2 hours after a meal. Additionally, the AUC of the capsules are unaffected by concomitant administration with antacids containing aluminum and magnesium hydroxide; however, the Cmax was reduced by 24%. Antacids containing aluminum and magnesium hydroxide did not alter the rate or extent of absorption from the ER oral suspension. Cimetidine (800 mg) given 2 hours before azithromycin capsules had no effect on azithromycin absorption.

Zithromax Powder for Oral Suspension(Pwd F/Recon 1 g)

Distribution of azithromycin throughout the body is extensive. Azithromycin exhibits significant intracellular penetration and concentrates within fibroblasts and phagocytes. As a result, tissue levels are significantly higher than are plasma concentrations. Azithromycin is distributed widely into brain tissue but not into cerebrospinal fluid or aqueous humor of the eye. Protein binding varies with plasma concentration; 51% of the drug is bound at low concentrations (0.02 mcg/ml) and decreasing to 7% at higher concentrations (2 mcg/ml). Azithromycin has a long half-life (68 hours), which is partially explained by its extensive tissue uptake and slow release. The drug is not metabolized, and elimination is largely in the feces, following excretion into the bile, with less than 10% excreted in the urine.