Zithromax - Drug Monograph

Introduction

Zithromax (azithromycin) is a broad-spectrum macrolide antibiotic belonging to the azalide subclass. It is widely prescribed for its convenient once-daily dosing and favorable pharmacokinetic profile. Originally approved by the FDA in 1991, azithromycin has become one of the most commonly prescribed antibiotics worldwide for treating various bacterial infections.

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 translation of mRNA and subsequent protein production, ultimately halting bacterial growth and replication. Azithromycin demonstrates concentration-dependent killing and exhibits significant tissue penetration, with tissue concentrations often exceeding plasma concentrations by 10- to 100-fold.

Indications

FDA-approved indications include:

• Community-acquired pneumonia caused by Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, or Streptococcus pneumoniae
• Acute bacterial exacerbations of chronic obstructive pulmonary disease
• Acute bacterial sinusitis
• Pharyngitis/tonsillitis caused by Streptococcus pyogenes
• Uncomplicated skin and skin structure infections
• Urethritis and cervicitis caused by Chlamydia trachomatis or Neisseria gonorrhoeae
• Genital ulcer disease caused by Haemophilus ducreyi

Non-FDA approved uses (off-label):

• Mycobacterium avium complex prophylaxis and treatment
• Pertussis (whooping cough) treatment and post-exposure prophylaxis
• Lyme disease
• Babesiosis
• Traveler's diarrhea

Dosage and Administration

• Oral: 500 mg as a single dose on day 1, followed by 250 mg once daily on days 2-5
• IV: 500 mg once daily for at least 2 days, followed by oral therapy

• Renal impairment: No dosage adjustment required
• Hepatic impairment: Use with caution; no specific dosage recommendations
• Pediatric patients: 10 mg/kg on day 1 (maximum 500 mg), then 5 mg/kg on days 2-5 (maximum 250 mg)
• Geriatric patients: No dosage adjustment required

• Take orally 1 hour before or 2 hours after meals
• IV formulation should be infused over 60 minutes (not as bolus)

Pharmacokinetics

• Absorption: Rapid but incomplete (approximately 37% bioavailability); food decreases absorption
• Distribution: Extensive tissue distribution with high concentrations in lungs, tonsils, prostate, and other tissues; Vd: 31 L/kg
• Metabolism: Hepatic demethylation; not significantly metabolized by CYP450 system
• Elimination: Biliary excretion (50%) and renal excretion (6%); terminal elimination half-life: 68 hours
• Protein binding: 7-50% depending on plasma concentration

Contraindications

• Known hypersensitivity to azithromycin, erythromycin, or other macrolide antibiotics
• History of cholestatic jaundice/hepatic dysfunction associated with prior azithromycin use
• Concomitant use with ergot derivatives or pimozide

Warnings and Precautions

• Increased risk in patients with known QT prolongation, hypokalemia, hypomagnesemia, bradycardia, or concomitant use of other QT-prolonging drugs
• Use with caution in patients with hepatic impairment
• May cause exacerbation of myasthenia gravis
• Clostridium difficile-associated diarrhea reported with use
• Potential for drug-resistant bacteria development

Drug Interactions

• Antacids containing aluminum or magnesium: Decreased azithromycin absorption
• Warfarin: Potential increased anticoagulant effect (monitor INR)
• Nelfinavir: Increased azithromycin concentrations
• Other QT-prolonging agents (antiarrhythmics, antipsychotics, antidepressants): Increased arrhythmia risk
• Digoxin: Possible increased digoxin concentrations
• Colchicine: Increased colchicine toxicity risk

Adverse Effects

• Diarrhea (5-10%)
• Nausea (3-5%)
• Abdominal pain (3-5%)
• Headache (1-3%)
• Dizziness (1-2%)

• QT prolongation and torsades de pointes
• Hepatotoxicity
• Clostridium difficile-associated diarrhea
• Allergic reactions including anaphylaxis
• Hearing loss (usually reversible)
• Maculopapular rash

Monitoring Parameters

• Clinical response to therapy
• Signs of superinfection or C. difficile infection
• ECG monitoring in high-risk patients (baseline and during therapy)
• Liver function tests in patients with hepatic impairment
• Hearing assessment in prolonged therapy
• INR monitoring in patients on warfarin
• Electrolytes (potassium, magnesium) in patients at risk for QT prolongation

Patient Education

• Complete the entire course of therapy even if feeling better
• Take on empty stomach (1 hour before or 2 hours after meals)
• Report any signs of allergic reaction (rash, swelling, difficulty breathing)
• Report severe diarrhea, abdominal pain, or bloody stools
• Be aware of potential dizziness and avoid driving if affected
• Inform healthcare providers of all medications being taken
• Use additional contraception if taking oral contraceptives (potential decreased efficacy)
• Report any palpitations, dizziness, or fainting episodes

References

1. Zithromax [package insert]. New York, NY: Pfizer Inc; 2022. 2. Bradshaw S, Faasse K, Grey A, et al. Macrolide antibiotics and the risk of cardiac arrhythmias: a systematic review and meta-analysis. Drug Saf. 2022;45(7):713-728. 3. O'Connor A, Lopez MJ, Eranki AP. Azithromycin. [Updated 2023 May 22]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024. 4. FDA Drug Safety Communication: Azithromycin (Zithromax or Zmax) and the risk of potentially fatal heart rhythms. US Food and Drug Administration. 2013. 5. Mandell LA, Wunderink RG, Anzueto A, 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. 6. Workowski KA, Bachmann LH, Chan PA, et al. Sexually Transmitted Infections Treatment Guidelines, 2021. MMWR Recomm Rep. 2021;70(4):1-187.