When to Use Azithromycin
Azithromycin should be used as first-line therapy for outpatient community-acquired pneumonia in previously healthy adults without comorbidities or recent antibiotic exposure, particularly when atypical pathogens are suspected, but must be avoided in areas with high macrolide resistance (>25%) and should never be used as monotherapy for severe pneumonia requiring hospitalization. 1, 2
Primary Indications for Use
Respiratory Tract Infections
Community-acquired pneumonia (CAP): Use azithromycin as monotherapy for previously healthy outpatients without comorbidities or recent antibiotic use, as it provides excellent coverage against atypical pathogens including Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella species 1, 2, 3
Hospitalized non-ICU patients with CAP: Combine azithromycin with a β-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) rather than using it alone 1, 2
ICU patients with CAP: Always combine azithromycin with a β-lactam to ensure dual coverage for S. pneumoniae and Legionella species—never use as monotherapy in this setting 1, 2
Acute bacterial exacerbations of COPD: Use azithromycin for infections caused by H. influenzae, M. catarrhalis, or S. pneumoniae 2, 3
Bronchiectasis: Consider long-term therapy (≥2 months) at 500mg three times weekly or 250mg daily for patients with ≥3 exacerbations in the previous 12 months 2
Sexually Transmitted Infections
Chlamydia trachomatis urethritis/cervicitis: Azithromycin 1g as a single oral dose provides effective treatment with superior compliance compared to multi-day regimens 3
Uncomplicated gonorrhea: Previously recommended in combination with ceftriaxone, but current guidelines now favor ceftriaxone alone due to rising macrolide resistance in N. gonorrhoeae 1
Chancroid: Use azithromycin for genital ulcer disease in men caused by Haemophilus ducreyi 3
Other Bacterial Infections
Cholera in children: Azithromycin is the first-choice agent, particularly useful in epidemic situations where single-dose treatment optimizes compliance 1
Pertussis: Azithromycin is the preferred macrolide for both treatment and postexposure prophylaxis, especially in infants <1 month where it has a better safety profile than erythromycin 1
Skin and soft tissue infections: Use for uncomplicated infections caused by S. aureus, S. pyogenes, or S. agalactiae 3, 4
Acute bacterial sinusitis: Indicated for infections due to H. influenzae, M. catarrhalis, or S. pneumoniae 3
Critical Contraindications and When NOT to Use
Absolute Contraindications
Known or suspected non-tuberculous mycobacteria (NTM) infection: Never initiate azithromycin monotherapy without first screening for NTM, as single-agent macrolide use can rapidly induce resistance that makes subsequent treatment extremely difficult 1, 2
High local macrolide resistance (>25%): Do not use azithromycin monotherapy for pneumonia in areas where S. pneumoniae macrolide resistance exceeds 25% 1, 2
Severe pneumonia requiring hospitalization: Azithromycin monotherapy is contraindicated in patients with moderate-to-severe illness, bacteremia, cystic fibrosis, nosocomial infections, elderly/debilitated patients, or those with immunodeficiency or functional asplenia 1, 3
History of hypersensitivity: Absolute contraindication in patients with previous allergic reactions to any macrolide, including rare but potentially fatal Stevens-Johnson syndrome or toxic epidermal necrolysis 3
Relative Contraindications and High-Risk Situations
QT prolongation risk: Exercise extreme caution in patients with known QT prolongation, history of torsades de pointes, congenital long QT syndrome, bradyarrhythmias, uncompensated heart failure, uncorrected electrolyte abnormalities (hypokalemia/hypomagnesemia), or those taking Class IA or III antiarrhythmics—azithromycin can cause fatal cardiac arrhythmias in these populations 3
Hepatic dysfunction: Discontinue immediately if signs of hepatitis occur, as azithromycin has been associated with hepatic necrosis and hepatic failure resulting in death 3
COVID-19: Do not use azithromycin routinely for COVID-19 in the absence of bacterial co-infection, as multiple trials showed no mortality benefit and its use promotes antimicrobial resistance 1
Pregnancy considerations: While azithromycin is the preferred macrolide during pregnancy (safer than clarithromycin which is teratogenic), use only when clinically necessary 1, 5
Dosing Strategies
Standard respiratory infections: 500mg on day 1, followed by 250mg daily on days 2-5 for adults 1, 3
Single-dose regimens: 1g single dose for chlamydia or 2g single dose for gonorrhea (though no longer first-line) 3
Long-term bronchiectasis prophylaxis: 500mg three times weekly or 250mg daily 2
Infants <6 months: 10mg/kg daily for 5 days (azithromycin preferred over erythromycin due to lower risk of infantile hypertrophic pyloric stenosis) 1
Common Pitfalls to Avoid
Failing to assess local resistance patterns: Always consider local S. pneumoniae macrolide resistance rates before prescribing monotherapy—resistance >25% mandates combination therapy or alternative agents 1, 2
Using monotherapy for severe infections: Never use azithromycin alone for hospitalized patients with pneumonia or those with risk factors for poor outcomes—combination with a β-lactam is mandatory 1, 2
Neglecting NTM screening: Before starting long-term macrolide therapy, always screen patients for NTM infection through sputum examination if any clinical suspicion exists 1, 2
Ignoring cardiac risk factors: Screen for QT prolongation risk factors and obtain baseline ECG in high-risk patients before initiating therapy 3
Treating viral infections: Azithromycin has no role in treating viral respiratory infections including COVID-19 without documented bacterial co-infection—inappropriate use drives resistance 1
Assuming coverage for all pneumonia pathogens: Azithromycin has poor activity against Pseudomonas aeruginosa and should not be used when this pathogen is suspected 1