Azithromycin Monograph

Introduction/Overview

Azithromycin, a 15‑membered macrolide antibiotic, has become a cornerstone in the treatment of a broad spectrum of bacterial infections. Its distinctive pharmacokinetic properties, including extensive tissue penetration and a prolonged half‑life, enable convenient dosing regimens that are often superior to other macrolides. The clinical relevance of azithromycin extends beyond its antibacterial activity; it possesses anti‑inflammatory and immunomodulatory effects that are exploited in various respiratory and sexually transmitted infections.

Learning objectives for this chapter are:

• Identify the chemical and pharmacological classification of azithromycin.
• Explain the molecular mechanism underlying its antibacterial activity.
• Describe the pharmacokinetic profile, including absorption, distribution, metabolism, and excretion.
• Summarize approved therapeutic indications and common off‑label uses.
• Recognize the principal adverse effects, drug interactions, and special population considerations.

Classification

Drug Classes and Categories

Azithromycin belongs to the macrolide class of antibiotics, characterized by a macrocyclic lactone ring. Within this class, it is classified as a 15‑membered macrolide, distinct from the more common 14‑membered macrolides such as erythromycin and clarithromycin. The 15‑membered structure confers superior pharmacokinetic attributes and a broader spectrum of activity.

Chemical Classification

The molecular formula is C₃₈H₇₂N₂O₁₂. Azithromycin is a semi‑synthetic derivative of erythromycin, modified through the addition of a 4‑deoxy‑4‑(azidomethyl) group, which reduces protonation at the 3′‑position and increases lipophilicity. These structural changes contribute to its enhanced tissue penetration and reduced susceptibility to the efflux mechanisms that limit other macrolides.

Mechanism of Action

Pharmacodynamics

Azithromycin exerts its antibacterial effect by binding reversibly to the 50S ribosomal subunit of susceptible bacteria. This interaction inhibits the translocation step of protein synthesis, thereby preventing the peptide chain extension. The binding affinity is concentration‑dependent, and the drug demonstrates a post‑antibiotic effect that allows for prolonged suppression of bacterial growth even after plasma concentrations fall below the minimum inhibitory concentration (MIC).

Receptor Interactions

At the molecular level, azithromycin interacts primarily with the peptidyl transferase center on the 23S rRNA component of the 50S subunit. This interaction blocks the exit tunnel for the nascent peptide chain, effectively halting translation. The drug’s affinity for the ribosomal RNA is reduced in bacteria that express macrolide‑resistance mechanisms such as methylation of the 23S rRNA by Erm methylases or active efflux pumps encoded by mef genes.

Molecular/Cellular Mechanisms

Beyond its direct antibacterial action, azithromycin modulates host immune responses. It inhibits the release of pro‑inflammatory cytokines (e.g., TNF‑α, IL‑6) from macrophages and neutrophils, thereby reducing tissue damage in inflammatory respiratory conditions. The drug also interferes with intracellular replication of certain pathogens, including Mycobacterium tuberculosis and Chlamydia trachomatis, by disrupting phagolysosomal fusion and altering intracellular pH gradients. These additional mechanisms support its off‑label use in chronic obstructive pulmonary disease (COPD) exacerbations and cystic fibrosis.

Pharmacokinetics

Absorption

Azithromycin is available in oral tablets, oral suspension, and intravenous formulations. Oral absorption is relatively efficient, with a bioavailability of approximately 37 % when administered as a tablet. Food intake modestly increases absorption; however, the drug can be taken with or without food. Peak plasma concentrations (C_max) are typically achieved within 2–3 hours post‑dose. The oral suspension demonstrates slightly higher C_max values due to the absence of a gastrointestinal matrix that could impede dissolution.

Distribution

Azithromycin displays extensive distribution into tissues, with tissue/plasma concentration ratios ranging from 10 to 100 × in epithelial and phagocytic cells. The drug accumulates preferentially in macrophages, neutrophils, and monocytes, reaching concentrations that exceed plasma levels by an order of magnitude. This accumulation is partly mediated by lysosomal trapping, attributable to the drug’s weakly basic nature. The large volume of distribution (V_d) is approximately 500 L in adults, indicating extensive peripheral compartment penetration.

Metabolism

Azithromycin undergoes limited hepatic metabolism. The predominant metabolic pathway involves oxidation to an inactive metabolite (azithromycin N‑oxide) via cytochrome P450 3A4 (CYP3A4). The metabolic contribution to overall clearance is minor (< 10 %). Consequently, azithromycin is not a potent inducer or inhibitor of CYP3A4, reducing the risk of pharmacokinetic drug interactions involving this pathway.

Excretion

Renal excretion accounts for approximately 30–35 % of the administered dose, primarily as unchanged drug and its N‑oxide metabolite. The remaining drug is eliminated via bile and feces. The terminal half‑life (t_1/2) is approximately 68 hours, allowing for once‑daily dosing and, in many regimens, single‑dose therapy. The prolonged half‑life is attributed to the slow release of drug from tissue stores back into circulation.

Half‑Life and Dosing Considerations

The long terminal half‑life permits the use of abbreviated dosing schedules. Standard regimens include a 500 mg loading dose followed by 250 mg once daily for 4 days, or a single 1‑gram dose for uncomplicated pneumonia. For patients with renal impairment, dose adjustments are necessary. The drug is safe to use in mild to moderate renal dysfunction (creatinine clearance ≥ 30 mL min^-1), but caution is advised in severe impairment (creatinine clearance < 30 mL min^-1) due to reduced elimination.

Therapeutic Uses/Clinical Applications

Approved Indications

Azithromycin is approved by the U.S. Food and Drug Administration for the treatment of the following infections:

• Acute bacterial sinusitis
• Acute exacerbations of chronic bronchitis
• Community‑acquired bacterial pneumonia
• Skin and soft tissue infections caused by susceptible organisms
• Chlamydia trachomatis and Neisseria gonorrhoeae (single‑dose therapy)
• Mycoplasma pneumoniae and Legionella pneumophila infections
• Pertussis (whooping cough) in infants and adults

Off‑Label Uses

Azithromycin is frequently employed off‑label in various clinical scenarios:

• Management of COPD exacerbations to reduce inflammation and mucus production
• Cystic fibrosis patients for chronic airway colonization with Pseudomonas aeruginosa
• Recurrence prevention of chronic sinusitis in patients with nasal polyps
• Treatment of bacterial vaginosis and certain sexually transmitted infections when other antibiotics are contraindicated
• Adjunctive therapy in heart failure with reduced ejection fraction, based on anti‑inflammatory properties (investigational)

Adverse Effects

Common Side Effects

Gastrointestinal disturbances are the most frequently reported adverse reactions. These include nausea, vomiting, abdominal pain, and diarrhea. While the incidence of diarrhea is comparable to other macrolides, the risk of severe colitis, particularly Clostridioides difficile–associated colitis, is a concern. Minor local reactions at the injection site are observed with intravenous administration, including pain and erythema.

Serious or Rare Adverse Reactions

Cardiac arrhythmias, notably QT interval prolongation and torsades de pointes, have been documented, especially in patients with pre‑existing heart disease or electrolyte disturbances. Hepatotoxicity is rare but may manifest as elevated transaminases or cholestatic jaundice. Anaphylactic reactions, though uncommon, have been reported and warrant immediate discontinuation of therapy. Visual disturbances, including blurred vision and transient photophobia, may arise in cases of retinal toxicity, particularly with high cumulative doses.

Black Box Warnings

Azithromycin carries a boxed warning for the risk of serious arrhythmias, including torsades de pointes, in patients with prolonged QT intervals or those receiving other QT‑prolonging agents. The warning also highlights the potential for Clostridioides difficile colitis, especially when used in conjunction with other broad‑spectrum antibiotics. Appropriate monitoring of electrolytes and cardiac rhythm is recommended for at-risk populations.

Drug Interactions

Major Drug‑Drug Interactions

Azithromycin exhibits minimal interaction with cytochrome P450 enzymes; however, concurrent use with potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole) may modestly increase plasma concentrations. The drug interacts with agents that prolong the QT interval, including fluoroquinolones, macrolides, and certain antipsychotics, necessitating caution. Concomitant use with oral anticoagulants may increase bleeding risk due to potential alterations in platelet function.</

Contraindications

Azithromycin is contraindicated in patients with hypersensitivity to macrolides or any excipient component. It should be avoided in patients with a history of ventricular arrhythmias, congenital long QT syndrome, or significant electrolyte abnormalities (hypokalemia, hypomagnesemia). Caution is advised when prescribing in combination with other QT‑prolonging drugs or in patients with hepatic dysfunction, as the risk of hepatotoxicity may be amplified.

Special Considerations

Use in Pregnancy and Lactation

The safety profile in pregnancy has been extensively reviewed, and azithromycin is classified as category B. Available data suggest no teratogenic risk, and the drug can be considered when benefits outweigh potential risks. Azithromycin is excreted in breast milk at low concentrations; however, it is generally regarded as compatible with lactation based on limited case reports. Monitoring for infant gastrointestinal disturbances is advisable.

Pediatric Considerations

Azithromycin dosing in children is weight‑adjusted, commonly 10 mg kg^-1 on day 1 followed by 5 mg kg^-1 on subsequent days for most indications. The drug is approved for use in infants as young as 6 months for pertussis and for older infants and children for other respiratory infections. Pediatric patients may exhibit higher rates of gastrointestinal upset; thus, dose adjustment or supportive care is often required.

Geriatric Considerations

In elderly patients, altered pharmacokinetics due to decreased renal function and comorbidities may necessitate dose adjustment. The risk of QT prolongation is heightened in this demographic, particularly when polypharmacy is involved. Vigilant cardiac monitoring and avoidance of concurrent QT‑prolonging agents are recommended.

Renal and Hepatic Impairment

Azithromycin is primarily eliminated via the kidneys; therefore, dose reduction is required in patients with creatinine clearance < 30 mL min^-1. Hepatic impairment does not significantly affect drug clearance, but caution is advised if severe hepatic disease is present. Monitoring liver enzymes is advisable when long‑term therapy is indicated.

Summary/Key Points

• Azithromycin is a 15‑membered macrolide antibiotic with broad antibacterial activity and anti‑inflammatory properties.
• Its mechanism involves reversible binding to the 50S ribosomal subunit, inhibiting protein synthesis and exerting a post‑antibiotic effect.
• Excellent tissue penetration and a long half‑life facilitate convenient once‑daily or single‑dose regimens.
• Approved indications include respiratory infections, sexually transmitted infections, and pertussis; off‑label uses encompass COPD, cystic fibrosis, and chronic sinusitis.
• Common adverse effects are gastrointestinal; serious risks include QT prolongation and clostridial colitis.
• Drug interactions are limited but include additive QT‑prolongation with other agents and modest increases in plasma levels when combined with CYP3A4 inhibitors.
• Special populations—pregnant women, lactating mothers, children, and the elderly—require dose adjustments and monitoring for specific risks.

Clinical pearls: The convenience of azithromycin dosing enhances adherence, particularly in outpatient settings. However, careful patient selection is essential to mitigate the risk of cardiac arrhythmias and antimicrobial resistance. Monitoring of electrolytes, liver function, and cardiac rhythm should be considered in high‑risk groups. When prescribing azithromycin, it remains prudent to evaluate potential drug–drug interactions, especially in patients on multiple medications or with underlying cardiac disease.

References

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