Ocular infections present an interesting challenge for the clinician. Cultures may not be obtained routinely, and treatment is often prescribed empirically driving the choice of antimicrobial agent.

When choosing an antibiotic, ophthalmologists should consider the spectrum of activity against the most likely pathogens as well as the safety of the agent and how quickly the patient can expect to benefit. The direct topical application of ophthalmic formulations allows for higher local concentrations of the antibiotic than may be achievable through systemic administration. Effective treatment of an ocular infection depends on patient compliance with the medication.

Macrolide antibiotics are ordinarily used to treat upper respiratory infections. Common pathogens found in these infections include Haemophilus species, staphylococcal and streptococcal organisms. These pathogens typically cause ocular infections. Macrolide antibiotics achieve high concentrations intracellularly, thus atypical bacterial species are also generally quite susceptible.

Azithromycin is a member of the azalide sub-class of macrolides and is differentiated from erythromycin by its enhanced potency against gram-negative pathogens such as Haemophilus influenzae while maintaining similar levels of efficacy against gram-positive pathogens.The pharmacokinetic profile of azithromycin is also quite different from erythromycin, having a higher affinity for tissues and a longer elimination time.

Ophthalmic formulation

In an ophthalmic formulation of azithromycin, the high bioavailability in target tissues such as the conjunctiva and cornea enables microbial eradication not only of susceptible pathogens but also of bacterial strains that would be considered “resistant” at concentrations achievable with systemic delivery. Challenges in developing the ophthalmic formulation — specifically the instability in aqueous solutions and heat instability — were addressed by utilizing a vehicle (DuraSite, InSite Vision) that enabled a stable suspension of azithromycin and further enhanced the bioavailability. Safety and efficacy studies indicated a relatively low incidence of ocular adverse events with an efficacy profile similar to other recently developed ophthalmic antibiotic formulations.

One aspect of macrolide antibiotics that is pertinent to ophthalmology is their anti-inflammatory and immunomodulatory effects. These effects have been well characterized in laboratories and in human respiratory diseases such as cystic fibrosis and community acquired pneumonia. These effects include immunomodulation (a reduction in the hyperimmune response without overt immunosuppression) through a reduction in inflammatory cell infiltration. Other anti-inflammatory effects may be achieved through decreased levels of inflammatory mediators including cytokines, chemokines and adhesion molecules.

Distinguishing characteristics

A distinguishing characteristic of macrolide antibiotics is the distribution and pharmacokinetic profile of the antibiotics in target tissues. Tissue concentrations exceed serum concentrations by as much as 100-fold following a single 500-mg oral dose of azithromycin. Macrophages and polymorphonuclear leukocytes concentrate azithromycin at levels greater than those found in tissues themselves. Particularly with azithromycin, these “tissue-directed antibiotics” have been shown to rapidly transition from fluids to intracellular compartments, especially in phagocytic cells such as polymorphonuclear neutrophils. This attribute may assist in the targeting of drug retention in infected and inflamed tissues.

Animal studies have verified that the accumulation of azithromycin occurs in ocular tissues. The pharmacokinetics of azithromycin in ocular tissues (conjunctiva, cornea and lid tissue) after instillation of the ophthalmic formulation on the ocular surface indicates a rapid distribution out of fluids and into the tissue compartments. A human study confirmed this differential profile through a comparison of the ocular distribution of azithromycin and moxifloxacin after topical instillation of ophthalmic formulations. Two studies have corroborated the anti-inflammatory and immunomodulatory properties of azithromycin in ocular tissue through the reduction of inflammatory cell migration and inflammatory mediator expression (cytokines, chemokines and matrix metalloproteinases). The ophthalmic formulation of azithromycin has also recently been shown to have an impact on staphylococcal biofilm formation, which may be a source of chronic ocular infection and inflammation.

In summary, the broad spectrum of coverage, high tissue concentrations, anti-inflammatory and immune-modulatory effects, and convenient dosing regimen in an enhanced delivery system achieved by topical azithromycin (AzaSite, Inspire Pharmaceuticals) make it an attractive and practical option.

According to the package insert, the most frequently reported ocular adverse event reported in clinical trials was eye irritation, which occurred in 1% to 2% of patients.

References:

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