A nurse is preparing to administer azithromycin to a client who is at 16 weeks of gestation

Azithromycin is an antimicrobial medication used to treat and manage bacterial infections, including community-acquired pneumonia and sexually transmitted diseases. It is in the macrolide class of antimicrobials. The disorders treated by azithromycin are important causes of infectious disease morbidity and mortality in the United States. This activity reviews the indications, contraindications, mechanism of action, and toxicities of azithromycin therapy in the clinical setting and important prescribing and management considerations for the healthcare team.

Objectives:

• Identify the mechanism of action and administration of azithromycin.

• Describe the adverse effects and contraindications of azithromycin.

• Summarize the appropriate monitoring of azithromycin therapy and its toxicities.

• Review considerations relevant to the interprofessional team and discuss strategies for enhancing patient outcomes and care coordination.

Azithromycin is a broad-spectrum macrolide antimicrobial and is among the most prescribed antimicrobial drugs in the United States. It is a derivative of erythromycin with greatly enhanced activity against gram-negative bacteria (including Enterobacteriaceae) and provides coverage of many gram-positive organisms.[1][2] 

• As an inhibitor of bacterial protein synthesis (rather than a peptidoglycan cell-wall inhibitor like beta-lactam agents), azithromycin is effective against many “atypical” bacteria such as chlamydiae (e.g., Chlamydia trachomatis and Chlamydophila psittaci), legionella (i.e., Legionella pneumophila), mycoplasma (e.g., Mycoplasma pneumoniae), and mycobacteria (e.g., Mycobacterium avium).[3] 

• Together with its activity against Streptococcus pneumoniae, Hemophilus influenzae, and Moraxella catarrhalis, azithromycin is indicated—and FDA approved—for the treatment of community-acquired pneumonia (CAP).[4]  

• Azithromycin also has approval for use in other upper respiratory infectious processes, including acute otitis media and acute exacerbation of chronic obstructive pulmonary disease (COPD).[5]

• Additionally, azithromycin has approval for the treatment of pharyngitis caused by Streptococcus pyogenes, as an alternative to a beta-lactam agent; skin or skin structure infection due to S. pyogenes, Streptococcus agalactiae, or Staphylococcus aureus;  M. avium complex (MAC) infection treatment and prophylaxis for patients with advanced acquired immunodeficiency syndrome (AIDS); and sexually transmitted infections including chlamydia, gonococcal disease, chancroid (caused by Hemophilus ducreyi), and Mycoplasma genitalium.[6][7][8][9][10]

• Azithromycin also has efficacy against some protozoal organisms such as Babesia sp. (e.g., B. microti), Plasmodium sp. (i.e., malaria), and Toxoplasma gondii and is sometimes used off-label for the treatment of these parasitic diseases in combination with antiprotozoal drugs (e.g., atovaquone).[11][12][13]

• The role of azithromycin in the treatment of viral infections, including the respiratory syncytial virus and novel coronavirus SARS-CoV-2, is indeterminate.[14][15][16][17][18][17]

• Lastly, azithromycin is also used off-label as long-term prophylaxis for bronchiolitis obliterans (BO) in patients who have undergone lung transplantation.[19]

Like other macrolide antimicrobials, azithromycin binds to the 23S portion of the 50S bacterial ribosomal subunit. It inhibits bacterial protein synthesis by preventing the transit of aminoacyl-tRNA and the growing protein through the ribosome. Compared to erythromycin, azithromycin is less prone to disassociation from the gram-negative ribosome, conferring its greater efficacy against gram-negative pathogens.[20] Like other macrolides and protein-synthesis inhibitors, azithromycin primarily acts as a bacteriostatic agent, meaning it inhibits bacterial growth rather than directly killing organisms.  However, especially at higher doses, azithromycin has been shown to have a bactericidal effect against certain bacteria such as streptococci and H. influenzae.[21][22]

Pharmacokinetically, azithromycin rapidly moves from the bloodstream into tissues and, once there, readily crosses cellular membranes, allowing efficacy against intracellular pathogens.[20][22] In non-bacterial organisms (i.e., apicomplexan parasites such as Babesia sp., Plasmodium sp., and Toxoplasma sp.), azithromycin inhibits the 50S ribosome found in the parasite apicoplast, an endosymbiosis-derived organelle with bacteria-like protein-synthesis machinery that performs critical metabolic functions.[23][24]

In addition to azithromycin’s antimicrobial activity, it is also a potent immunomodulator that has been shown to markedly reduce airway neutrophilia, IL-8 gene expression, and C-reactive protein levels in lung transplant recipients.[25] Azithromycin has in vitro antiviral properties, which has created interest in the experimental treatment of SARS-CoV-2. By inducing the expression of RIG-I-like helicases, azithromycin enhanced rhinovirus-induced expression of interferons in cultured cells of  COPD patients but not in cultured cells of healthy patients in vitro.[26]

Azithromycin is available for both oral and parenteral (intravenous) administration. The extended-release formulation of azithromycin has been discontinued. The usual dose is 250 mg or 500 mg given once daily for 3 to 5 days, and in severe infections, a higher dose is used. 

• Oral formulations include tablets (250 mg, 500 mg), packets (1 gram dissolved in ¼ cup or 60 ml of water), and suspension for reconstitution (100 mg/5 ml, 200 mg/5 ml). Dosing can be administered with or without food.

• Intravenous (IV) azithromycin is available in a 500 mg preservative-free solution for reconstitution. It should be infused over at least 60 minutes, and azithromycin administration should not be via intramuscular injection or IV bolus.

• The ophthalmic solution (1%) is available in a 2.5 ml bottle which is used in bacterial conjunctivitis.

Azithromycin demonstrates excellent tissue penetration and intracellular accumulation. Metabolism is hepatic, and excretion is mainly biliary.[27] Its long half-life and extensive tissue and intracellular distribution permit once-daily dosing and a shorter course of treatment than other antimicrobials (e.g., treatment of chlamydia infection with a single administration of 1 g of azithromycin versus 100 mg of doxycycline twice daily for seven days).

Azithromycin may be administered to patients with renal disease or failure without regard for creatinine clearance. No dose adjustment is usually necessary.[28]

Azithromycin is generally regarded as a safe antimicrobial agent, and only a few patients discontinue azithromycin due to adverse effects.[29] It is also considered to be safer and with fewer cardiac adverse effects than other macrolides (i.e., erythromycin and clarithromycin).

• Azithromycin, like other macrolides, can cause QTc prolongation and has been associated with torsades de pointes and polymorphic ventricular tachycardia.[30] In a large retrospective cohort study, azithromycin use correlated with a small but significant absolute increase in cardiovascular death as well as an increased risk of cardiovascular death relative to amoxicillin. These results were most pronounced among those patients with the highest baseline cardiovascular risk.[30] However, another large cohort study failed to detect an increased risk of death from cardiovascular causes in a population of young and middle-aged adults.[31] 

• Azithromycin is also rarely associated with hepatotoxicity, consisting mainly of hepatocellular injury within 1 to 3 weeks of medication use. Clinical features of hepatotoxicity include cholestatic jaundice and elevated transaminase concentrations.[32]

• Like other macrolides, gastrointestinal adverse effects such as nausea and diarrhea are commonly reported for azithromycin. All macrolides exhibit dose-dependent activation of intestinal motilin receptors, which stimulate gastric motility. (Clinicians widely prescribe erythromycin for the treatment of gastroparesis due to this mechanism.)[33]

• Life-threatening hypersensitivity reactions to azithromycin, such as anaphylaxis and Stevens-Johnson syndrome (SJS), are extremely unusual.[34][35] 

• Macrolides also correlate with the development of Clostridioides difficile infection, but to a lesser degree than other common antimicrobial classes (e.g., clindamycin, fluoroquinolones, and cephalosporins).[36][37][38]

Contraindications

• Azithromycin is contraindicated in patients with a history of severe hypersensitivity (e.g., anaphylaxis or SJS) to azithromycin or another macrolide antimicrobial. In addition, clinicians should be cautious regarding the concomitant use of azithromycin and other medications that prolong the QTc interval (e.g., antipsychotics).

• Azithromycin is contraindicated for patients taking the first-generation antipsychotic pimozide. Macrolide antimicrobials inhibit CYP3A4, the same cytochrome that metabolizes pimozide; concomitant use of azithromycin with pimozide can cause dangerous plasma concentrations of pimozide, leading to QTc prolongation and, potentially, lethal arrhythmias. While azithromycin is a poor inhibitor of CYP3A4 relative to other macrolides, avoidance of this interaction is still advisable.[39][40]

• Additionally, azithromycin is an inhibitor of p-glycoprotein/ABCB1, a cell membrane glycoprotein transporter. Drugs that are substrates of P-glycoprotein, particularly those that are also substrates of CYP3A4, may represent a relative contraindication to azithromycin. Examples include colchicine and small-molecule calcitonin gene-related peptide (CGRP) antagonists.[41][42]

• Azithromycin effectively preserves FEV and ameliorates bronchiolitis obliterans (BO) with no effect on overall survival in lung transplant patients; however, a study comparing azithromycin with placebo for the prevention of BO in hematopoietic stem cell transplant (HSCT) recipients demonstrated decreased BO-free and overall survival with azithromycin.[43] Hence, long-term azithromycin prophylaxis in HSCT recipients is inadvisable.

Most courses of treatment with azithromycin are short, and adverse effects requiring therapy adjustment or discontinuation of azithromycin are rare.[29] Azithromycin should be immediately discontinued if signs of hepatotoxicity develop (e.g., jaundice or elevated transaminases). For patients receiving long-term azithromycin prophylaxis (e.g., AIDS patients for MAC prophylaxis or lung transplant recipients for BO prophylaxis), many patients experience gastrointestinal adverse effects, especially at higher doses (e.g., 600 mg or 1200 mg). In these patients, reduction of the dose or twice-daily dosing may be a consideration.[44][45]

Azithromycin, like other macrolides, is associated with QTc prolongation. Particularly in patients with a known history of QTc interval perturbation, cardiac arrhythmia, or concomitant use of other medications associated with QTc prolongation, azithromycin can result in dangerous or potentially lethal arrhythmias such as torsades de pointes. In animal studies, although azithromycin was associated with similar QTc prolongation compared to other macrolides, azithromycin seemed to have a smaller proarrhythmic effect.[46]

While significant hepatoxicity resulting from azithromycin is relatively rare, macrolides are an established cause of mixed hepatocellular/cholestatic drug-induced liver injury. With prompt discontinuation of azithromycin, liver injury is almost always reversible with minimal residual impairment. Often, azithromycin-induced hepatotoxicity has associated immunoallergic features such as rash, fever, and eosinophilia. Severe forms of immunoallergic reaction, such as anaphylaxis, SJS, and drug reaction with eosinophilia and systemic symptoms (DRESS), are rare.[47]

Gastrointestinal toxicity is common but typically mild, and most patients complete the prescribed course of azithromycin. This toxicity stems largely from azithromycin’s activation of pro-motility receptors in the gastrointestinal tract.

Although azithromycin is a generally well-tolerated, efficacious antimicrobial agent, with many clinical indications, it is commonly inappropriately prescribed, particularly in the primary care setting. Several large retrospective cohort studies that demonstrated high levels of inappropriate antimicrobial prescribing overall singled out azithromycin as the most frequently misused drug.[48][49][50][51][52] [Level 1][Level 3]

Azithromycin is frequently prescribed when there is no clinical indication for antimicrobials and in many instances in which azithromycin is not first-line therapy (e.g., acute otitis media).[48][52] [Level 1][Level 3]

Azithromycin is a frequent antimicrobial therapy prescribed in situations in which a narrow-spectrum beta-lactam (e.g., amoxicillin) is the indicated first-line therapy (e.g., acute otitis media).[48] [Level 1] Increasing levels of resistance to azithromycin, particularly among S. pneumoniae isolates, make the widespread use of azithromycin for upper respiratory illness particularly concerning.[53][54] [Level 3] Broad-spectrum antimicrobial use for upper respiratory infection is also associated with increased rates of adverse effects compared with narrow-spectrum agents.[55] [Level 3]

One possible association with high rates of azithromycin prescription is patient-reported penicillin allergy.[56] [Level 1] Macrolides, particularly azithromycin, are preferred to beta-lactam drugs for many clinical indications. Researchers found 12.8% of patients in a large electronic medical records database to have a penicillin allergy listed in one large cohort.[57] [Level 3] Patients with a reported penicillin allergy are as much as four times more likely to be prescribed a macrolide antimicrobial.[56] [Level 1] However, a detailed history of a patient’s adverse reaction(s) to penicillin, paying close attention to features suggestive of IgE-mediated hypersensitivity (e.g., urticaria, anaphylaxis), is often sufficient to clarify, and possibly remove, a listing of penicillin allergy.[58] [Level 5] Patients with more concerning histories may be administered allergy testing or referred to an allergy specialist. Lastly, providers should be aware of the low cross-reactivity rates with cephalosporins—especially third- and higher-generation agents—and other beta-lactams in penicillin allergy.[59] [Level 1]

Healthcare professionals in many different roles can contribute to the appropriate use of azithromycin and all antimicrobial agents. MDs, DOs, NPs, and PAs should prescribe azithromycin judiciously and make use of available evidence and society guidelines. Clinicians working with and/or supervising non-physician prescribers should ensure that all prescriptions accord with evidence and guideline-based practice.[50] [Level 3] Additionally, patients requesting antimicrobial therapy when it is not necessary, or sharing concerns about drug allergies, should be provided with education and appropriate follow-up. Nurses can play an essential role in addressing patient questions and facilitating continuity of care. Pharmacists are an invaluable resource for helping providers select the most appropriate antimicrobial agent, dosing, and duration of treatment. They can also help providers and patients avoid interactions between azithromycin and other drugs that affect the QTc interval.

While azithromycin is a safe and effective antimicrobial drug, practitioners must take care to prescribe it appropriately. Not only does the appropriate choice of antimicrobial therapy enhance treatment and support public health, but it avoids placing patients at unnecessary risk of adverse effects.

Review Questions

1.

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