Topical 5% Natamycin With Oral Ketoconazole in Filamentous Fungal Keratitis: A Randomized Controlled Trial

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1 ORIGINAL CLINICAL STUDY With Oral in Filamentous Fungal Keratitis: A Randomized Controlled Trial Revathi Rajaraman, MS,* Parameshwar Bhat, MS,* Vikram Vaidee, DNB,* Sowmyalatha Maskibail, MS,* Anita Raghavan, DO, FRCS,* Siddharthan Sivasubramaniam, DNB, FRCS,* and Venkatesh Prajna Namperumalsamy, DO, DNBÞ Purpose: To assess the role of additive oral antifungal therapy in deep keratitis caused by filamentous fungi. Design: A randomized, masked, double-blind clinical trial. Methods: All patients presenting with culture-positive fungal keratitis with a size measuring 2 to 60 mm 2 and involving more than 50% of stromal depth were enrolled in 1 of the 2 treatment arms. Group A received 5% natamycin, whereas Group B was given 200mg of oral ketoconazole twice a day in addition to 5% natamycin. Patients were followed up for 4 weeks. Liver function was assessed at baseline and at exit. Tests for significance included t test to compare the means of continuous variables, chi-square and Fisher s exact tests for comparing categorical variables and Kaplan-Meier procedure to estimate the survival rate. Results: Of the 115 patients enrolled, 108 completed the study. Fiftyeight patients were in group A and 57 in group B. There was no significant difference in baseline characteristics or in ulcer characteristics between the 2 groups. In group A, 68.5% of the patients responded favorably to medical therapy, whereas in group B, 72.2% responded favorably. There was no statistically significant difference in healing between the 2 groups (P = j0.618). All patients had normal liver functions during the study. Conclusions: Although safe, oral ketoconazole did not add significant benefit to topical natamycin therapy in treating deep fungal keratitis. The efficacy of newer antifungal agents and drug delivery routes needs to be explored. Key Words: fungal keratitis, filamentous fungi, clinical trial, medical therapy, ketoconazole (Asia Pac J Ophthalmol 2015;4: 146Y150) Keratitis caused by filamentous fungi is the most common type of suppurative corneal infection in tropical countries and is emerging as an important hazard globally. 1Y4 Filamentous fungi can affect healthy individuals. Once it enters an otherwise healthy cornea through a microabrasion, the proliferating hyphae can invade deeply even across an intact Descemet membrane. 5Y7 Failure to respond to topical medical therapy is common because most of the available antifungal agents penetrate the cornea poorly. Even when the superficial lesion shows signs of healing and scarring, a smoldering infection may still linger From the *Department of Cornea and Refractive Services, Aravind Eye Hospital, Coimbatore; and Department of Cornea and Refractive Services, Aravind Eye Hospital, Madurai, Tamil Nadu, India. Received for publication June 22, 2013; accepted December 30, The authors have no funding or conflicts of interest to declare. Reprints: Revathi Rajaraman, MS, Cornea and Refractive Surgery Services, Aravind Eye Hospital and Postgraduate Institute, Coimbatore, India. revathi@cbe.aravind.org. Copyright * 2014 by Asia Pacific Academy of Ophthalmology ISSN: DOI: /APO in the deeper cornea and anterior chamber. The efficacy of adding an oral antifungal agent with better aqueous penetration such as ketoconazole, itraconazole, or voriconazole to topical therapy has been studied for deep-seated fungal ulcers. 8Y11 In his report, Ishibashi 11 observed good response in 2 cases of fungal keratitis treated with oral ketoconazole only. However, Komadina et al 12 didnotfindagoodresponsetoketoconazole alone in an experimental rabbit model with Aspergillus keratitis and suggested an augmentation of response when combined with topical natamycin. Although Agarwal et al 13 carried out a randomized clinical trial to study the additive effect of oral itraconazole, only anecdotal reports were available about the usefulness of oral ketoconazole. 8,9,12 This randomized clinical trial was aimed to study the effectiveness of oral ketoconazole as an adjuvant to topical treatment of deep filamentous fungal keratitis. MATERIALS AND METHODS This was a randomized, double-masked clinical trial carried out in a tertiary eye care referral center in south India. During the study period from August 2009 to December 2010, a total of 404 cases of fungal keratitis were screened. Patients with culture-positive filamentous fungal keratitis with mid to deep stromal infiltrate who fulfilled the inclusion and exclusion criteria (Table 1) were enrolled after obtaining informed consent. Randomization was done based on a computer-generated list created using statistical software. The sample size was calculated based on the primary efficacy variable, which was the rate of favorable outcome to medical therapy. Based on literature reports and our clinical experience, the proportion of success rate in the active control arm was assumed to be 34%, and the proportion in the study arm was assumed to be 60%. A total of 96 patients with 48 patients in each group were needed to test at 5% level of significance with a power of 90%. A sample size of 115 subjects was chosen, taking into consideration a 20% loss to follow-up. All patients presenting with a corneal ulcer underwent a detailed history and clinical examination, with details being noted in a structured questionnaire. The ulcer characteristics were recorded as schematic diagrams with measurements. The sizes of the epithelial defect and stromal infiltration were measured using Haag-Streit 900 slit-lamp biomicroscope by aligning the slit beam to the largest diameter and the diameter perpendicular to the first 1 and that of hypopyon at its highest point. The microbiologic work-up included scraping the ulcer by a platinum spatula and plating the material on blood agar and chocolate agar incubated at 37-C, as well as potato dextrose agar slopes kept at 25-C. Smears were examined in 10% potassium hydroxide wet mount and with Gram stain. Fungal filaments in smears or a strong clinical suspicion of fungal keratitis warranted the therapy with antifungals. natamycin (Nata drops; Cipla, India), which is our firstline antifungal agent, was started hourly during waking hours (7 A.M.Y10 P.M.) along with 1% homatropine drops (Homide; Asia-Pacific Journal of Ophthalmology & Volume 4, Number 3, May/June 2015

2 Asia-Pacific Journal of Ophthalmology & Volume 4, Number 3, May/June 2015 Oral in Fungal Keratitis TABLE 1. Inclusion and Exclusion Criteria Inclusion criteria 1. Culture-positive fungal keratitis involving more than 50% of stromal thickness and measuring 2Y60 mm 2 2. Aged 16 years or above 3. Subjects must be capable of understanding the purpose and the risks of the study and be able to comply with the study requirements. Exclusion criteria 1. Ulcers measuring less than 2 mm 2 or more than 60 mm 2 2. Perforated corneal ulcer 3. Infiltrates involving limbus 4. Hypopyon more than 4 mm at enrollment 5. Mixed infections 6. One-eyed patients 7. Uncontrolled diabetes mellitus 8. Pregnancy and lactation 9. Subjects with known hypersensitivity to ketoconazole 10. Abnormal results in liver function tests before enrollment Warren, India) 3 times a day. Once the culture reports were available, a written informed consent was obtained. All patients older than 16 years with positive smears and growth in 1 medium or with negative smears but growth in 2 culture media were randomized into 2 groups in the study. A baseline liver function test was done to assess serum bilirubin, protein, and enzyme levels such as aspartate aminotransferase, alanine aminotransferase, aspartate aminotransferase/alanine aminotransferase ratio, and alkaline phosphatase, along with random blood glucose assessment before randomization. Transaminase levels between 250 and 1000 U/L were considered significant to discontinue the therapy. The visual acuity was measured at baseline and 4 weeks using both Snellen and ETDRS charts. Randomization and drug allocation was done by 1 of the authors and kept concealed from other examiners till the patients left the study. Ulcer size measuring 2 to 60 mm 2 and involving more than 50% of stromal thickness (Table 1) was considered for randomization to either of the 2 treatment arms. Subjects in group A were treated with topical 5% natamycin (Nata drops; Cipla) hourly and a placebo tablet (vitamin C) 2 times a day, whereas group B received 200 mg oral ketoconazole (Nizoral; Johnson & Johnson) 2 times a day along with topical natamycin. is routinely used in our institute as a systemic oral antifungal adjuvant in deep keratitis. Ulcers measuring less than 2 mm 2 or greater than 60 mm 2, presence of limbal involvement, imminent perforation, hypopyon measuring greater than 4 mm, mixed infections on smear or culture, pregnant or lactating women, 1-eyed patients, patients with abnormal liver function, or uncontrolled diabetes mellitus were excluded from the study. Patients were hospitalized for the first 2 weeks, with medications being dispensed by ward nurses. Thereafter, they were seen once a week over the next 28 days with a window period of 5 days. Each subject in the study had clinical photographs taken at baseline and weekly till the end of the study by 1 of the coauthors who was blind to the randomization. Ulcer evaluation was done at each follow-up by a single-masked investigator till the final outcome was reached. The topical therapy was kept as hourly application till approximately 50% reduction in infiltration size, then tapered to every 2 hours till complete healing and continued for 2 weeks thereafter. Oral ketoconazole was stopped once the ulcer healed completely. In case the ulcer did not heal, the drug was continued for 28 days, and liver function was tested again. This was an intention-to-treat analysis, with outcomes defined as success if there was a clinical cure (healed) or clinical improvement (healing) at 4 weeks and as a failure if the infection worsened and the ulcer perforated during the course of the treatment or remained the same at 4 weeks. An ulcer was defined as healed when the stromal infiltration cleared completely and was replaced by a scar, the reepithelialization completed, and the hypopyon disappeared. Clinical improvement was defined when scarring started at the edges, the hypopyon disappeared, and the size of the epithelial defect and stromal infiltration reduced in size by 80% or above. The ulcers, which showed signs of worsening as evidenced by an increase in size, depth, and increasing hypopyon, were left out of the study. These patients were further managed with topical 0.15% amphotericin B drops, intracameral 8 Kg per 0.1 ml amphotericin B drops, or therapeutic keratoplasty. All applicable institutional and governmental regulations concerning the ethical use of human volunteers were followed during this research. Statistical Analysis The tests for significance included t test to compare the means of continuous variables, Pearson W 2 and Fisher s tests for comparing categorical variables, log-rank test for the mean of survival rates, and Kaplan-Meier procedure to estimate the survival rate at each point of time with a healed or healing ulcer considered as an event. RESULTS During the study period, 404 cases of fungal keratitis were screened, 115 eligible eyes of 115 patients who had given informed consent were enrolled in the study. Fifty-eight patients were randomized to group A and 57 patients to group B. Male patients were predominant in a ratio of 2.2 to 1. The mean age was T 13.5 years, ranging from 23Y80 years. The age distribution (P = 0.79) and sex distribution (P = j0.38) were comparable in both groups. There was no significant difference in baseline ulcer characteristics such as epithelial defect (P = 0.22), infiltration size (P = 0.22), and infiltration depth (P = 0.12) between the 2 groups (Table 2). The isolated fungi species were also distributed evenly between the 2 groups (Table 3). Six patients had diabetes mellitus controlled by medications. Although 108 patients completed the study, 4 in group A and 3 in group B were lost to follow-up (Supplemental Digital Content 1, Patients were followed up for T 8.04 days in group A and T 8.34 days in FIGURE 1. Kaplan-Meier survival analysis. * 2014 Asia Pacific Academy of Ophthalmology 147

3 Rajaraman et al Asia-Pacific Journal of Ophthalmology & Volume 4, Number 3, May/June 2015 TABLE 2. Demographic and Ulcer Characteristics + Oral n Sex distribution j0.386 Male Female Mean T SD age, (range, 23Y80), y Age T T 12.8 Epithelial defect, mm 2 j0.224 G Infiltration size, mm 2 j0.227 G Infiltration depth j0.127 Anterior 1/ Posterior 1/ group B (P = 0.72).Thirty-seven (68.5%) eyes in group A and 39 (72.2%) eyes in group B had a resolution of infection. There was no statistically significant difference in clinical cure of infection between the group treated with topical natamycin alone and the group treated with natamycin with oral ketoconazole (log-rank, 0.249; P = 0.61; Table 4). There was no clinically significant difference in treatment outcome (P = 0.25) when the 2 groups were further analyzed based on ulcer size measuring less than or greater than 15 mm 2. Among the healed cases, the ulcers healed at T 6.32 days ingroupa and at 21.07T 7.52 daysingroupb. Therewas no statistically a significant difference (P = 0.54). The Kaplan- Meier survival analysis based on healing time showed that the median survival time of the two groups was as 20 and 21 days, respectively (Fig. 1). Our data also showed that among the Fusarium species, 75% of the ulcers responded to topical natamycin and 72% of the ulcers to natamycin with oral ketoconazole. The liver function test revealed that serum enzyme levels remained within the normal limits after completion of oral therapy in both groups. The baseline best spectacle corrected visual acuity in group A was 0.86 T 0.76, and improved to 0.51 T 0.5 at 4 weeks. In TABLE 3. Etiologic Organisms Species P + Oral Aspergillus flavus 4 3 Aspergillus fumigatus 3 3 Aspergillus species V 1 Bipolaris species 3 1 Curvularia species 1 1 Fusarium species Penicillium species V 1 Unidentified dematiaceous 4 8 fungus Unidentified hyaline fungus 7 2 Total TABLE 4. Clinical Outcomes Outcome + Oral Success Healed 28 (52) 27 (50) Healing 9 (16.7) 12 (22.22) Failed Remained the 1 (1.85) V same Worsened 9 (16.7) 9 (16.7) Perforated 7 (12.96) 6 (11.1) Lost to follow-up 4 3 Total Values are presented as n (%). group B, the mean baseline BCVA was 1.13 T 0.87 and improved to 0.77 T 0.71 at final visit. There was no statistically significant difference in the baseline and the final visual acuity between the 2 groups (P =0.112). Among the 17 ulcers that failed to respond to therapy in group A, 7 perforated within the study period. In group B, 6 ulcers perforated out of the 15 that failed to respond to therapy. The same causative organism was isolated on repeated cultures in 3 patients who failed to respond to therapy. Seventeen patients, 8 in group A and 9 in group B, underwent therapeutic keratoplasty for perforation or worsening of the infection. The excised recipient corneal buttons were cultured and the same fungi grew in six of them. DISCUSSION Fungal keratitis is commonly seen in tropical countries. However, a recent outbreak of contact lensyrelated Fusarium infection, which occurred globally including countries with temperate climate, exposes their emergence as a global problem. 1Y4 Management is associated with significant ocular morbidity because of the limited availability of effective antifungals, poor intraocular penetration, and toxicity of these agents. Fungal keratitis thus remains a therapeutic challenge to ophthalmologists. Mycotic keratitis seen in the tropics is commonly due to filamentous fungi such as Fusarium and Aspergillus with the former showing an increased tendency to invade the eye more deeply. 5 Topical natamycin (5%) or amphotericin B (0.15%) is the first-line agent of choice for superficial keratitis with additional systemic therapy using oral azoles for deeper lesions. 10Y13 Although iodides and imidazole antifungals have been recommended for the management of fungal infections of the skin and the mucosa, poor ocular penetration and toxicity limit their use in the cornea. Amphotericin B is a fungicidal with a high penetrability but it causes both systemic and ocular toxicity., on the other hand, is fungistatic, well tolerated, and effective in superficial keratitis. However, it demonstrates poor ocular penetration. As topical antifungal agents have poor penetration to the deeper layers of cornea, other routes of drug delivery have to be explored. The addition of oral therapy with an agent having good aqueous penetration with topical antifungals would be a sound approach to manage severe keratitis. Studies have evaluated the role of antifungals such as itraconazole, ketoconazole, fluconazole, voriconazole and amphotericin B for systemic therapy in deep keratitis * 2014 Asia Pacific Academy of Ophthalmology

4 Asia-Pacific Journal of Ophthalmology & Volume 4, Number 3, May/June 2015 Oral in Fungal Keratitis Agarwal et al 13 studied the effect of oral itraconazole along with topical 1% itraconazole in a randomized trial and found no statistical difference in response. Kuriakose et al 14 reported complete healing in 3 of the 4 patients with intracameral amphotericin B. The Cochrane review of medical interventions for fungal keratitis pointed out a lack of prospective randomized clinical trials with an adequate sample size. This review could identify only 6 clinical trials studying the effectiveness of individual agents such as itraconazole, chlorhexidine, silver sulfadiazine, and econazole. 15Y18 Ophthalmic preparation of 5% natamycin is the first-line management in tropical countries where Fusarium keratitis is common. In their comprehensive review of mycotic keratitis, Thomas et al 19 observed 56% healing with natamycin, which was reduced to 34% in severe keratitis. Data about in vivo efficacy of combination therapies are restricted to very few randomized clinical trials. 20 Although several newer antifungal agents are available, the treatment plan for individual patients still remains empirical. Anecdotal case reports, in vitro sensitivity reports, and animal studies have helped to assess the effectiveness of the antifungal agents available. 11Y15,21,22, a lipophilic, synthetic, inexpensive, antimycotic imidazole derivative, has been administered orally to treat human mycosis, with hepatotoxicity being a potential adverse effect. In vivo animal experiments have shown good ocular penetration and tolerability to oral ketoconazole. Thomas et al 19 found that 60% of severe fungal keratitis responded to ketoconazole and advocated that 5% natamycin with oral ketoconazole or itraconazole should constitute primary therapy for severe keratitis 9. Xie et al 22 found that both Fusarium and Aspergillus were insensitive to azoles, including ketoconazole, in their ex vivo antifungal susceptibility study. 21 We assessed the safety and the efficacy of oral ketoconazole in addition to topical 5% natamycin in the treatment of filamentous fungal keratitis involving mid to deep stroma. The comparable baseline demographic and ulcer characteristics between the 2 groups showed a fair randomization. In their report, Thomas et al 19 showed that oral ketoconazole was more effective in ulcers caused by Curvularia as compared with Fusarium and Aspergillus species. 9 Our data show that oral ketoconazole did not have any additional benefit to topical natamycin therapy in deep fungal keratitis. The visual outcomes were comparable between the 2 groups for ulcers measuring greater than 15 mm 2. natamycin with oral ketoconazole was found to be safe for long-term use in deep fungal keratitis as evidenced by the absence of any systemic adverse effects during this study. The peak serum concentration of ketoconazole was 1.5 to 3.1 Kg/mL after a 200-mg oral dose, whereas in vitro studies have shown a high minimal inhibitory concentration (10Y30 Kg/mL) for Fusarium species. 23Y30 A low serum concentration of ketoconazole achieved after oral administration and an emerging resistance pattern could explain our clinical observations although further studies are warranted. 22,23,30 Our study is a prospective randomized trial evaluating the role of intensive systemic ketoconazole therapy in filamentous keratitis with a considerable sample size. Nevertheless, a limitation of our study is a relatively short follow-up period. Few anecdotal case series about the efficacy of newer oral antifungal agents such as voriconazole are encouraging. 31Y33 A recent randomized trial comparing topical voriconazole with natamycin in mycotic keratitis could not find a statistically significant difference in their effect. 34 The paucity of large studies showing a definitive benefit from the drug coupled with its high cost has been a limiting factor in the developing world. Reports have shown the effectiveness of intrastromal antifungal therapy in recalcitrant cases. 33,35 These modes of drug delivery will help achieve a high stromal and anterior chamber concentration of the drug with a reduction in systemic toxicity. This further reiterates the need for randomized clinical trials with a larger sample size to assess the effectiveness of the newer class of antifungals and drug delivery methods. REFERENCES 1. Srinivasan M. Fungal keratitis. Curr Opin Ophthalmol. 2004;15:321Y Alfonso EC, Cantu-Dibildox J, Munir WM, et al. 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