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   Table of Contents      
ORIGINAL ARTICLE
Year : 2001  |  Volume : 49  |  Issue : 3  |  Page : 173-176

Efficacy of topical and systemic itraconazole as a broad-spectrum antifungal agent in mycotic corneal ulcer. A preliminary study


1 MBBS. Regional Institute of Ophthalmology, Medical College, Calcutta, India
2 MS. Regional Institute of Ophthalmology, Medical College, Calcutta, India
3 MD. Regional Institute of Ophthalmology, Medical College, Calcutta, India
4 MD,MNAMS,FRCS. Regional Institute of Ophthalmology, Medical College, Calcutta, India

Correspondence Address:
Pankaj K. Agarwal
MBBS. Regional Institute of Ophthalmology, Medical College, Calcutta, India

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Source of Support: None, Conflict of Interest: None


PMID: 15887725

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  Abstract 

Purpose: To evaluate the efficacy of topical (1%) and systemic itraconazole against common fungi such as Aspergillus and other filamentous fungi that cause mycotic corneal ulcer.
Methods: A prospective randomised, controlled study was done in 54 clinically suspected cases of fungal keratitis of which 44 were culture proven. Half the cases (n=27) with superficial involvement were treated with only topical itraconazole (1%) and the other half were treated with both topical and systemic itraconazole.
Results:Aspergillus, Penicillium and Fusarium were the most common fungi isolated. The ulcer resolved in 42 eyes (77%) and 12 eyes (23%) did not respond well to treatment. Four of 12 non-responding eyes were caused by Fusarium species.
Conclusion: Itraconazole, given either topically or systemically, is effective in treating mycotic corneal ulcers.

Keywords: Mycotic keratitis, itraconazole, natamycin, fluconazole.


How to cite this article:
Agarwal PK, Roy P, Das A, Banerjee A, Maity PK, Banerjee AR. Efficacy of topical and systemic itraconazole as a broad-spectrum antifungal agent in mycotic corneal ulcer. A preliminary study. Indian J Ophthalmol 2001;49:173-6

How to cite this URL:
Agarwal PK, Roy P, Das A, Banerjee A, Maity PK, Banerjee AR. Efficacy of topical and systemic itraconazole as a broad-spectrum antifungal agent in mycotic corneal ulcer. A preliminary study. Indian J Ophthalmol [serial online] 2001 [cited 2019 Nov 17];49:173-6. Available from: http://www.ijo.in/text.asp?2001/49/3/173/22631

FIGURES WITHIN THE PARANTHESIS INDICATE PERCENTAGE. T - TOPICAL ; S+T - SYSTEMIC AND TOPICAL

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FIGURES WITHIN THE PARANTHESIS INDICATE PERCENTAGE. T - TOPICAL ; S+T - SYSTEMIC AND TOPICAL

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A corneal ulcer is a break in the epithelium with underlying stromal necrosis.[1] Fungal corneal ulcers account for large number of cases. At least 70 genera of fungi have been associated with keratomycosis. Both Aspergillus and Fusarium species are reported from all over the world. [2, 3] Septate filamentous fungi are the most frequent causative agents in mycotic corneal infections, particularly following trauma with vegetable matter. While the distinctive clinical features of infectious keratitis lead to strong suspicion, it is not possible to absolutely identify the agents of infection.[4] In order to make a specific diagnosis and to institute appropriate treatment it is necessary to subject to the case meticulous laboratory investigation. This includes microscopy and culture of corneal scrappings. But this is neither possible nor practical in an outpatient setting in every case. Because the ulcer occurs on the exterior surface of the avascular structure like cornea, direct application of topical antifungals has become the most accepted mode of treatment. Systemic antifungals could possibly present deeper progression of keratitis.

In systemic mycoses, in-vitro antifungal sensitivity often greatly differs from in-vivo efficacy. But such drug sensitivity results should corroborate in cases of corneal ulcers because the drugs act directly unmodified by host and the host defense system.[5] Due to limited efficacy and paucity of commercially formulated ophthalmic antifungal medications, most topical medications used for treatment of mycotic keratitis are custom-formulated from parenteral antifungal medication. In this study our aim was to test the efficacy of topical and oral itraconazole against mycotic keratitis both as initial treatment, and also in failed cases that had been treated with other antifungal agents.

Itraconazole, a member of the triazole group of antifungal agents, has a broad spectrum of activity. There is indirect evidence that it has greater efficacy against filamentous fungi, particularly Aspergillus fumigatus, one of the common fungal causative agents in the India. Itraconazole shows a much higher affinity in vitro for cytochrome P450 than either fluconazole or miconazole.[3]


  Materials and Methods Top


A randomized, two-period crossover institutional study was conducted at Regional Institute of Ophthalmology (RIO), Calcutta in collaboration with the Department of Mycology, School of Tropical Medicine, Calcutta. This study was approved by the Institutional Review Board (IRB) and informed consent was obtained from all patients recruited to the study. The study period was June, 1999 to September, 2000. Clinically suspected cases of fungal corneal ulcers were selected for study. The patients were divided into two groups. Group-I (n=22) comprised new patients and Group-II (n=32) consisted of patients who had already received treatment with another agent (topical natamycin, topical natamycin and systemic fluconazole, or topical and systemic fluconazole).

After obtaining a proper history regarding the events leading to ulcers, a complete ocular examination was done. This included slitlamp examination of cornea, fluorescein staining of cornea, applanation or digital pressure of the eye as much as possible, and syringing to determine for patency of the nasolacrimal duct. The visual acuity was recorded in all cases, and fundus evaluation where possible. Scraping of the corneal ulcer was done at multiple areas using a sterile Bard-Parker blade no. 15 under topical 4% lidocaine anaesthesia. Scrapings were collected under direct visualisation through the slitlamp. The multiple scrapings were processed both for microscopy and culture. To prepare the potassium hydroxide (KOH) mount, the corneal scraping was first transferred on to a clean slide. One or two drops of 10% KOH containing 1% glycerol were added over the smear and a coverslip was placed over it. Sabouraud's dextrose agar (SDA) with chloramphenicol was used for fungus culture. The scrapings were also subjected to Gram stain, Giemsa stain and culture in blood and chocolate agar for bacteria.

A 1% suspension of itraconazole was indigenously prepared by mixing 100 mg of itraconazole powder with 100 ml of artificial tear solution under sterile conditions.

Of 54 patients, 27 (50%) with superficial keratitis were treated with only topical itraconazole (1%); other patients were treated with both oral Itraconazole (100 mg twice daily for 3 weeks) and topical iatraconazole every hour. Cycloplegics were used in all cases. Antiglaucoma therapy was given in cases suspected to have raised IOP. Antibacterials (topical ciprofloxacin) were applied in all cases at the beginning of treatment. This was discontinued once the fungal aetiology was confirmed. After three weeks, oral itraconazole was discontinued, but topical 1% itraconazole was continued for 6 weeks after keratitis was resolved. The baseline factors evaluated to assess the response to treatment were: 1) degree of congestion, 2) height of hypopyon, 3) healing of ulcers and 4) visual acuity. Patients were examined daily in the first week and then weekly thereafter. The therapeutic efficacy was graded on a 4-point scale. Eyes with a score of grade I had least dense corneal opacity and best visual recovery and grade 4 eyes had the most dense corneal opacity and least visual recovery. Patients were followed up for 6 months.


  Results Top


Most patients were male (68.5%) and half the patients (49.9%) were between 21-40 years. Majority (85.2%) came from rural areas; 72.2% had history of trauma or a corneal foreign body. The central cornea was affected in 92.5% cases and in 85.2% cases hypopyon was present at the time of initial examination. Culture was positive on 81.5% cases and half of them showed Aspergillus species. The patient characteristics are shown in [Table - 1]. Of 54 cases treated with topical or combined systemic and topical itraconazole, 42 (77.78%) cases responded, 16 (29.63) in Group-I and 26 (48.15) in Group-II [Table - 2]. 12 (22.22%) cases did not respond.

Of 42 patients who respond favourably to treatment the ocular findings were as follows: Grade I residual corneal opacity and improvement in vision by 3 lines - 6 patients (11.11%); Grade II residual corneal opacity and improvement in vision by 2 lines - 10 patients (18.5%); Grade III residual corneal opacity and improvement in vision by one line - 20 patients (37.04%); and Grade IV residual corneal opacity with minimal improvement in vision - 6 patients (11.11%). penetrating keratoplasty was done in the last group of patients.

Out of the 12 (22.22%) patients (6 in each group) who did not respond, 4 had Fusarium spp infection. They were treated with topical natamycin and systemic itraconazole. Three of 4 eyes responded and visual acuity improved to 6/60. One patient developed panophthalmitis; this eye had no light perception and hence evisceration was done. In 8 (14.8%) patients, early therapeutic grafts were done. The antifungal (topical and systemic) agents were continued after keratoplasty. Most eyes were quiet in six weeks. The mild side effects noted with topical Itraconazole included 1) corneal oedema in 2 (3.71%) cases, 2) increased IOP in 2 (3.71%) cases, and 3) prolonged conjunctival congestion in 4 (7.4%) cases. No significant side effects were noted in any of the patients with oral iatroconazole.


  Discussion Top


Mycotic corneal ulcer is a major cause of corneal blindness in most developing countries including India[6]. The incidence is reported as 82.3% in North India [7, 8] and 46.1% in South India. [9, 10] The reported incidence of mycotic keratitis in Eastern[11] and Western[12] regions of India is 32% and 38.9% respectively.

Aspergillus spp. is the organism most commonly responsible for fungal keratitis worldwide.[13] In India the most common isolates are Aspergillus sp. (27-64%) followed by Fusarium (6-32%), Penicillium (2-29%), and a number of other rare organisms. [14, 15]

The present study showed that:



  1. 1. Aspergillus is the most common causative organism for fungal keratitis in our setting.


  2. 2. It is most common among the younger age group (21-40 years), and among male agriculturists.


  3. 3. It is commonly caused by foreign body mainly vegetable particles, and use of corticosteroid.


  4. 4. The ulcer is typically central and varies in depth and size depending upon the time of presentation, and patients most commonly presented late with hypopyon.


  5. 5. The primary criterion to indicate therapeutic efficacy of itraconazole was healing of the corneal ulcer within 6 weeks. Based on all the parameters used in the study including residual corneal opacity and best corrected visual acuity, patients in each group showed comparable improvement. Patients presenting for the first time showed marginally faster and greater improvement. This suggests that initial treatment with itraconazole has greater efficacy.




Currently available antifungal preparations such as fluconazole and natamycin often fail to cure many fungal corneal ulcers.[5] Topical and systemic fluconazole are not very effective against Aspergillus spp.[2] These agents are better than itraconazole in Candida infection, relatively rare in our surrounding. Topical natamycin is effective against Aspergillus and other filamentous fungi. However, it is available only in topical form, and unfortunately does not have good ocular penetration. It is therefore beneficial in superficial mycoses.[16] On the other hand, Fusarium has a tendency to invade the eye deeper,[17] so systemic itraconazole could be more useful in such situations.

Itraconazole is a broad-spectrum triazole antifungal with a high degree of efficacy against Aspergillus and other filamentous fungi. A definite, broad spectrum, nontoxic role of itraconazole as an empirical first-line treatment of fungal corneal ulcer was observed in 77% patients in our study. Topical itraconazole is not yet available in the market. So 1% topical itraconazole[18] was prepared in our laboratory and used to treat corneal ulcer along with systemic itraconazole.

Human clinical trial[19] and experimental evidences[20] have shown the efficacy of itraconazole in mycotic corneal ulcer. In a study of 40 patients receiving oral itraconazole (200 mg once daily), an 80% cure rate was achieved in Aspergillus keratitis. No significant complication of topical 1% itraconazole was observed during the trial.

This preliminary study indicates an immediate need for topical 1% itraconazole ophthalmic solution, as a first-line broad spectrum antifungal in our setting, together with initial loading dose of systemic itraconazole. Further studies on spore inhibition, and the relative efficacy of topical and systemic drugs are needed. Availability of injectable forms of itraconazole for subconjunctival and intravitreal application will be an added advantage.

While no significant local and systemic toxicity was noted of the drug in the trial, it must be noted that the trial was conducted using an indigenously made topical preparation without standardization, dilution and ideal solvent. The other weakness of the study was the small sample size; hence statistical analysis was not possible.



 
  References Top

1.
Reddy M, Sharma S, Rao GN. Corneal ulcer. In : Dutta LC, editor. Modern Ophthalmology. New Delhi : Jaypee Brothers Medical Publishers (P) Ltd.; 2000. Vol 1, pp 200-209.  Back to cited text no. 1
    
2.
Bennett JE. Diagnosis and treatment of fungal infections. In : Fauci AS, Braunwald E, Isselbacher KJ, Wilson JD, Martin IB, Kasper DL, et al, editors. Harrison's Principles of Internal Medicine. 14th ed. New York : McGraw - Hill; 1998, Vol 1, pp 1148-54.  Back to cited text no. 2
    
3.
O'Day DM. Fungal keratitis. In : Pepose JS, Holland GN, Wilhelmus KR, editors. Ocular Infections and Immunity. St. Louis : Mosby; 1996, pp 1048-58.  Back to cited text no. 3
    
4.
Arffa RC. Grayson's Diseases of the Cornea, 4th ed. St. Louis : Mosby; 1997. pp 263-64.  Back to cited text no. 4
    
5.
Jones RN, Pfaller MA, Lormican MG. Infectious Diseases (bacterial and fungal): Principles & practice of antimicrobial therapy. In : Trevor MS Holford NHG. Editors. Avery's Drug treatment. 4th ed. Sydney : Adis International. 1997. pp 1501-505.  Back to cited text no. 5
    
6.
World Health Organisation. Report of Inter-regional meeting on control of corneal blindness within primary health care systems. Geneva: WHO. November, 1988.  Back to cited text no. 6
    
7.
Chander J, Sharma A. Prevalence of fungal corneal ulcers in Northern India. Infection 1994;22:207-9.  Back to cited text no. 7
[PUBMED]  [FULLTEXT]  
8.
Grover S. Jagiap P, Sharma KD. Mycotic keratitis.Indian J Ophthalmol 1975;23:7-10.  Back to cited text no. 8
    
9.
Kotigadde S, Ballal M, Jyothirlatha, Kumar A, Rao SPN, Shivananda PG. Mycotic keratitis: A study in coastal Karnataka. Indian J Ophthalmol 1992;40:31-33.  Back to cited text no. 9
    
10.
Pankajalakshmi V, Taralakshmi V, Gomathi A, Ramakrishan ES, Illavarasi S. Mycotic keratitis in Madras. Indian J Pathol Microbiol 1989;32:190-97.  Back to cited text no. 10
    
11.
Dutta LC, Dutta D, Mohanty P, Sharma J. Study of fungal keratitis. Indian J Ophthalmol 1981;29:407-40.  Back to cited text no. 11
    
12.
Varenkar MP, Borkar Shubhangi, Pinto MJM, Naik PA. Study of mycotic keratitis in Goa. Indian J Med Microbiol 1998;16:58-60.  Back to cited text no. 12
    
13.
Foster CS. Fungal keratitis. Infect Dis Clin North Am 1992;6:851-57.  Back to cited text no. 13
[PUBMED]  [FULLTEXT]  
14.
Srinivasan R, Kanungo R, Goyal Jt. Spectrum of oculomycosis in South India. Acta Ophthalmol (Copenh) 1991;69:744.  Back to cited text no. 14
    
15.
Sundaram BM, Badrinath S. Study on mycotic keratitis. Mycoses 1989;32:568-72.  Back to cited text no. 15
    
16.
Mauger TF, Graig EL. Havener's Ocular Pharmacology. 6th ed. St. Louis: Mosby; 1994. pp 318-21.  Back to cited text no. 16
    
17.
Abad JC, Foster CS. Fungal keratitis. In: Albert DM, Jakobiec FA. editors. Principles and Practice of Ophthalmology. 2nd ed. Philadelphia : W.B. Saunders Company; 2000. Vol 2, pp 908-13.  Back to cited text no. 17
    
18.
Mcleod S. Fungal keratitis. In : Yanoff M, Duker JS. editors. Ophthalmology. Mosby; St Louis: 1999. pp 10.1-10.3.  Back to cited text no. 18
    
19.
Thomas PA, Abraham DJ, Kalavathy CM, Rajasekaran J. Oral Itraconozole therapy for mycotic keratitis. Mycoses 1988;31:271-79.  Back to cited text no. 19
[PUBMED]  [FULLTEXT]  
20.
Savani DV, Perfect JR, Cebo M, Durack DT: Penetration of new azole compounds into the eye and efficacy in experimental Candida endophthalmitis. Antimicrob Ag Chemother 1987;31:6.  Back to cited text no. 20
    



 
 
    Tables

  [Table - 1], [Table - 2]


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