Agarwal et al1 report the results of a study that has relevance in the Indian scenario of infectious keratitis. Their data confirms the findings of previous studies that filamentous fungi cause most of the mycotic corneal infections in India. Since in-vitro antifungal sensitivity studies are difficult to perform and the results correlate poorly with in-vivo efficacy, and clinical data is welcome.
While we congratulate the authors on their study, we would appreciate it if the following points could be clarified. A 1% solution indicates a dilution of 1 gram of the drug in 100 ml of solution (10 mg/ml). The authors used a 1 mg/ml solution of itraconazole, which constitutes a 0.1% solution, although the study repeatedly mentions the dosage as 1%. The study is described as a randomized, crossover design. Since the authors also indicate that patients with superficial keratitis were assigned to the topical therapy arm of the study, it is not clear how and when randomisation was performed. The crossover aspect of the study is also not mentioned in detail.
The stated purpose of the study is to evaluate the efficacy of topical and systemic itraconazole and this is reflected in the study methods. However, in the results the authors state that itraconazole is useful, when used either topically or systemically, although no patients received only oral itraconazole. In their support of itraconazole therapy, the authors mention in the discussion that ’patients presenting for the first time showed marginally faster and greater improvements’. They therefore suggest that ’initial treatment with itraconazole has greater efficacy’. Their data however, indicate that 16 of 22 (72.7%) patients in Group 1 (new patients) and 26 of 32 (81.3%) in Group II (those already on treatment) improved with itraconazole therapy, and this does not support their conclusion. The authors also make the point that systemic itraconazole therapy is possibly better than natamycin, especially in deep infections caused by Fuasarium since penetration of itraconazole is better. Considering that all 4 Fuasarium infections in their study failed therapy, and 3 of these responded to the addition of topical natamycin therapy, the claim appears unjustified. Earlier studies have also indicated the poor inhibitory and fungicidal activities of itraconazole against Fusarium species when compared with natamycin.
Finally, although the study was conducted in two arms, one in patients with superficial keratitis and the other in those with presumably deeper keratitis, the analysis of results does not reflect the outcome in these 2 groups. Since currently available polyenes treat superficial keratitis efficiently, in the absence of the above data, it is difficult to support the authors’ claim that itraconazole has an extended in vitro spectrum against filamentous fungi like Aspergillus, compared to fluconazole and other imidazoles. It is possibly not as effective against filamentous fungi as natamycin. In our earlier study, we found topical fluconazole treatment to be ineffective when compared with natamycin.
Therefore, while we commend the authors on their results using itraconazole, we believe that further studies are required comparing its efficacy with existing antifungal agents, before propagating its use as a first-line drug in the treatment of infectious keratitis.
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Conflict of Interest:
1. Agarwal PK, Roy P, Das A, Banerjee A, Maity PK, Banerjee AR. Efficacy of topical and stystemic itraconazole as a broad-spectrum antifungal agent in mycotic corneal ulcer. A preliminary study Indian J Ophthalmol. 2001;49:173–76
2. Reuben A, Anaissie E, Nelson PE, Hashem R, Legrand C, Ho DH, Brodey GP. Antifungal susceptibilities of 44 clinical isolates of Fusarium species determined by using a broth microdilution method Antimicrob Agents Chemother. 1989;33:1647–49
3. Rotowa NA, Shadomy HJ, Shadomy S. In vitro activities of polyene and imidazole antifungal agents against unusual opportunistic fungal pathogens Mycoses. 1990;33:203–11
4. Rao SK, Madhavan HN, Rao G, Padmanabhan P. Fluconazole in filamentous fungal keratitis (letter) Cornea. 1997;16:700