Azithromycin

Generic Name

Azithromycin

Brand Names

Zithromax

Zithromax Z-Pak

Zithromax Tri-Pak

Azax

Azee

Zmax (extended-release oral suspension, U.S.)

Also available in numerous generics globally

Drug Class

Macrolide antibiotic

Specifically an azalide subclass

Bacteriostatic (inhibits growth), but can be bactericidal at high concentrations or against highly susceptible organisms

Systemic antibacterial agent (ATC code: J01FA10)

Mechanism of Action

Azithromycin inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit of susceptible bacteria

This binding interferes with the translocation step of protein elongation, preventing the addition of new amino acids to the growing peptide chain

It does not affect human ribosomes, which are structurally different

Azithromycin accumulates in phagocytes and fibroblasts and is released at infection sites, enhancing its efficacy

Compared to erythromycin, it has a longer half-life, higher tissue penetration, and greater acid stability

Spectrum of Activity

Covers Gram-positive cocci (Streptococcus pneumoniae, Streptococcus pyogenes)

Covers some Gram-negative organisms (Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoeae)

Excellent coverage of atypical bacteria (Mycoplasma pneumoniae, Chlamydia trachomatis, Legionella pneumophila, Ureaplasma urealyticum)

Some activity against Mycobacterium avium complex (MAC) and Toxoplasma gondii

Limited activity against Enterobacteriaceae and anaerobes

Indications

Approved Indications

Community-acquired pneumonia (CAP)

Acute bacterial exacerbations of chronic bronchitis

Pharyngitis or tonsillitis (as alternative to penicillin)

Acute otitis media

Uncomplicated skin and soft tissue infections

Chlamydia trachomatis infections (e.g. cervicitis, urethritis)

Non-gonococcal urethritis

Gonorrhea (as part of combination therapy)

Pelvic inflammatory disease (as part of combination)

Travelers’ diarrhea (selected cases)

Mycobacterium avium complex (MAC) infection prophylaxis or treatment

Sinusitis

H. pylori eradication (off-label, in some regimens)

Off-Label Uses

COVID-19 (investigational, not recommended by major guidelines)

Toxoplasmosis in immunocompromised patients

Cystic fibrosis lung infection management

Pertussis treatment or post-exposure prophylaxis

Lyme disease (in penicillin-allergic patients)

Babesiosis (with atovaquone)

Granuloma inguinale (Klebsiella granulomatis)

Malaria (as adjunct)

Preterm labor prevention related to intraamniotic infection (limited evidence)

Dosage and Administration

Adults

Oral

Community-acquired pneumonia, bronchitis, sinusitis:

– 500 mg once on day 1, then 250 mg once daily on days 2 to 5

Chlamydia:

– 1 g orally as a single dose

Gonorrhea:

– 2 g orally as a single dose (in combination with ceftriaxone, depending on guidelines)

Pelvic inflammatory disease:

– 500 mg IV daily for 1–2 days followed by 250 mg orally for 7 days

MAC prophylaxis (HIV):

– 1200 mg orally once weekly

MAC treatment:

– 500–600 mg once daily, with ethambutol and possibly rifabutin

Intravenous (IV)

500 mg IV once daily for 1–2 days, then switch to oral therapy

Infuse over at least 60 minutes to prevent thrombophlebitis

Children

10 mg/kg on day 1, then 5 mg/kg on days 2 to 5

Alternatively: 10 mg/kg/day for 3 days

Acute otitis media: 30 mg/kg as a single dose or over 3 days

MAC prophylaxis: 20 mg/kg once weekly

Renal and Hepatic Impairment

No dose adjustment needed in mild to moderate renal impairment

Use with caution in severe hepatic impairment (major route of elimination is biliary)

Pharmacokinetics

Absorption: Oral bioavailability ~37%

Peak plasma concentration: 2–3 hours after oral dose

Half-life: 68 hours (long)

Tissue penetration: Excellent; concentrations up to 100x plasma in lungs, tonsils, prostate

Excretion: Mainly via bile (unmetabolized); small fraction excreted renally

Minimal interaction with CYP450 enzymes compared to erythromycin or clarithromycin

Contraindications

Known hypersensitivity to azithromycin or other macrolides

History of cholestatic jaundice or hepatic dysfunction associated with prior azithromycin use

Severe liver disease

Concomitant use with drugs known to prolong QT interval (depending on risk factors)

Warnings and Precautions

QT prolongation—avoid in patients with known QT prolongation, uncorrected hypokalemia or hypomagnesemia, or use of other QT-prolonging agents

Risk of hepatotoxicity—monitor for signs of liver dysfunction

Clostridioides difficile-associated diarrhea—may occur during or after treatment

Superinfection risk with prolonged use

Risk of myasthenia gravis exacerbation

Caution in severe renal impairment

In patients with cystic fibrosis or HIV, prolonged use may lead to macrolide resistance

Adverse Effects

Very Common

Diarrhea

Nausea

Abdominal pain

Common

Vomiting

Flatulence

Headache

Dizziness

Rash

Elevated liver enzymes

Uncommon to Rare

Allergic reactions (urticaria, angioedema)

Anaphylaxis

Stevens–Johnson syndrome

QT prolongation, arrhythmia

Hepatitis, cholestatic jaundice

Pancreatitis

Hearing loss (reversible) with long-term use

Neutropenia or thrombocytopenia (rare)

Taste disturbances

Photosensitivity

Pregnancy and Lactation

Pregnancy Category B (FDA)

No evidence of risk in animal studies

Used safely in pregnancy for chlamydia or respiratory infections

Preferred over doxycycline for pregnant patients with chlamydia

Lactation

Excreted in breast milk in small amounts

Considered compatible with breastfeeding

Infant may experience diarrhea or rash

Drug Interactions

Antacids (containing aluminum or magnesium)

Delay and reduce peak absorption—separate doses by at least 2 hours

Warfarin

May enhance anticoagulant effects—monitor INR closely

Cyclosporine, digoxin

Increased bioavailability due to P-glycoprotein inhibition—monitor levels

Drugs that prolong QT interval (e.g., amiodarone, sotalol, fluoroquinolones, antipsychotics)

Additive QT-prolongation risk—use with caution or avoid

Nelfinavir

Increased azithromycin concentrations—monitor for toxicity

Statins

May increase risk of myopathy—caution with concomitant use

Monitoring Parameters

Resolution of infection symptoms (fever, cough, discharge)

ECG in high-risk patients (QT interval)

Liver function tests (with prolonged therapy)

Signs of superinfection or C. difficile-associated diarrhea

Counseling Points

Take azithromycin once daily—do not double dose if missed

Extended-release formulations (Zmax) should be taken on an empty stomach

Regular tablets or capsules can be taken with or without food

Complete full course even if symptoms improve

Do not take with antacids within 2 hours

Report signs of rash, jaundice, palpitations, or persistent diarrhea

Store oral suspension at room temperature; shake well before use

Comparative Notes

Azithromycin vs Clarithromycin

Azithromycin has fewer CYP450 interactions

Better tolerated gastrointestinally

Longer half-life allows once-daily dosing

Clarithromycin has broader activity against some Gram-positive organisms

Azithromycin vs Doxycycline

Azithromycin preferred in pregnancy and for shorter courses

Doxycycline preferred for acne, malaria prophylaxis, and tick-borne illnesses

Azithromycin vs Erythromycin

Azithromycin better tolerated (less GI distress)

Does not inhibit CYP3A4 to the same extent

Longer duration of action

More acid-stable

Regulatory and Legal Status

Prescription-only medicine

Included in WHO Model List of Essential Medicines

Approved by FDA, EMA, MHRA for multiple bacterial infections

Widely available as tablets, capsules, oral suspension, and IV