Introduction
Azithromycin is a broad-spectrum macrolide antibiotic widely used in clinical practice. First approved by the FDA in 1991, it has become one of the most commonly prescribed antibiotics worldwide due to its favorable pharmacokinetic profile, convenient dosing regimen, and broad antimicrobial coverage. As a semi-synthetic derivative of erythromycin, azithromycin offers improved gastrointestinal tolerability while maintaining efficacy against many Gram-positive, Gram-negative, and atypical pathogens.
Mechanism of Action
Azithromycin exerts its antibacterial effects by binding to the 50S ribosomal subunit of susceptible microorganisms, thereby inhibiting bacterial protein synthesis. This bacteriostatic action prevents the translocation of peptides during translation, effectively halting microbial growth and reproduction. The drug demonstrates concentration-dependent killing activity and exhibits significant post-antibiotic effect, allowing for prolonged antimicrobial activity even after serum concentrations decline below the minimum inhibitory concentration.
Indications
FDA-Approved Indications:- Community-acquired pneumonia caused by Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, or Streptococcus pneumoniae
- Pharyngitis/tonsillitis caused by Streptococcus pyogenes
- Acute bacterial exacerbations of chronic obstructive pulmonary disease
- Acute bacterial sinusitis
- Uncomplicated skin and skin structure infections
- Urethritis and cervicitis due to Chlamydia trachomatis
- Genital ulcer disease due to Haemophilus ducreyi (chancroid)
- Mycobacterium avium complex prophylaxis and treatment in HIV patients
- Traveler's diarrhea caused by enterotoxigenic E. coli
- Pertussis prophylaxis and treatment
- Lyme disease (early stage)
- Babesiosis (in combination with atovaquone)
Dosage and Administration
Standard Adult Dosing:- Community-acquired pneumonia: 500 mg as single dose on day 1, followed by 250 mg daily on days 2-5
- Acute bacterial sinusitis: 500 mg daily for 3 days
- Pharyngitis/tonsillitis: 12 mg/kg once daily for 5 days (maximum 500 mg/day)
- Chlamydial infections: Single 1 g dose
- No dosage adjustment required for mild to moderate renal impairment
- Use with caution in severe renal impairment (CrCl <10 mL/min)
- No dosage adjustment necessary
- Acute otitis media: 10 mg/kg as single dose on day 1 (maximum 500 mg), then 5 mg/kg on days 2-5 (maximum 250 mg/day)
- Community-acquired pneumonia: 10 mg/kg as single dose on day 1 (maximum 500 mg), then 5 mg/kg on days 2-5 (maximum 250 mg/day)
- Oral formulation should be taken at least 1 hour before or 2 hours after meals
- IV formulation requires reconstitution and dilution; administer over 60 minutes
Pharmacokinetics
Absorption: Rapidly absorbed after oral administration with approximately 37% bioavailability. Food decreases absorption by approximately 50%. Distribution: Extensive tissue distribution with tissue concentrations 10-100 times higher than plasma concentrations. Volume of distribution is approximately 31 L/kg. Demonstrates excellent penetration into lungs, prostate, and phagocytes. Metabolism: Minimally metabolized in the liver through demethylation. Not significantly affected by cytochrome P450 enzymes. Elimination: Primarily excreted unchanged in bile (50%) with renal excretion accounting for approximately 6% of elimination. Terminal elimination half-life ranges from 68 hours due to extensive tissue binding and slow release.Contraindications
- Known hypersensitivity to azithromycin, erythromycin, or any macrolide antibiotic
- History of cholestatic jaundice/hepatic dysfunction associated with prior azithromycin use
- Concomitant use with ergot derivatives or pimozide
Warnings and Precautions
Cardiovascular Effects:- Prolongation of QT interval and risk of torsades de pointes
- Increased mortality in patients with cardiovascular risk factors
- Avoid use in patients with known QT prolongation, hypokalemia, hypomagnesemia, or bradycardia
- Rare cases of hepatic necrosis and fulminant hepatitis reported
- Monitor liver function tests in patients with pre-existing liver disease
- May occur during or several months after antibiotic treatment
- Consider in patients presenting with diarrhea after antibiotic use
- Exacerbation of symptoms or new onset myasthenia gravis reported
Drug Interactions
Contraindicated Combinations:- Ergot alkaloids (increased risk of ergotism)
- Pimozide (increased risk of QT prolongation)
- Warfarin: May potentiate anticoagulant effect (monitor INR)
- Nelfinavir: Increases azithromycin concentrations
- Cyclosporine: May increase cyclosporine levels
- Digoxin: May increase digoxin concentrations
- Antacids: Reduce peak serum concentrations (separate administration by 2 hours)
Adverse Effects
Common (≥1%):- Diarrhea (5-7%)
- Nausea (5%)
- Abdominal pain (3-4%)
- Vomiting (2-3%)
- Headache (1-2%)
- QT prolongation and torsades de pointes
- Hepatotoxicity
- Clostridium difficile-associated diarrhea
- Allergic reactions including anaphylaxis
- Hearing loss (usually reversible)
- Hematologic abnormalities (neutropenia, thrombocytopenia)
Monitoring Parameters
- Clinical response to therapy
- Signs and symptoms of superinfection
- Liver function tests (in patients with pre-existing liver disease or prolonged therapy)
- ECG monitoring in patients with cardiac risk factors
- INR in patients taking warfarin
- Digoxin levels if co-administered
- Signs of C. difficile infection (watery diarrhea, abdominal pain)
Patient Education
- Complete the entire course of therapy even if symptoms improve
- Take on an empty stomach (1 hour before or 2 hours after meals)
- Report any signs of allergic reaction (rash, itching, swelling)
- Notify healthcare provider of diarrhea that occurs during or after treatment
- Inform provider of any personal or family history of heart rhythm problems
- Avoid antacids within 2 hours of taking azithromycin
- Report any hearing changes, dizziness, or ringing in ears
- Use additional contraception if taking oral contraceptives (potential decreased efficacy)
References
1. Zithromax® (azithromycin) prescribing information. Pfizer Laboratories. 2. FDA Drug Safety Communication: Azithromycin and risk of potentially fatal heart rhythms. US Food and Drug Administration. 3. Bradley JS, et al. The Management of Community-Acquired Pneumonia in Infants and Children Older Than 3 Months of Age: Clinical Practice Guidelines by the Pediatric Infectious Diseases Society and Infectious Diseases Society of America. Clin Infect Dis. 2011;53(7):e25-e76. 4. Albert RK, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689-698. 5. Ray WA, et al. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012;366(20):1881-1890. 6. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing. CLSI supplement M100. 7. Mandell LA, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44 Suppl 2:S27-S72.