New Horizons in One of Ophthalmology's Challenges

Fungal Keratitis

Bozorgmehr Pouyeh; Anat Galor; Darlene Miller; Eduardo C Alfonso

Disclosures

Expert Rev Ophthalmol. 2011;6(5):529-540. 

In This Article

Medical Treatment

For decades, natamycin has been the first line of treatment for fungal keratitis. It is the only antifungal eye drop that is commercially available. Unfortunately, natamycin is not effective against Candida and its usage has been limited to superficial fungal keratitis caused by filamentous fungi. Natamycin is especially effective against Fusarium. In a controlled trial, 50 consecutive patients were treated with natamycin 5% eye drops hourly, followed by 50 consecutive patients treated with itraconazole 1% eye drops hourly. The primary efficacy criteria were the physician's judgment of clinical success, cure rate, and the rate of treatment failure. The study demonstrated that in the natamycin group, the outcome of patients with Fusarium keratitis was better than average (79 vs 71%), and that in the itraconazole group, the outcome was worse than average (44 vs 60%; p = 0.02).[47]

Since the US FDA approval of natamycin in the 1960s, many antifungal agents have been evaluated in experimental animal studies, case series and a few randomized controlled trials (RCTs) (Table 3).[48–56,103] In a systematic review in 2008, two independent reviewers included six RCTs and 369 participants overall to compare the treatment effect of itraconazole, miconazole, chlorhexidine, sulfdiazine, econazole or natamycin on fungal keratitis. The reviewers concluded that these trials had a small sample size, and based on current evidence, it is difficult to conclude which medication is the best and the most cost effective. They recommended that a large multicenter RCT would address this question.[57]

Recent studies suggested that voriconazole may be a good alternative to natamycin. First, susceptibility studies implied that voriconazole is not only active against filamentous fungi, but also against Candida (Table 3).[48,58] Second, voriconazole has a wide therapeutic window. The result of a toxicity study of voriconazole on rodents showed that voriconazole has no adverse effect on the retina of an animal model in concentrations as high as 25 µg/ml.[59] On the other hand, MIC90 (minimum inhibitory concentrations of medication that inhibits the growth of 90% of the fungus) of voriconazole is <0.5 µg/ml for many fungi, except the Fusarium species, which is 2.0–8.0 µg/ml.[56] In addition, the concentration of voriconazole in the human aqueous humor has been measured in a few studies.[60,61] If systemic and topical forms are administered together, the concentration is consistently ≥2.93, which is above the MIC90 of most fungi; however, when 1% eye drops are administered every hour, the concentration is highly variable (0.61–3.30).[60] Finally, a review of 40 case reports demonstrated that voriconazole is safe and effective against the major ocular fungal infections.[56]

To compare safety, efficacy and cost–effectiveness of voriconazole with natamycin, a double-blinded RCT was conducted in two hospitals in India in 2010. The design was superior to antecedent controlled trials (Table 4).

The study concluded that there is no significant difference between the two medications.[23] Natamycin is commercially available, and there is more experience with using it. Topical voriconazole is not commercially available; however, it has a wider antifungal coverage. Voriconazole may be the first choice in patients who have a higher risk for Candida keratitis but also require a good antifungal coverage against other species.

Treatment failure and subsequent surgical intervention in these RCTs ranged between 11 and 18% (Table 4).[23,62,63] In all of them, a single topical medication was used, and the medication was given by nurses in the hospital during the first week. By contrast, many retrospective case series in different parts of the world at different times have reported that 23–36% of patients require surgical intervention.[4,64,65] In these RCTs, there was no significant difference in the outcome using either natamycin, voriconazole or econazole, although the frequency of filamentous fungi species was different (e.g., frequency of Fusarium was 35–38% in one study and 54–60% in the other). A Cochrane systematic review could not conclude that any antifungal medication was superior to the other. In addition, in retrospective studies the type of medications used did not seem to influence the need for surgical intervention. In a retrospective case series of 330 patients, 69% of patients responded to ketoconazole, 66% to itraconazole, 53% to amphotericin B and 56% to natamycin.[66] Furthermore, a combination of antifungal therapy does not seem to be superior to single therapy.[67–69] In a retrospective case series, 358 patients were hospitalized and treated with topical 1% fluconazole combined with 0.25% amphotericin B or 5% natamycin drops every hour, alternating on the half hour. All patients were also treated with oral fluconazole. An antifungal ointment was applied to the scraped lesions during sleep. Some patients with hypopyon were given 100 mg fluconazole intravenously twice a day. However, 30% of the patients required surgical intervention.[70] By contrast, in a case series, 16% (two out of 12) of patients who were treated with intrastromal voriconazole required surgical intervention.[71] In two other different case series, overall, six patients were treated with intrastromal voriconaozle and, again, 16% (one out of six) did not respond to treatment.[72,73] Although it is difficult to compare the reported treatment failure in these RCTs (11–18%) with other retrospective case series (23–36%) and intrastromal injection of voriconazole (16%), these results suggest that the outcome of medical treatment may not be directly related to whether single or a combination of antifungal therapy is used, or whether it is given topically or systemically. What seems to be more important is to ensure that the concentration of the medication is always maintained above the MIC90 of the fungus – as is presumably achieved in these RCTs by administering the medication in the hospital by nurse or by intrastromal injection of voriconazole. One can conclude that adherence of patients to treatment is an important factor that influences the outcome, especially when the majority of fungal keratitis patients are working-class young males who must administer natamycin eye drops into an inflamed eye every hour during the day and every 2 h during the night. Adherence to treatment depends on the availability of the medication, its low cost, ease of use and side-effect profile. The patient needs to have a clear understanding of the duration of treatment and the likelihood of response.

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