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In a recent issue of Clinical Ophthalmology, Friedlaender and Protzko (2007) review the development and efficacy of 1% azithromycin in DuraSite® (AzaSite™, Inspire Pharmaceuticals, Inc., Durham, NC) for the treatment of bacterial conjunctivitis. The authors conclude that 1% azithromycin in DuraSite offers a simplified dosing regimen with sustained bactericidal levels that decrease resistance development. While 1% azithromycin in DuraSite is a new formulation of azithromycin that allows topical ocular use, azithromycin and DuraSite have been around for many years. Evidence demonstrates a greater potential for emerging resistance with azithromycin, an older drug, especially when formulated in a vehicle that prolongs low levels of antibiotic exposure over time.  Azithromycin is derived from the parent class of macrolides, known to be bacteriostatic. The ability of azithromycin to achieve high intracellular concentrations compared with other macrolides is credited for its bactericidal activity. However, in clinical practice, given the high level of Gram-positive resistance patterns, azithromycin demonstrates time-dependent, bacteriostatic kill against most bacteria within its clinical spectrum. DuraSite technology allows azithromycin to stay in contact with the ocular surface longer than conventional aqueous eye drops; a potential concern for resistance that led to a US Food and Drug Administration (FDA) warning on their package insert regarding missing doses: “Skipping doses or not completing the full course of therapy may … increase the likelihood that bacteria will develop resistance and will not be treatable by AzaSite (azithromycin ophthalmic solution) or other antibiotic drugs in the future.” (Azasite 2007). In contrast, potent, rapid-killing, broad-spectrum topical anti-infectives are less likely to promote resistance and do not carry such an FDA warning. Among these agents are the ophthalmic fourth-generation fluoroquinolones (FQs) that demonstrate concentration-dependent bactericidal kill and are not reliant on time as suggested by the authors.  The authors state that changing trends in the activity of newer-generation FQs demonstrate increased resistance among common bacterial conjunctivitis pathogens such as Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae. However, within the article, all 3 cited references (Goldstein et al 1999; Venezia et al 2001; Ambrose et al 2004) document resistance patterns in older-generation FQs instead of newer fourth-generation agents such as moxifloxacin 0.5% and gatifloxacin 0.3%. The distinction is critical. The development of resistance to older FQs develops through a single-step topoisomerase mutation (topoisomerase II or topoisomerase IV). However, resistance to newer FQs requires 2 spontaneous mutations at both topoisomerase II and topoisomerase IV and occurs much less frequently (Hwang 2004). In fact, in isolates of S. aureus, S. pneumoniae, and H. influenzae from conjunctivitis patients seen in a community practice setting, resistance to a fourth-generation agent, moxifloxacin, was not observed (Ohnsman et al 2007).  This study showed that only when combined with extra vehicle drops (likely containing preservative) for a total of 4 applications per day could 1% azithromycin in DuraSite (dosed twice daily for the first 2 days, then daily for 3 days) achieve a success profile similar to tobramycin dosed four times daily for 5 days. Since the clinical resolution rate of 1% azithromycin in DuraSite dosed in combination with 13 drops of vehicle (total of 20 drops) in the comparative tobramycin study was higher (79.9%) than reported in the comparative vehicle study (63.1%) with only 7 drops of azithromycin, it is probable that the numerous extra drops of vehicle created a washout effect or provided some antibacterial activity. In fact, given that the 2 arms of the study were performed simultaneously, the data indicate that without the 13 extra washout drops of vehicle, azithromycin would not have even reached equivalence to tobramycin.  Furthermore, a numerical advantage and statistical trend toward greater bacterial eradication with 0.3% tobramycin (94.3%) compared with 1% azithromycin in DuraSite (88.1%) (p = 0.073) was observed, although there was no overall difference in the rate of clinical resolution at the test-of-cure visit on Day 6 between agents; a finding we suggest may be related to the self-limiting nature of the disease. High failure rates of bacterial eradication (ie, resistant isolates of S. aureus and S. pneumoniae 50% and 40%, respectively) were observed as were lower rates of overall clinical resolution (70.6% and 85.5%, respectively) in all patients infected with azithromycin-resistant isolates.  Clinicians should consider the speed in which a therapy eradicates infection, the anticipated spectrum of activity, tolerability, compliance, and cost of therapy when choosing empiric antibiotic therapy. While 1% azithromycin in DuraSite offers the perceived advantage of fewer doses, equivalence to tobramycin was only reached by administering 1 drop of 1% azithromycin in DuraSite with 3 drops of vehicle (ie, 4 drops) in the eye each day, questioning the overall efficacy of a true once-daily regimen. Also disconcerting is this agent’s potential to select for resistant pathogens that can be transmitted to the fellow eye of the patient or to other close contacts as warned by the FDA in the package insert. Furthermore, less frequent dosing does not always translate into increased compliance. If a therapy is not tolerable, the benefit of less frequent dosing may not be realized. In a recently completed study, the fourth-generation FQ, moxifloxacin 0.5%, was found to be more comfortable, resulted in less blurring, and was preferred (84% to 16%) over 1% azithromycin in DuraSite (Granet et al 2007).  After reviewing the data from the authors presented in their article we must disagree that 1% azithromycin in DuraSite “appears more favorable than the currently available choices in the UK and US.” When clinicians consider all factors related to therapy (eg, bacterial resistance, blurriness, dosing compliance, and comfort) we suggest rapid-killing bactericidal agents such as ophthalmic fourth-generation fluoroquinolones are better options for the treatment of conjunctivitis.

clinical ophthalmology

Fluoroquinolones compared to 1% azithromycin in DuraSite&reg; for bacterial conjunctivitis [from Lichenstein and Granet] and Response to correspondence [from Friedlaender and Protzko] ||FREE PAPER||