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   Table of Contents      
ARTICLE
Year : 1987  |  Volume : 35  |  Issue : 4  |  Page : 197-203

Oral Ketoconazole in Keratomycosis


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Date of Web Publication20-Dec-2008

Correspondence Address:
Philip A Thomas
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Source of Support: None, Conflict of Interest: None


PMID: 3506929

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  Abstract 

We treated 30 patients with Keratomycosis (11 with Aspergillus infections, 6 with Fusarium infections, 3 with Curvularia infections and 10 with infections caused by other fungi) with Ketoconazole administered orally. Progressive comeal ulceration stopped in 20 cases clinical evidence of corneal infection disappeared and post treatment visual acuities were better than pre-treatment visual acuities. 10 cases did not respond to therapy and developed progressive corneal ulceration, necessitating other measures The presence of deep lesions in all these 10 cases and the recovery of Aspergillus flaws or Fusarium from 9 of these cases appeared to influence non-responsiveness to therapy. There was no evidence of serious systemic or ocular toxicity in any of the patients.


How to cite this article:
Thomas PA, Kalavathy C M, Abraham D J, Rajasekaran J. Oral Ketoconazole in Keratomycosis. Indian J Ophthalmol 1987;35:197-203

How to cite this URL:
Thomas PA, Kalavathy C M, Abraham D J, Rajasekaran J. Oral Ketoconazole in Keratomycosis. Indian J Ophthalmol [serial online] 1987 [cited 2019 Sep 22];35:197-203. Available from: http://www.ijo.in/text.asp?1987/35/4/197/26180


  Introduction Top


The Management of fungal corneal ulcers is often protracted and frustrating due to lack of safe and effective antifungal agents that adequately penet­rate the ocular structures Antifungal agents ranging from the old iodides to the new imida­zoles have found widespread use in the therapy of fungal diseases in various parts of the body. However, only a limited number of these agents have been used for fungal corneal ulcers and even these have limitations Amphotericin B has a high degree of penetrability but can cause systemic as well as ocular toxicity, as shown in experimental studies . Natamycin is useful for superficial cor­neal ulcers caused by sensitive fungi but has poor intraocular penetration . Ketoconazole, a new antimycotic, imidazole derivative has been admi­nistered orally to treat human mycotic cases. This broad-spectrum antifungal agent has already proven to be safe and effective in human Kerato­mycosis. In animal experiments, this drug was well tolerated and it penetrated the ocular coats readily. In this study, clinical trials using oral ketoconazole have been performed on a larger number of cases of fungal corneal ulcers in the hope of providing more conclusive evidence of the efficacy of this drug in the therapy of human Keratomycosis.


  Materials and Methods Top


30 cases of fungal corneal ulcers seen at the cornea clinic of this Institute were studied. The diagnosis of Keratomycosis was established by clinical features, direct microscopic examination of material from the ulcer and culture of the material from the ulcer. Material was taken from the depth of the ulcer using a sterile knife. Part of this material was inoculated into Sabouraud's broth (Emmon's modification) for recovery of fungus, and into glucose broth for recovery of bacteria Multiple tubes of each medium were inoculated to rule out contamination. The Sabou­raud's broth was incubated at room temperature and glucose broth was incubated at37° C Material from the ulcer was also taken for microscopic examination in both unstained (10% KOH) and stained (Gram's and Giemsa) preparations. Material was also taken from the conjunctival sac of both eyes for microscopic examination and culture, in order to determine whether the fungus isolated was exogenous in origin or from the flora of the patient's conjunctiva In most cases, oral ketoconazole therapy was instituted on finding fungal hyphae or yeast cells in the material from the ulcer. In some of the cases, where direct microscopic examination was inconclusive, oral ketoconazole therapy was instituted only after the fungus was grown in culture.

Aetiological Agents Isolated

Bacteria and fungi were isolated in 8 cases while fungi alone were isolated in 20 cases In 2 cases, fungal hyphae were detected in the direct smear but repeated cultures failed to recover these organisms. The fungi were identified by standard methods; these fungi are tabulated in [Table 1].

In-vitro testing of the susceptibility of the isolated fungi to Ketoconazole was also performed Keto­conazole was incorporated into Sabouraud'sagar (Emmon's modification). A standard suspension (200 spores/ml.) of each fungus was inoculated onto the medium. If complete inhibition of growth occurred at a concentration of Ketocona­zole of less than 6 ug/ml, the fungus was said to be sensitive to ketoconazole.

Tests of statistical significance (the chi square test) were applied, wherever appropriate, to evalu­ate the significance of certain findings

Observations

The response of fungal comeal ulcers to keto­conazole is given in [Table 2]. 20 cases healed with oral ketoconazole therapy, 10 cases did not heal with oral ketoconazole therapy. The ulcer performed in 7 of these cases while keratoplasty was performed on the remaining.

The bacteria which were recovered along with fungi in 8 cases were Coagulase positive Staphy lococus, Pseudomonas Species and Micro­coccus.

The dosage was lowered in the case of younger patients No antibiotics were administered either topically or systemically. Only mydriatics and analgesics were given. Prior to the institution of therapy and on completion of therapy, serum was taken for the detection of the Serum Glutamate Oxalo-acetate Transaminase (SGOT) and Serum Glutamate Pyruvate Transaminase (SGPT) levels This was to monitor any possible cardiotoxicity or hepatotoxicity due to the drug. The patient was 3150 observed daily for any untoward side effects.

The patient's response to the drug was assessed clinically everyday by recording the vision staining with fluorescein and inspecting the size and depth of the ulcer and infiltration.

In this study, the treatment schedule of oral ketoconazole therapy was as follows:[Additional file 1]

16 cases presented with ulcers with deep lesions while 14 cases presented with ulcers with superfi­cial lesions The response to therapy is shown in [Table 3]. 16 cases presented with ulcers with deep lesions; 6 of these healed while 10 did not heal 14 cases presented with ulcers with superficial lesions. All of these healed The correlation between the presence of deep lesions or superfi­cial lesions and the response to therapy was highly significant (p < .001).

A correlation was sought between the duration of the ulcer and the response to therapy. This is shown in [Table 4]. 16 cases had had the ulcer for less than one weep in 11 of these, the ulcer healed while in 5 the ulcer did not heal 14 cases had the ulcer for more than a week here, 9 cases healed while 5 did not heal The correlation between the duration of the ulcer and the res­ponse to therapy was not significant (p > 0.1).

Another correlation sought was between a history of prior treatment and response to therapy. This is shown in [Table 5].

In 20 cases, the ulcer healed with oral ketoconazole therapy. Of these 18 had had prior treatment (9 with antibiotics, 3 with other antifungal agents and 6 with native medicines). In 10 cases, the ulcer did not heal with ketoconazole therapy. 9 of these had had prior treatment (7 with antibiotics and 2 with native medicines). Here also, the correlation between a history of prior treatment and the response to therapy was not significant (P > 0.1).

It was thought that there might be a correlation between the type of aetiologic agent isolated and the response to therapy. As far as the bacteria were concerned, no significant correlation was found [Table 6].

In 8 cases, there was associated bacterial infection; 5 of these healed and 3 did not heal In 22 cases, there was no associated bacterial infection; 15 of these healed while 7 did not heal. This correlation was not significant (P > 0.1). However, with regard to the aetiological fungi isolated, there were significant findings [Table 7].

20 cases responded to therapy, Aspergillus flaws was recovered in 3 of these patients, Curvilaria in 3 patients, Fusarium in two patients, Aspergillus fumigatus and other Aspergillus Species in 3 patients and Mucor in 2 patients. Candida, Clado­sponum, Penicillium, Beauveria and Trichosporon were recovered from one each of the patients whose ulcers healed In 10 cases, the ulcer did not heal with oral ketoconazole therapy. Aspergillus flavus was recovered in culture in 5 of these patients, Fusarium in 4 and Penicillium in 1. The correlation between the type of fungus and the response to therapy was significant (05 > P > .02), particularly with regard to Fusarium and Curvularia.

In-vitro sensitivity testing to Ketoconazole was performed on each of the fungi isolated. The correlation between in-vitro sensitivity and clinical response to ketoconazole is shown in [Table 8]

The fungi recovered from 16 cases were found to be sensitive by in-vitro senstivity testing In 15 of these 16 cases, the ulcer healed; in one case, the ulcer did not heal The fungi recovered from 12 cases were found to be not sensitive to ketocona­zole in vitro. In 3 of the 12 cases, the ulcer healed while in 9 of these cases, the ulcer did not heal No fungi were recovered in culture from 2 cases (whose ulcers healed with ketoconazole therapy). The correlation between the clinical response and in vitro sensitivity testing was highly significant (P < .001).

None of the patients reported adverse effects to the drug nor was there any significant rise in the Serum Glutamate Oxalo-acetate Transaminase (SGOT) or Serum Glutamate Pynuate Transa­minase (SGPT) levels.


  Discussion Top


Fungal comeal ulcers are often difficult to treat because of three important problems:- The limited selection of antifungalagents available, the poor intraocular penetration of many of the agents and the systemic and ocular toxicity of these agents.

Amphotericin B produces much ocular toxicity; Pimaricin has very poor intraocular penetration. Jones suggested that the imidazole antifungal agents, like miconazole, might be useful in keratomycosis because they were not toxic, capable of intraocular penetration and had a broad range of antifungal activity. Ketoconazole is one such imidazole derivative (R41400). It has been administered orally in the treatment of fungal infections of the skin and mucous memb­ranes with success.In vivo data in animals suggest that orally administered ketoconazole penetrates the cornea extremely well. This mode of administration of ketoconazole is useful in the treatment of certain types of experimental kerato­mycoses. Reports of clinical trials with orally administered ketoconazole are conflicting with regard to its usefulness in human ketato­mycoses. We felt therefore, that a clinical trial on a large number of cases would be helpful.

In this clinical trial on 30 cases with keratomy cosec, 20 cases showed complete healing of their ulcer after oral ketoconazole therapy, while 10 cases did not respond to this drug. The response to treatment appeared to be independent of variable such as duration of the ulcer, history of prior treatment or associated bacterial infection. The two variables which apparently influenced the response to therapy were : the presence of deep lesions and the aetiological fungi isolated The response of ulcers with superficial lesions only was significantly better than that of ulcers with deep lesions In addition to this, the ulcers from which curvularia was isolated appeared to heal well, whereas those from which Fusarium was isolated appeared not responsive (except in two cases which healed very slowly). The response of the ulcers from which Aspergillus flavus was isolated was variable. Other types of fungi were isolated in small numbers so that no comment can be made regarding these The in-vitro findings correlate well with the clinical response with regard to fungi like Aspergillus Flavus, Fusarium and Curvularia. Oral ketoconazole therapy thus appears to be very useful in treating fungal corneal ulcers without deep lesions and ulcers which are caused by fungi like Curvularia Its usefulness appears limited in the treatment of fungal corneal ulcers with deep lesions and in those caused by Fusarium and Aspergillus Flavus. These preliminary findings need to be substanti­ated by clinical trials on a larger number of patients, and using more intensive therapy with local and Intravenous ketoconazole- However, ketoconazole administered orally appears to be a safe and effective therapy for keratomycosis.[Figure 1],[Figure 2],[Figure 3],[Figure 4],[Figure 5],[Figure 6]


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]


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