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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 29  |  Issue : 3  |  Page : 601-605

Topical amphotericin B versus subconjunctival fluconazole injection in the management of fungal keratitis


1 Department of Ophthalmology, Faculty of Medicine, Menoufia University, Menoufia Governorate, Egypt
2 Department of Shebin El Kom Ophthalmology Hospital, Menoufia University, Menoufia Governorate, Egypt

Date of Submission14-Jan-2015
Date of Acceptance16-Apr-2015
Date of Web Publication23-Jan-2017

Correspondence Address:
Eman F Mottawea
Department of Shebin El Kom Ophthalmology Hospital, Menoufia University, Ahmed Abu Sena Street, Shebin El Kom, Menoufia, 32511
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.198726

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  Abstract 

Objectives
The aim of this study was to compare the use of topical amphotericin B (0.5 mg/ml) eye drops with the use of subconjunctival injection of fluconazole (2 mg/ml) in dealing with cases of fungal keratitis.
Background
Fungal keratitis is considered one of the serious ocular infections that lead to ocular morbidity and visual loss, especially in developing countries.
Materials and methods
This study was carried out on 50 eyes of 50 patients with resistant corneal ulcers attending Menoufia University Hospital outpatient clinic between July 2012 and February 2014.
Results
Group  1 included 25 cases treated with topical amphotericin B; the study revealed healing of corneal ulcers in six cases (24%), and 19 cases (76%) developed  complications. Group 2 included 25 cases treated with subconjunctival fluconazole injection; the study revealed statistically significant result (P < 0.01) of healing of corneal ulcers in 23 cases (92%), and in two cases (8%) complications developed.
Conclusion and recommendations
Fungal keratitis has proven to be a continually challenging ocular disease for patients, providers, and society. The most common etiologic agents have been identified to be diabetes and plant ocular trauma. Our study states that the administration of a subconjunctival injection of fluconazole was more effective compared with the administration of topical amphotericin B eye drops, as evidenced by the healing of the fungal corneal ulcer and shorter duration of healing.

Keywords: fungal keratitis, management of fungal keratitis, subconjunctival fluconazole injection, topical amphotericin B


How to cite this article:
El-Sayed SH, Wagdy FM, El-Hagaa AA, Mottawea EF. Topical amphotericin B versus subconjunctival fluconazole injection in the management of fungal keratitis. Menoufia Med J 2016;29:601-5

How to cite this URL:
El-Sayed SH, Wagdy FM, El-Hagaa AA, Mottawea EF. Topical amphotericin B versus subconjunctival fluconazole injection in the management of fungal keratitis. Menoufia Med J [serial online] 2016 [cited 2020 Oct 31];29:601-5. Available from: http://www.mmj.eg.net/text.asp?2016/29/3/601/198726


  Introduction Top


Fungal keratitis is considered one of the serious ocular infections that leads to ocular morbidity and visual loss, especially in developing countries. The clinically suspicious features of the presented cases of fungal keratitis are blurred vision, redness and pain, sensitivity to light, excessive discharge, and tearing. The fungal organism causing fungal keratitis is Aspergillus spp [1] .

The types of fungal species isolated in patients with microbial keratitis are as follows: [2]

Hyaline fungi

Fusarium solani , F. culmorum, Aspergillus flavus, A. fumigatus, A. terreus, A. niger, and other Aspergillus spp., Acremonium strictum, Scedosporium apiospermum, Clavulina humicola, Penicillium roqueforti, Phoma spp., and Rhizopus nigricans.

Molds dematiaceous fungi

Curvularia lunata , Curvularia spp., Bipolaris incurvata, Exserohilum rosratum, Cladosporium dominicanum, Lasiodiplodia theobromae, Alternaria alternata, Torula (Candida utilis), Aureobasidium pullutans, Nigrospora gallarum and Epicoccum spp.

Yeasts

Candida albicans and other Candida spp.

As soon as one is diagnosed with fungal keratitis, immediate theoretical therapy is required. The management of fungal keratitis represents a challenge for many ophthalmologists. Except for natamycin, ophthalmic antifungal agents are not commercially available in many countries, including Egypt. Topical fortified antifungal drops of the commercially available antifungal agents play an important role in the treatment of fungal keratitis cases [3] .

Amphotericin B is one of the broad-spectrum antifungal agents. It is generally effective topically for most cases of fungal keratitis [4] . It is used topically at a concentration of 0.05% in 5% dextrose (0.5 mg/ml) [5] . Fluconazole is an effective antifungal agent against most cases of fungal keratitis [6] .

Researchers  have suggested the use of antifungal agents through an ocular injection route in the form of either a subconjunctival injection of fluconazole or an intrastromal injection of voriconazole [7] . Subconjunctival use of fluconazole may potentiate the efficacy of this drug in the treatment of fungal keratitis and also increases the chance of least side effects and hazards for the cornea and conjunctival tissues [8] . Subconjunctival injection of fluconazole 2 mg/ml had the advantage of lower incidence of the complications of local use of amphotericin B and a broader spectrum of antifungal coverage [9] .

A detailed history and thorough clinical examination using the slit-lamp biomicroscope are important steps in the diagnosis of corneal ulcer. Although clinical signs may be insufficient to confirm infection, a break in the continuity of the epithelium associated with underlying stromal infiltrate should be considered infectious unless proved otherwise. Similarly, there are no distinctive or exclusive signs to identify the responsible organisms, but clinical experience and careful slit-lamp examination can point toward a probable etiological diagnosis in some cases [10] .

Fungal keratitis is usually characterized by a dry raised slough, stromal infiltrate with feathery edges, satellite lesions, and a thick endothelial exudate [10] .

Polyenes include natamycin, nystatin, and amphotericin B. Polyenes disrupt the cell by binding to fungal cell wall ergosterol and are effective against both filamentous and yeast forms. Amphotericin B is particularly effective against yeasts, but less effective against filamentous fungi; it is therefore the first agent of choice against yeasts [11] . Amphotericin B (0.15%) drops can be considered alone or in combination with natamycin in refractory cases; however, their penetration through an intact epithelium is less compared with natamycin [11] .

Azoles (imidazoles and triazoles) include ketoconazole, miconazole, fluconazole, itraconazole, econazole, and clotrimazole. Imidazoles and triazoles are synthetic chemical antifungal agents. Because of excellent penetration in ocular tissue, these medications, given systemically, are the preferred treatment of keratitis caused by filamentous fungi and yeast [12] .


  Materials and methods Top


A prospective  and follow-up study was conducted on 50 eyes of 50 patients with resistant corneal ulcers attending the outpatient clinic of Shebin El-Kom Ophthalmology Hospital between July 2012 and February 2014.

The patients were classified into two groups:   group 1 included 25 eyes treated with topical amphotericin B (fungizone) eye drops at a concentration of 0.5% in 5% dextrose (0.5 mg/ml), prepared from the commercially available 50 mg vial with 5% dextrose dilution to obtain the 0.05% concentration, used every 2 h.

For both groups, in addition to the use of antifungal agents, topical 1% ciclopentolate drops three times daily, 0.3% gatifloxacin eye drops five times daily in cases of negative bacterial results, specific antibacterial drops based on the sensitivity reaction of bacterial culture, and regular debridement of the ulcers using sharp corneal keratome (each 48 h) were included in the treatment. Group 2 included 25 eyes treated with 1 ml subconjunctival injection containing 0.5 ml of 2% lidocaine and 0.5 ml of fluconazole 2 ml prepared directly from the commercially available intravenous infusion from of fluconazole solution (diflucan) injected daily for 10 injections and each 48 h for another 10 injections.


  Results Top


The ages of patients in both groups ranged from 20 to 80 years, with a mean age of 45 years; 31 patients (62%) were under 45 years of age and 19 patients (33%) were older than 45 years of age ([Table 1]). As regards sex, 36 cases (62%) were male and 14 cases (28%) were female ([Table 1]).
Table 1 Number and percent distribution of the studied patients based on sociodemographic data


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The study revealed that 24 cases (48%) were diabetic. [Table 2] shows significant statistical difference (P < 0.01) in the presence of diabetes in relation to developing fungal keratitis in both groups.
Table 2 Number and percent distribution of the studied patients based on diabetes mellitus as risk factor data


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On analyzing the occupation of the patients, it was found that 38 cases (76%) were farmers and 12 cases (24%) were from different occupations. A total of 38 patients complained of trauma with plant materials. No significant statistical difference was found in the origin of trauma in relation to developing fungal keratitis in both groups (P > 0.05) ([Table 3]).
Table 3 Number and percent distribution of the studied patients based on the origin of trauma data


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As regards group 1, which was treated with topical amphotericin B for 25 cases, the study revealed healing of corneal ulcers in six cases (24%), and 19 cases (76%) developed complications. There was significant statistical difference in  the effect of the treatment on fungal keratitis; 86.7% of eyes of group 2 patients treated with fluconazole healed compared with 40.0% of eyes of group 1 patients treated with amphotericin B (P < 0.01) ([Table 4]).

As regards group 2, which was treated with subconjunctival fluconazole injection for 25 cases, the study revealed statistically significant result (P < 0.01) of healing of corneal ulcers in 23 cases (92%) and two cases (8%) developed complications. There was significant difference between the two groups (before treatment) in terms of the ulcer size (P < 0.05) ([Table 4] and [Table 5]).
Table 4 Number and percent distribution of the studied patients based on the fate of ulcer


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Table 5 Mean and SD of the studied patients based on the size of ulcer before treatment


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  Discussion Top


The treatment of keratomycosis is a challenge for ophthalmologists because the clinical picture is the same in all cases, and also the antifungal agents are not always available in many countries [13] . Antifungal medications commonly used in ophthalmologic department include polyene (natamycin and amphotericin B) and azoles (ketoconazole, fluconazole, itraconazole, and miconazole) [14] . There are many factors that increase the risk of fungal keratitis. Mahdy et al. [15] conducted their study on 48 eyes and they found that 58% of cases presented a resistant corneal ulcer, 38% were diabetic, and 21% received organic trauma. This was in agreement with that reported by El-Gohary et al., [16] who postulated that diabetes, vegetable ocular trauma, and presence of pre-existing corneal ulcer are considered risk factors for keratomycosis. In our study, we found that the risk factors for fungal keratitis are diabetes and plant ocular trauma, 48% of cases were diabetic and 76% of cases had plant ocular trauma.   The present study conducted laboratory investigations to confirm the clinical diagnosis, similar to the work by Leibowitz [17] . Garg et al. [18] reported that laboratory diagnosis is highly superior to clinical diagnosis in the management of fungal keratitis. The present study reported that direct corneal smear revealed only 38% of cases with positive fungal results, but Sharma et al. [19] reported the sensitivity of gram staining for corneal smear as 61%. Moreover, Gopinathan et al. [20] reported a high percentage for gram staining (88%). The low sensitivity of direct microscopic examination in the present study may be due to deep penetration of fungi in the cornea, which was not detected in the scrapped material. However, the culture results in the present study were more promising than a direct gram staining smear, as it reported that 75% of cases presented positive culture results, in agreement with Nayak, [21] who reported 77.8%, and Al-Hussaini et al., [22] who reported 75%. The present study was performed to compare the use of topical amphotericin B eye drops with the use of subconjunctival fluconazole injection in the treatment of fungal keratitis. Our study revealed that subconjunctival use of fluconazole may potentiate the efficacy of this drug in the treatment of fungal keratitis and also increase the chance of least of side effects and hazards for the corneal and conjunctival tissues [8] . This is in agreement with that reported by Prakash et al., [9] who stated that subconjunctival injection of fluconazole 2 mg/ml had the advantage of lower incidence of complication on local use of amphotericin B and broader spectrum of antifungal coverage. Avunduk et al. [23] reported that fluconazole is also considered one of the safest and efficient drugs, especially when used as subconjunctival injection. The efficacy of subconjunctival use of fluconazole was more compared with oral use. Yilmaz and Maden [6] proved that subconjunctival fluconazole covers large spectrum of fungi. Isipradit [7] proved that subconjunctival fluconazole was more effective compared with topical use. Our study revealed higher percentage (92%) of healing of corneal ulcers in group 2, which was treated with subconjunctival fluconazole, compared with group 1, which was treated with topical amphotericin B (29%).

Patel and colleagues found that the majority of fungus are susceptible to amphotericin B, followed by fluconazole and ketoconazole. A total of 90 isolates (25 yeast and 65 filamentous fungi) were included. The drugs were added in serial double dilution to a medium containing yeast nitrogen base. The minimum inhibitory concentration was determined by inhibition of visible growth on the lowest concentration of drug containing media as compared with visible growth on drug-free media. Out of 25 yeast isolates, all were sensitive to amphotericin B, and 8 and 12% were resistant to fluconazole and ketoconazole, respectively. Out of 65 filamentous fungi, 3, 20, and 28% were resistant to amphotericin B, fluconazole, and ketoconazole, respectively. The emergence of antifungal resistance has made susceptibility testing important, and the applicability of in-vitro antifungal sensitivity testing directly correlates with clinical outcome [24] .


  Conclusion and recommendations Top


On the basis of the findings of the present study, we can conclude that, fungal keratitis has proven to be a continually challenging ocular disease for patients, providers, and society. The most common etiologic agents have been identified to be diabetes and plant ocular trauma. Our study states that the administration of a subconjunctival injection of fluconazole was more effective compared with the administration of topical amphotericin B eye drops, as evidenced by the healing of the fungal corneal ulcer and by the shorter duration of healing. Laboratory diagnosis should be started before treatment, which is important for early detection, management, and less complication of fungal keratitis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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Yilmaz S, Maden A. Severe fungal keratitis treated with subconjunctival fluconazole. Am J Ophthalmol 2005; 140 (3) :454-458.  Back to cited text no. 6
    
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Isipradit S. Efficacy of fluconazole subconjunctival injection as adjunctive therapy for severe recalcitrant fungal comeal ulcer. J Med Assoc Thai 2008; 91 :309-315.  Back to cited text no. 7
    
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Al-Hussaini AX, El-Shanawany A, Daef EA, Abd El-Latif MM. Topical clotimazole versus topical miconazole nitrate in the treatment of experimental keratomycosis. Bull Ophthalmol Soc Egypt 1997; 90 :809-812.  Back to cited text no. 13
    
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Mahdy RA, Nada WM, Wageh MM. Topical amphotericin B and subconjunctival injection of fluconazole (combination therapy) versus topical amphotericin B (monotherapy) in treatment of keratomycosis. J Ocul Pharmacol Ther 2010; 26 :281-285.  Back to cited text no. 15
    
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Sharma S, Kunimoto DY, Gopinathan U, Athmanathan S, Garg PR. Evaluation of corneal scrapping smear examination method in diagnosis of bacterial and fungal keratitis: a survey of 18 years of laboratory experience. Cornea 2002; 21 :643-647.  Back to cited text no. 19
    
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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