Azithromycin
azithromycin dihydrate — marketed as Zithromax (Z-Pak, Tri-Pak)
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Community-acquired pneumonia (mild, oral-appropriate) | Adults; children ≥6 months | Monotherapy | FDA Approved |
| Acute bacterial sinusitis | Adults; children ≥6 months | Monotherapy | FDA Approved |
| Acute otitis media | Children ≥6 months | Monotherapy | FDA Approved |
| Acute bacterial exacerbation of chronic bronchitis | Adults | Monotherapy | FDA Approved |
| Pharyngitis / tonsillitis (second-line) | Adults; children ≥2 years | Alternative to first-line | FDA Approved |
| Uncomplicated skin and skin structure infections | Adults | Monotherapy | FDA Approved |
| Urethritis and cervicitis (chlamydial, gonococcal) | Adults | Monotherapy | FDA Approved |
| Genital ulcer disease (chancroid) | Adult men | Monotherapy | FDA Approved |
Azithromycin covers atypical pathogens (Mycoplasma, Chlamydophila, Legionella) that beta-lactams miss, making it a key agent for community-acquired pneumonia. For pharyngitis, it is explicitly a second-line option — penicillin or amoxicillin remains first-line per IDSA guidelines. Azithromycin should not be used for pneumonia in patients judged inappropriate for oral therapy due to moderate-to-severe illness or significant risk factors.
Traveler’s diarrhea — 1 g single dose or 500 mg daily for 3 days; preferred in South/Southeast Asia where fluoroquinolone resistance is high. Evidence quality: High.
Pertussis (whooping cough) — treatment and post-exposure prophylaxis — CDC recommends azithromycin as first-line: adults 500 mg Day 1 then 250 mg Days 2–5; infants <6 months 10 mg/kg/day for 5 days. Evidence quality: High.
Mycobacterium avium complex (MAC) prophylaxis in HIV — 1200 mg once weekly; FDA-approved for the IV/600 mg tablet formulation but commonly used off-label with standard tablets. Evidence quality: High.
Non-tuberculous mycobacteria (NTM) — M. avium complex lung disease — ATS/IDSA 2020 guidelines recommend azithromycin-based regimens as first-line. Evidence quality: High.
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Community-acquired pneumonia (mild, outpatient) | 500 mg Day 1 | 250 mg once daily Days 2–5 | 1.5 g total course | 5-day Z-Pak regimen; covers atypicals (Mycoplasma, Chlamydophila) FDA PI §2.1 |
| Acute bacterial sinusitis | 500 mg once daily | Same for 3 days | 1.5 g total course | 3-day course; Tri-Pak FDA PI §2.1 |
| ABECB (mild-moderate) | 500 mg Day 1 | 250 mg Days 2–5 OR 500 mg daily for 3 days | 1.5 g total course | Either 5-day or 3-day regimen acceptable FDA PI §2.1 |
| Pharyngitis / tonsillitis (second-line) | 500 mg Day 1 | 250 mg Days 2–5 | 1.5 g total course | Second-line only — penicillin/amoxicillin is first-line FDA PI §2.1; IDSA 2012 |
| Uncomplicated skin/soft tissue infection | 500 mg Day 1 | 250 mg Days 2–5 | 1.5 g total course | 5-day course FDA PI §2.1 |
| Chlamydial urethritis / cervicitis | 1 g single dose | Single dose | 1 g | Single-dose directly observed therapy possible; test for syphilis at diagnosis FDA PI §2.1; CDC 2021 STI guidelines |
| Gonococcal urethritis / cervicitis | 2 g single dose | Single dose | 2 g | Higher GI side effects at this dose (nausea 18%, diarrhea 14%) FDA PI §2.1 |
| Chancroid (genital ulcer disease) | 1 g single dose | Single dose | 1 g | Efficacy not established in women FDA PI §2.1 |
| Pertussis — treatment/prophylaxis (off-label) | 500 mg Day 1 | 250 mg Days 2–5 | 1.5 g total | CDC first-line for pertussis treatment and post-exposure prophylaxis CDC pertussis guidelines |
Pediatric Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Acute otitis media (≥6 months) — 5-day regimen | 10 mg/kg Day 1 | 5 mg/kg/day Days 2–5 | 30 mg/kg total course | Total dose 30 mg/kg over 5 days FDA PI §2.2 |
| Acute otitis media (≥6 months) — 3-day regimen | 10 mg/kg/day for 3 days | Same | 30 mg/kg total course | Total dose 30 mg/kg over 3 days FDA PI §2.2 |
| Acute otitis media (≥6 months) — single-dose | 30 mg/kg single dose | Single dose | 30 mg/kg | Highest diarrhea rate (4.3%) of the three AOM regimens FDA PI §2.2 |
| Acute bacterial sinusitis (≥6 months) | 10 mg/kg/day for 3 days | Same | 500 mg/day | 3-day course FDA PI §2.2 |
| Community-acquired pneumonia (≥6 months) | 10 mg/kg Day 1 | 5 mg/kg Days 2–5 | 500 mg Day 1, 250 mg Days 2–5 | 5-day regimen only (3-day and 1-day not established for CAP) FDA PI §2.2 |
| Pharyngitis / tonsillitis (≥2 years) | 12 mg/kg/day for 5 days | Same | 500 mg/day | Second-line only; higher daily dose than other indications FDA PI §2.2 |
Azithromycin’s uniquely long terminal half-life (~68 hours) and extraordinary tissue accumulation (tissue:serum ratios up to 100:1) mean that a 5-day oral course maintains therapeutic tissue concentrations for 7–10 days after the last dose. This is the pharmacokinetic basis for the short treatment courses and the effectiveness of single-dose regimens for STIs. The drug is concentrated within phagocytes and delivered directly to sites of infection, which is why low serum levels do not reflect its clinical efficacy. The PK/PD driver for azithromycin is AUC/MIC ratio, not time above MIC.
Pharmacology
Mechanism of Action
Azithromycin is an azalide — a subclass of macrolide antibacterials created by inserting a nitrogen atom into the lactone ring of erythromycin, producing a 15-membered ring structure. It binds to the 50S ribosomal subunit of susceptible bacteria, specifically at domain V of the 23S rRNA within the peptide exit tunnel (PET). This binding physically obstructs the tunnel through which the growing polypeptide chain must pass, inhibiting bacterial protein synthesis. Azithromycin is considered bacteriostatic at standard therapeutic concentrations, though bactericidal activity has been observed at higher concentrations against particularly susceptible organisms. Its spectrum includes gram-positive organisms (S. pneumoniae, S. pyogenes, S. aureus), gram-negatives (H. influenzae, M. catarrhalis), and critically, atypical pathogens (Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella).
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Oral bioavailability ~37% (capsules ~38%); Tmax 2–3 h; food increases Cmax by ~23% (tablets) with no change in AUC; antacids reduce Cmax by ~24% | Can be taken with or without food (tablets); avoid simultaneous administration with aluminum/magnesium antacids; low oral bioavailability offset by extraordinary tissue accumulation |
| Distribution | Vd ~23–31 L/kg (extremely large); tissue:serum ratio up to 100:1; concentrated in phagocytes (WBCs transport drug to infection sites); protein binding concentration-dependent: 51% at 0.02 mcg/mL, 7% at 2 mcg/mL | Low serum levels are misleading — tissue and intracellular concentrations far exceed MICs; high Vd enables short-course therapy; good penetration to lungs, tonsils, prostate, middle ear; poor CNS penetration |
| Metabolism | Hepatic demethylation (CYP3A4) to inactive metabolites; minimal CYP3A4 inhibition (unlike erythromycin/clarithromycin) | Far fewer CYP-mediated drug interactions than erythromycin or clarithromycin; PK in hepatic impairment not established — use with caution |
| Elimination | Terminal t½ ~68 h (tissue); initial serum t½ 11–14 h; primarily biliary/fecal excretion (~50% in feces); ~6% excreted unchanged in urine (oral); no dose adjustment for renal impairment | Prolonged tissue half-life supports short courses (5-day course provides 7–10 days of therapeutic tissue levels); no renal dose adjustment needed; not removed by dialysis |
Side Effects
Side effect rates vary significantly by regimen. The 2 g single dose causes markedly more GI effects than the 5-day multi-dose regimen.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Diarrhea / loose stools | 4–5% (up to 7% with 1 g dose; 14% with 2 g dose) | Most common effect; dose-related; usually self-limiting; evaluate for C. difficile if severe/bloody |
| Nausea | 3% (5% with 1 g; 18% with 2 g dose) | Significantly worse with 2 g single dose; taking with food improves tolerability |
| Abdominal pain | 2–3% (5% with 1 g; 7% with 2 g dose) | Dose-related; usually resolves after course completion |
| Vomiting | <1% multi-dose (2% with 1 g; 7% with 2 g dose) | Significant concern with single 2 g dose; vomiting within 30 min may require re-dosing |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| QT prolongation / torsades de pointes | Rare; dose- and concentration-dependent | During treatment; risk greatest during first 5 days | Avoid in patients with known QT prolongation, uncorrected hypokalemia/hypomagnesemia, bradyarrhythmias, or concurrent Class IA/III antiarrhythmics; ECG if risk factors present |
| Cardiovascular death | ~2-fold increased short-term risk vs amoxicillin (observational data); 20–400 per million courses | First 5 days of use | Weigh risk vs benefit; greatest concern in patients with pre-existing cardiovascular disease; FDA PI §5.5 warning added 11/2021 |
| Hepatotoxicity (hepatitis, cholestatic jaundice, hepatic necrosis/failure) | Rare; some fatal | During or after treatment; allergic symptoms may recur due to long tissue t½ | Discontinue immediately if signs of hepatitis; monitor LFTs; prior azithromycin hepatotoxicity is a contraindication |
| Anaphylaxis / SJS / TEN / DRESS / AGEP | Rare; fatalities reported | During or after treatment; may recur after stopping due to long tissue t½ | Discontinue; appropriate therapy; allergic symptoms may recur when symptomatic treatment stopped — prolonged observation needed |
| Infantile hypertrophic pyloric stenosis (IHPS) | Rare; neonates (≤42 days of life) | Days to weeks after neonatal exposure | Monitor for projectile vomiting, irritability with feeding; surgical consultation if suspected |
| C. difficile-associated diarrhea | Uncommon | During or up to 2 months after treatment | Stop azithromycin; test for C. difficile; treat if confirmed |
| Hearing impairment | Rare; 5.6% in HIV-infected children on prolonged high-dose therapy | Variable; reported with prolonged courses | Usually reversible; audiometric monitoring for prolonged courses (e.g., MAC prophylaxis) |
| Myasthenia gravis exacerbation | Rare | Variable | Avoid in myasthenia gravis if possible; new-onset myasthenic syndrome also reported |
Observational studies have shown an approximately two-fold increased short-term risk of acute cardiovascular death in adults taking azithromycin compared with amoxicillin. The five-day cardiovascular mortality ranged from 20 to 400 per million treatment courses. This risk was greatest during the first five days and does not appear limited to patients with pre-existing cardiovascular disease. The FDA advises clinicians to balance this potential risk with treatment benefits. This risk is not shared with amoxicillin, and azithromycin should be used judiciously in patients with significant cardiovascular risk factors.
Drug Interactions
Azithromycin has a substantially more favorable drug interaction profile than erythromycin or clarithromycin because it has minimal CYP3A4 inhibitory activity. The primary interaction concerns are QT prolongation (pharmacodynamic) and P-glycoprotein inhibition.
Unlike erythromycin and clarithromycin (which are potent CYP3A4 inhibitors), azithromycin has minimal CYP3A4 inhibitory activity. This means azithromycin does not significantly interact with statins, cyclosporine, carbamazepine, or theophylline — a major clinical advantage for patients on complex medication regimens. However, azithromycin does retain P-glycoprotein inhibitory activity, which is relevant for digoxin and colchicine interactions.
Monitoring
- Clinical response48–72 h after initiation
RoutineAssess symptom improvement. Remember that tissue drug levels persist 7–10 days after the last dose, so the full clinical effect may not be apparent until several days after course completion. - ECG / QTcBaseline in at-risk patients
Trigger-basedObtain ECG before prescribing if patient has known QT prolongation, congenital long QT syndrome, bradyarrhythmias, uncompensated heart failure, concurrent QT-prolonging drugs, or uncorrected hypokalemia/hypomagnesemia. Elderly patients are more susceptible to QT effects. - Hepatic functionIf signs of hepatitis develop
Trigger-basedMonitor LFTs if patient develops jaundice, dark urine, abdominal pain, or unexplained fatigue. Discontinue immediately if hepatitis suspected. Note that allergic symptoms may recur after stopping azithromycin due to its long tissue half-life. - INR (with warfarin)During and after course
Trigger-basedMonitor prothrombin time if patient is on warfarin. Effects may persist after azithromycin course due to long tissue half-life. - HearingFor prolonged courses only
Trigger-basedAudiometric monitoring recommended for prolonged high-dose use (e.g., MAC prophylaxis/treatment). Hearing impairment reported in 5.6% of HIV-infected children on long-term therapy; usually reversible. - GI / C. difficileThroughout and up to 2 months after
RoutineEvaluate new persistent or bloody diarrhea for C. difficile. CDAD can present during or up to 2 months after treatment.
Contraindications & Cautions
Absolute Contraindications
- Known hypersensitivity to azithromycin, erythromycin, any macrolide, or any ketolide drug (FDA PI §4.1).
- History of cholestatic jaundice or hepatic dysfunction associated with prior azithromycin use (FDA PI §4.2).
Relative Contraindications (Specialist Input Recommended)
- Known QT prolongation or congenital long QT syndrome — risk of torsades de pointes.
- Concurrent use of Class IA or Class III antiarrhythmic drugs — additive QT prolongation.
- Myasthenia gravis — may exacerbate weakness or precipitate new-onset myasthenic syndrome.
Use with Caution
- Hepatic impairment — PK not established; azithromycin is hepatically metabolized and eliminated primarily via biliary excretion.
- Significant cardiovascular disease — observational data suggest increased short-term cardiovascular mortality risk.
- Uncorrected hypokalemia or hypomagnesemia — increases QT prolongation risk.
- Elderly patients — may be more susceptible to QT interval effects and torsades de pointes.
- Neonates (≤42 days of life) — risk of IHPS; monitor for vomiting/irritability with feeding.
Prolonged cardiac repolarization and QT interval, imparting a risk of cardiac arrhythmia and torsades de pointes, have been seen with azithromycin. Observational studies have shown an approximately two-fold increased short-term risk of cardiovascular death compared with amoxicillin (20–400 per million courses). Severe and sometimes fatal hepatotoxicity has been reported, including hepatic necrosis and hepatic failure. Due to azithromycin’s long tissue half-life, allergic and hepatic reactions may recur after the drug is stopped, requiring prolonged observation.
Patient Counselling
Purpose of Therapy
Azithromycin is an antibiotic used to treat bacterial infections including pneumonia, sinusitis, bronchitis, ear infections, skin infections, and certain sexually transmitted infections. It does not work against viral infections like the common cold or flu.
How to Take
Tablets can be taken with or without food. Do not take aluminum- or magnesium-containing antacids at the same time as azithromycin — separate by at least 2 hours. Complete the full course as prescribed even if you feel better before finishing. If using the liquid suspension, shake well and measure with the dosing device provided.
Sources
- ZITHROMAX (azithromycin) prescribing information. Pfizer Inc. Revised November 2021. FDA Label (PDF)Primary source for all dosing, indications, adverse reactions (diarrhea 4–14%, nausea 3–18% by regimen), QT/CV death warnings, contraindications, and PK data.
- Azithromycin. StatPearls [Internet]. Updated November 2024. NCBI BookshelfComprehensive review of azithromycin pharmacology, PK, indications, and contraindications including IHPS and myasthenia gravis warnings.
- Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012;366(20):1881-1890. doi:10.1056/NEJMoa1003833Landmark Tennessee Medicaid cohort study showing ~2.5-fold increased risk of cardiovascular death during 5-day azithromycin courses vs amoxicillin; basis for FDA CV death warning.
- Svanstrom H, Pasternak B, Hviid A. Use of azithromycin and death from cardiovascular causes. N Engl J Med. 2013;368(18):1704-1712. doi:10.1056/NEJMoa1300799Danish nationwide cohort study finding increased rate of cardiovascular death with azithromycin vs penicillin V, supporting the CV risk signal.
- Shulman ST, Bisno AL, Clegg HW, et al. Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis: 2012 update by the IDSA. Clin Infect Dis. 2012;55(10):e86-e102. doi:10.1093/cid/cis629IDSA guideline positioning azithromycin as second-line for GAS pharyngitis (only for penicillin-allergic patients); penicillin/amoxicillin remains first-line.
- Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with community-acquired pneumonia: an official clinical practice guideline of the ATS and IDSA. Am J Respir Crit Care Med. 2019;200(7):e45-e67. doi:10.1164/rccm.201908-1581STATS/IDSA 2019 CAP guideline: azithromycin monotherapy for outpatient CAP without comorbidities; with beta-lactam for patients with comorbidities.
- Workowski KA, Bachmann LH, Chan PA, et al. Sexually transmitted infections treatment guidelines, 2021. MMWR Recomm Rep. 2021;70(4):1-187. doi:10.15585/mmwr.rr7004a1CDC 2021 STI guidelines: azithromycin 1 g single dose for chlamydial infections; now second-line to doxycycline for chlamydia based on updated evidence.
- Tiwari T, Murphy TV, Moran J; National Immunization Program, CDC. Recommended antimicrobial agents for the treatment and postexposure prophylaxis of pertussis. MMWR Recomm Rep. 2005;54(RR-14):1-16. CDCCDC pertussis guideline recommending azithromycin as first-line for treatment and post-exposure prophylaxis across all age groups.
- Retsema J, Girard A, Schelkly W, et al. Spectrum and mode of action of azithromycin (CP-62,993), a new 15-membered-ring macrolide with improved potency against gram-negative organisms. Antimicrob Agents Chemother. 1987;31(12):1939-1947. doi:10.1128/AAC.31.12.1939Original characterization of azithromycin’s spectrum and mode of action as a novel 15-membered azalide macrolide.
- Foulds G, Shepard RM, Johnson RB. The pharmacokinetics of azithromycin in human serum and tissues. J Antimicrob Chemother. 1990;25(Suppl A):73-82. doi:10.1093/jac/25.suppl_A.73Key PK study establishing azithromycin’s ~37% bioavailability, extensive tissue accumulation (tissue:serum up to 100:1), and tissue half-lives of 2–3 days.
- Drew RH, Gallis HA. Azithromycin — spectrum of activity, pharmacokinetics, and clinical applications. Pharmacotherapy. 1992;12(3):161-173. doi:10.1002/j.1875-9114.1992.tb04504.xComprehensive early review of azithromycin PK including Vd ~23 L/kg, terminal t½ up to 5 days, and hepatic/biliary elimination pathway.
- Parnham MJ, Erakovic Haber V, Giamarellos-Bourboulis EJ, Perletti G, Verleden GM, Vos R. Azithromycin: mechanisms of action and their relevance for clinical applications. Pharmacol Ther. 2014;143(2):225-245. doi:10.1016/j.pharmthera.2014.03.003Review of azithromycin’s anti-inflammatory and immunomodulatory properties beyond its antibacterial activity, relevant to its use in NTM and COPD.