Response to correspondence from Lichtenstein and Granet Re: Fluoroquinolones compared to 1% azithromycin in DuraSite^® for bacterial conjunctivitis

In our review of the development and efficacy of 1% azithromycin in DuraSite^® (AzaSite™, InSite Vision, Alameda, CA, USA) published in Clinical Ophthalmology (Friedlaender and Protzko 2007), we describe azithromycin as a well known anti-infective agent with pharmacokinetic properties that were not sufficiently exploited for topical use in the eye until the development of AzaSite. A sustained release ocular antibiotic, AzaSite delivers sufficiently high concentrations of azithromycin to the eye to eradicate common causative pathogens of bacterial conjunctivitis. The means by which azithromycin is delivered to the eye in the AzaSite formulation gives it much greater tissue concentrations than expected.

The DuraSite vehicle completely solubilizes azithromycin in a matrix that stays in contact with the ocular surface longer than conventional aqueous drops. A full course of therapy of AzaSite for bacterial conjunctivitis requires only 9 drops. Drs Lichtenstein and Granet (2007) suggest that this is a potential concern for the development of drug resistance and it is also the reason why the US Food and Drug Administration (FDA) places a warning about skipping doses on the package insert.

We would like to point out that, regardless of the anti-infective used, the misuse of an antibiotic – including failure to complete therapy, skipping doses, or reuse of leftover antibiotic – may expose patients to the development of bacterial resistance. Warnings of this nature appear on the patient information inserts for a variety of antibiotics, including Avelox^® (oral moxifloxacin). The guidance in the patient counseling section of AzaSite’s prescribing information is reflective of the FDA’s acknowledgement of widespread antibiotic misuse and new requirements for labeling.

Aside from these matters of newer packaging guidelines, the potential for the development of resistance with topical 1% azithromycin in DuraSite is minimized by its newer delivery method and by azithromycin’s affinity for tissue, resulting in high concentrations of drug in tears and conjunctiva. During the pivotal trials for 1% azithromycin in DuraSite, no indication of the development of resistance to azithromycin was observed. MICs of cultured bacteria did not increase during treatment with AzaSite. Furthermore, in the vehicle trial, AzaSite effectively eradicated 85% (23/27) of azithromycin-resistant pathogens.

Pivotal trials for AzaSite were conducted in patients with bacterial conjunctivitis, which commonly presents as a self-limited disease but may be severe in some cases. The value of drug intervention to eradicate bacteria and speed resolution of the signs and symptoms must be measured at an early phase in the disease process in order to assess the efficacy of treatment. We reject the suggestion that the high rate of clinical cure measured at day 6 in the AzaSite pivotal trial was related to the self-limited nature of the disease.

In support of this, we point out that a comparison of clinical cure (resolution of all signs and symptoms) achieved with moxifloxacin and azithromycin yields highly similar results at the end of a 5-day dosing period – and in both cases the rates are significantly better than with vehicle – refuting the notion that by day 6 clinical cure rates would have improved without intervention. AzaSite attained the same level of clinical cure as moxifloxacin with 50% fewer active drops. Patients in the phase 3 trials for moxifloxacin were dosed three times a day for 4 days. Compared to vehicle, the difference in the rate of clinical cure was significant at day 5 but not at the test-of-cure on day 9, when according to most clinical accounts the symptoms had begun to resolve on their own (Table 1). The rate of bacterial eradication (82%) was measured at day 9 in the moxifloxacin group, compared to 89% on Day 6 + 1 in the AzaSite trial.

Table 1.

Clinical cure of bacterial conjunctivitis in 0.5% moxifloxacin vs. vehicle in phase 3 clinical trial (FDA 2003)^*

	Cumulative	% Clinical cure		p value
	Drops; No.	Moxifloxacin	Vehicle
Day 3	9	27	15	0.0186
Day 5 (end-of- therapy)	15	66	51	0.0096†
Day 9 (test-of- cure)	15	83	74	0.0991

^*Notes: Data are from modified intent-to-treat population and includes all patients who met inclusion criteria, received treatment, had at least 1 follow up visit, and were culture-positive for bacteria on day 1;

^†p < 0.05.

Lack of susceptibility to fourth-generation fluoroquinolones in vitro was reported in the AzaSite clinical trials. Although the number of instances was small, more than 50% of these fluoroquinolone-resistant isolates were susceptible to AzaSite. Recent clinical and epidemiologic studies have also reported resistance to the new fourth-generation fluoroquinolones, including moxifloxacin. In addition to the findings in the AzaSite clinical trials, reports of 4th generation fluroquinolone resistant bacteria have been growing in number as reported in bacterial keratitis and following cataract surgery, and refractive surgery (Jhanji et al 2007; Mamalis 2007; Melo et al 2007; Ta and Sahm 2007).

Smart use of the appropriate antibiotic is the key to controlling the spread of resistance (CDC 2006). Fourth generation fluoroquinolones are powerful drugs, but declining in vitro susceptibility as measured over the past 5 years has important implications for their use in relatively mild infections such as uncomplicated conjunctivitis or chronic infections such as blepharitis (Miller et al 2006; Mamalis 2007). A systematic meta-analysis of antibiotic misuse by Kardas and colleagues (2005) concludes that patient education and simpler antibiotic regimens should be encouraged to promote responsible use of antibiotic therapy. Most antibacterial eye drops currently available require 3 to 8 doses daily for 7 to 10 days, a demanding dosing schedule that can result in missed doses and unfinished courses of therapy (Kernt et al 2005). AzaSite is recommended for dosing twice daily on the first two days of treatment, followed by once-daily dosing on days 3 through 7. In interviews of 141 patients, Kass and colleagues (1982) concluded that simplifying patient instruction and dosing schedules for eye drops would improve compliance. With twice-daily dosing for the first two days and simple once-daily dosing for the remainder of the treatment period, AzaSite simplifies the regimen normally associated with antibiotic eye drops.

A patient’s level of adherence to an appropriate anti-infective treatment regimen is a key variable in curing acute bacterial infections. Adherance can be difficult for some patients to maintain and even more difficult for healthcare providers to measure (Schwartz et al 2004). This was demonstrated in the comparative tolerability study by Dr. Granet and colleagues (2007). Their study comparing assessments of Vigamox and AzaSite in healthy patients was not fully masked, and highly dependent on subjective descriptions of tolerability. The introduction of investigator bias in this type of study cannot by ruled out.

Most potent eye drops are associated with some transient sensations when they are first instilled and it is incorrect to label these sensations as “adverse events”. Loss of vision, glaucoma, and allergic reactions would be considered “adverse events” by most standards. The symptoms categorized as “adverse events” by Granet and colleagues (2007), would not. In two much larger studies, which were double-masked, we described transient symptoms, such as burning, stinging, and itching which were not statistically different in the AzaSite and vehicle groups. Furthermore, these were double-masked studies in inflamed red eyes which should have been highly sensitive to irritants.

Once-daily dosing of eye drops has been associated with enhanced patient compliance, which minimizes the potential for the development of resistant organisms. As a result, short and convenient means of treating ocular infection is essential to improve compliance, outcome, and minimize the potential for the development of resistance.