Comparative Evaluation of Topical versus Intrastromal Voriconazole as an Adjunct to Natamycin in Recalcitrant Fungal Keratitis

Namrata Sharma, MD,1 Jacob Chacko, MD,1 Thirumurthy Velpandian, PhD,2 Jeewan S. Titiyal, MD,1 Rajesh Sinha, MD,1 Gita Satpathy, MD,3 Radhika Tandon, MD,1 Rasik B. Vajpayee, FRCSEd, FRANZCO1,4
Objective: To compare the efcacy of topical voriconazole and topical natamycin with that of intrastromal voriconazole and topical natamycin in patients with recalcitrant fungal keratitis. Design: Randomized clinical trial. Participants: Forty eyes of 40 patients with fungal keratitis (positive smear or culture results or both) larger than 2 mm, involving up to two thirds of the stromal depth, and not responding to topical natamycin therapy for 2 weeks were recruited. Intervention: The patients were randomized to receive either topical 1% voriconazole therapy (n 20) or intrastromal injections of voriconazole 50 g/0.1 ml (n 20). The patients in both groups continued topical natamycin 5% every 4 hours until the ulcer healed. Main Outcome Measures: Primary outcome measure was best spectacle-corrected visual acuity (BSCVA) 3 months after intervention, and secondary outcome measures were time to healing and the size of the scar. Results: The patients in both groups had comparable baseline parameters. The mean BSCVA after treatment was 1.2950.5 logarithm of the minimum angle of resolution (logMAR) units in the topical group and 1.6920.29 logMAR units in the intrastromal group. The visual acuity after treatment was signicantly better in the topical voriconazole group (P 0.008). Nineteen patients receiving topical voriconazole and 16 patients who were given intrastromal voriconazole healed with therapy. Conclusions: Topical voriconazole seems to be a useful adjunct to natamycin in fungal keratitis not responding to topical natamycin. Intrastromal injections did not offer any benecial effect over topical therapy. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2013;120:677 681 2013 by the American Academy of Ophthalmology.

Microbial keratitis is a leading cause of blindness in the world. Fungal keratitis has been reported to cause 30% to 40% of keratitis in some parts of the world.13 Various antifungal agents are available. However, they have limitations in the form of poor bioavailability and limited ocular penetration, especially in deeper lesions.4 Natamycin is the preferred drug of choice for lamentous fungal keratitis. It is well tolerated and stable and has a broad spectrum of activity against lamentous fungi and yeasts causing corneal infections.4 However, topical natamycin poorly penetrates an intact epithelium and often requires manual debridement of the corneal epithelium. It is as effective as econazole,5 more effective than itraconazole,6 and more rapidly acting than terbinane,7 as established in various clinical trials. Voriconazole, a derivative of uconazole, has an increased afnity for 14 demethylase and increased potency to inhibit CYP51.8,9 It has excellent in vitro activity against Aspergillus species, Candida species (minimum inhibitory concentration for 90% of organisms [MIC90], 0.25 0.5 g/ ml), and Fusarium species (MIC90, 1 4 g/ml).10 A combination of a polyene (amphotericin B) and a triazole (voriconazole) is synergistic at low median concentrations when tested
2013 by the American Academy of Ophthalmology Published by Elsevier Inc.

against Aspergillus species in vitro, suggesting a concentrationdependent interaction between the 2 drugs.11 Topical voriconazole has been used successfully to treat fungal keratitis either as a standalone therapy12,13 or in conjunction with systemic voriconazole.14 16 The mycotic ulcer treatment trial (MUTT) randomized patients to receive either topical 5% natamycin or topical 1% voriconazole as a primary drug in patients with fungal corneal ulcers. Patients with a baseline best spectacle-corrected visual acuity (BSCVA) of 20/40 to 20/400 showed a trend toward a 2-line improvement with voriconazole that, however, fell short of statistical signicance (P 0.07).12 Targeted drug delivery in the form of intrastromal or intracorneal injections has been used to treat cases of fungal keratitis in anecdotal case reports1719 and case series.20 22 These have been used alone in cases of fungal keratitis that have occurred as a result of contact lenses,18 in cases of pseudophakic bullous keratopathy,19 after penetrating keratoplasty,17 and in recalcitrant20 22 and recurrent17 cases associated with endophthalmitis. However, there are no trials comparing different methods of drug delivery, that is, topical and intrastromal injections in cases of deep fungal keratitis. This study compared the efcacy of intrastromal
ISSN 0161-6420/13/$see front matter http://dx.doi.org/10.1016/j.ophtha.2012.09.023

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reconstituted with 19 ml Ringer lactate. One milliliter of this solution was diluted further with 20 ml Ringer lactate. The resulting 0.5 mg/ml (50 g/0.1 ml) solution was used for the intrastromal injection. All injections were given in an operating room under aseptic precautions after administering peribulbar anesthesia. After loading the drug into a 1-ml tuberculin syringe tted with a 26-gauge needle, it was inserted obliquely into the cornea from the uninvolved, clear area to reach just ush to the ulcer at the midstromal level in each case. Five divided doses were given around the ulcer to form a deposit of the drug around the circumference of the lesion. This was done in such a manner that the injected drug appeared to encompass the ulcer along each meridian. At least 3 injections were given 72 hours apart. Patients in this group also received topical therapy with 5% natamycin every 4 hours, cycloplegics, and 0.3% ciprooxacin hydrochloride every 6 hours. No patients in this group received voriconazole eye drops. Patients in both the groups were followed up on days 3, 7, 14, and 28 after 2 months and 3 months. Patients were asked about any adverse effects, including increased pain, burning, and itching, at each follow-up visit. The size of the epithelial defect and stromal inltrate and scar complex also were measured. Digital tonometry was carried out, and the presence of hypopyon, cataract, and posterior synechiae, if any, also were recorded. Patients with a visible red reex after full dilatation were refracted and the baseline BSCVA was recorded. In those patients in whom refraction was not possible, previous refractive correction, if available, was used. If previous records were not available, uncorrected visual acuity was recorded as the baseline vision and further recordings were carried out during the rst 4 follow-up visits, after which refraction again was attempted in those patients with a visible glow after full dilatation, and the BSCVA after treatment was recorded. The duration for healing, visual acuity after treatment (measured on the logMAR scale) after 3 months, size and depth of the scar, supercial and deep vascularization, and adverse effects, if any, were recorded, and results were compared between the 2 groups.

injection of 50 g/0.1 ml voriconazole versus topical 1% voriconazole as an adjunct to natamycin in recalcitrant cases of fungal keratitis in this randomized, controlled clinical trial.

Patients and Methods

Patients were recruited from Cornea Clinic of the Dr. Rajendra Prasad Center for Ophthalmic Sciences, a tertiary eye care hospital. Institutional review board approval was obtained. The inclusion criteria were smear- or culture-proven fungal ulcers larger than 2 mm involving up to two thirds of the stromal thickness and not showing any signs of clinical improvement after 2 weeks of topical natamycin therapy. Patients who were willing to be treated on an inpatient basis and were willing to follow up regularly and to return for medications every 48 to 72 hours were enrolled. The exclusion criteria were cases of mixed infection on smear or culture analysis, evidence of herpetic keratitis in history or upon examination, impending perforation, bilateral ulcers, those with vision less than 6/60 in the fellow eye, and patients younger than 18 years. The patients with positive smear results (KOH wet mount or gram stain), positive culture results, or both for fungal keratitis were started on topical natamycin hourly around the clock for 2 days and every 2 hours thereafter along with ciprooxacin hydrochloride 0.3% every 6 hours and cycloplegics. The patients were followed up closely for 2 weeks for signs of improvement. Ulcers with an increase in size of epithelial defect, a decrease of less than 20% of stromal inltrate or scar complex, or increasing hypopyon were enrolled. The details regarding the symptoms associated with the corneal ulcer, its onset and progression, and history of predisposing factors such as trauma, steroid use, recent surgery, and diabetes were elicited. Best spectacle-corrected visual acuity was recorded using both Snellen charts and the logarithm of the minimum angle of resolution (logMAR) scale. The values for vision less than counting ngers close to face (1.6 logMAR) were recorded as follows: counting ngers, 1.7; hand movements close to face, 1.8; light perception, 1.9; and no light perception, 2.0. The patients who did not respond to medical management were given a value of 1.9. This scale was used in the MUTT study, which compared topical voriconazole with topical natamycin in cases of fungal corneal ulcers.12 The size of the epithelial defect and that of the stromal inltrate were characterized by the geometric mean of the longest dimension and the longest perpendicular. The presence of hypopyon was noted, and digital tonometry was performed. Forty eyes of 40 patients were randomized (variable block) into 2 groups of 20 patients each in this randomized clinical trial. Group 1 received 1% topical voriconazole hourly for the initial 48 hours along with topical 5% natamycin eye drops every 4 hours, 0.3% ciprooxacin hydrochloride eye drops 4 times daily, and 2% homatropine eye drops 3 times daily. Topical voriconazole 1% eye drops were prepared in the Department of Ocular Pharmacology by reconstituting injection voriconazole 200 mg powder (VORAZE; Sun Pharma, Mumbai, India) in 19 ml Ringer lactate. The patients were instructed to keep the drops in a refrigerator. The topical voriconazole 1% drops then were tapered to every 2 hours while awake for 72 hours and thereafter the dosage was every 4 hours. After discharge, patients were instructed to report back to the center every 3 days to obtain fresh supplies of the medicine. Further tapering of the drug depended on the response of the infection to treatment and as per the clinicians judgment. Group 2 patients received 50 g/0.1 ml intrastromal voriconazole. VORAZE 200 mg powder (Sun Pharma, Mumbai, India) was

Statistical Analysis
The sample size for the study was calculated for a 2 parallel group superiority study with the primary outcome measure as BSCVA on the logMAR scale. Considering the mean standard deviation in BSCVA on the logMAR scale as 1.70.3, to detect a 20% gain in BSCVA on the logMAR scale resulting from topical voriconazole therapy with the 95% condence interval and 90% power, the required number of eyes would be 15 in each group. Twenty subjects were enrolled in each group. The randomization was carried out using computer-generated random numbers according to the variable block size. The data were recorded on a predesigned sheet and managed on an Excel spreadsheet (Microsoft, Redmond, WA). All the entries were double checked for any possible keyboard error. The baseline characteristics of the study subjects were compared between the 2 groups to detect any imbalance in the 2 groups. The data were analyzed by treatment as administered. The categorical variables were summarized by frequency (%), and these were compared between the 2 groups using the chi-square test or Fisher exact test as appropriate. The quantitative values were summarized as mean standard deviation, and the Student t test was used to compare difference in mean values between the 2 groups. For the primary outcome variable effect size, the difference in mean values of BSCVA on the logMAR scale and its 95% condence interval were computed. The criteria for the results were based on a null value not included in the 95% condence interval. Stata statistical software version 11.0 (Stata Corp, College Station, TX) was used for the data analysis.

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Table 1. Baseline Parameters in Cases of Recalcitrant Fungal Keratitis
Parameter Age (yrs) Male-to-female ratio Mean duration of symptoms (days) Mean size of epithelial defect (mm) Mean size of stromal inltrate (mm) Ulcers involving the central 3 mm of the cornea Hypopyon Mean BSCVA (logMAR) Topical Natamycin Plus Topical Voriconazole 40.8514.6 3:1 49.0526.23 4.831.5 5.051.3 18 9/20 (45%) 1.640.3 Topical Natamycin Plus Intrastromal Voriconazole 47.716.62 3:1 43.3522.64 5.171.9 5.561.06 14 13/20 (65%) 1.720.23 P Value 0.17 0.99 0.49 0.44 0.2 0.11 0.2 0.35

BSCVA best spectacle-corrected visual acuity; logMAR logarithm of the minimum angle of resolution.

Results
The baseline characteristics were comparable in the 2 groups (Table 1). Eleven patients (55%) in each group had a history of preceding trauma, with 6 of 20 patients (30%) and 4 of 20 patients (20%) sustaining trauma with vegetable matter in the topical and intrastromal groups, respectively. Two of 20 patients (10%) and 3 of 20 patients (15%) in the topical and intrastromal groups, respectively, were using topical steroids at presentation. Both groups were matched in terms of predisposing factors, that is, trauma (P 0.99), use of steroids (P 0.63), and diabetes (P 0.48). The mean duration of symptoms was 49.0526.2 days and 43.322.6 days in the topical and the intrastromal voriconazole groups, respectively (P 0.74). The average size of the ulcers measured along the longest axis and perpendicular to it was 4.831.5 mm in the topical group and 5.171.9 mm in the intrastromal group (P 0.443). Similarly, the average size of the stromal inltrate was 5.051.36 mm in the topical group and 5.561.06 mm in the intrastromal group (P 0.196). There were more central ulcers in the intrastromal voriconazole group (18/20) as opposed to the topical voriconazole group (14/20). Although the number of central ulcers was more in the intrastromal group, this difference was not statistically significant (P 0.114). The etiologic organism was isolated in 13 patients in the topical voriconazole group and in 12 patients in the intrastromal group (Table 2). The culture positivity rate was 62.5%. Aspergillus was the most common species (12/40; 30% cases) isolated, followed by Fusarium species (7/40; 17.5% cases), and both the groups were matched in terms of microbial organisms (Table 2). The treatment was successful in 19 of 20 patients in the topical group and in 16 of 20 patients in the intrastromal group (P 0.34). The BSCVA after treatment improved from baseline in 15 of 20 patients (75%) in the topical group and in 10 of 20 patients (50%)

in the intrastromal group. The mean BSCVA after treatment was 1.2950.5 logMAR units in the topical group and 1.6920.29 logMAR units in the intrastromal group. This amounts to a reduction in BSCVA by 0.38 logMAR units (95% condence interval, 0.11 0.65). The visual acuity after treatment was signicantly better in the topical voriconazole group (P 0.008). The mean duration for healing in the topical group was 28.919.1 days, whereas the mean duration for healing in the intrastromal group was 36.120.2 days. Thus, on average, ulcers healed faster in the topical group by 5.5 days compared with the intrastromal group (95% condence interval, 19.1 to 8). However, there was no statistical difference between the 2 groups (P 0.38). The mean size of the scar in the topical voriconazole group was 4.361.38 mm and that in the intrastromal voriconazole group was 5.31.4 mm, with no statistical difference between the 2 groups (P 0.06). In terms of depth, less than two thirds of the corneal involvement occurred in 19 eyes in the topical voriconazole group and in 16 eyes in the intrastromal group. The perforation of the corneal ulcer was seen in 1 eye in the topical group and in 4 eyes in the intrastromal group (P 0.22), for which therapeutic keratoplasty was carried out. There were no cases of drug deposits seen. Systemic antifungal therapy in the form of tablet voriconazole 200 mg twice daily was administered in 1 case in the topical group and in 4 cases in the intrastromal group. Supercial vascularization was present in all eyes in both groups at 3 months. The amount of deep vascularization was compared between the 2 groups. There were fewer than 2 clock hours of vascularization in 7 eyes in the intrastromal group and in 4 eyes in the topical voriconazole group, and more than 2 clock hours vascularization was present in 2 eyes in the intrastromal group and in 3 eyes in the topical voriconazole group. There was no statistically signicant difference in terms of deep vascularization between the 2 groups (P 0.48).

Table 2. Fungi Cultured in Cases of Recalcitrant Fungal Keratitis

Topical Natamycin Plus Topical Voriconazole (n 20) 4 5 1 3 7 Topical Natamycin Plus Intrastromal Voriconazole (n 20) 3 7 0 2 8

Organism Fusarium species Aspergillus species Alternaria species Curvularia species No growth

Total 7 12 1 5 15

P Value 0.99 0.73 0.99 0.99 0.77

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arium species, Candida species, or other fungal organisms are more common. The patients in the intrastromal group had signicantly worse BSCVA after treatment compared with the topical group. The time to healing was comparable between the 2 groups. Hence, it seemed pertinent to analyze the location of the ulcers in the 2 groups. There were more central ulcers involving the visual axis in the intrastromal group (18/20; 90%) compared with the topical group (14/20; 70%), and this may have affected the outcomes in terms of BSCVA after treatment. The difference in the number of central ulcers in each group was not statistically signicant. This may become important when a larger sample size is studied. The mean size and depth of the scar at 3 months was comparable between the 2 groups. Because intrastromal injection of drug was carried out in 1 group, whether these patients would have greater vascularization as an effect of the intracorneal injection per se was determined. There was no difference in supercial vascularization of the scars as well as the deep vascularization, which means that the patients who received intrastromal injections were not future candidates for high-risk optical keratoplasty. The limitation of this study is the fact that, practically, it may be difcult to reconstitute voriconazole, and some ophthalmologists may nd it difcult to obtain because it is not available commercially. Furthermore, a pharmacy is required to reconstitute it to the desired form. To conclude, the addition of topical voriconazole 1% to natamycin is benecial in cases of recalcitrant keratitis. Intrastromal voriconazole was not benecial over topical voriconazole in these cases. Further studies are required to corroborate the in vitro susceptibility data for fungal organisms with the clinical response.

Discussion
This study recruited patients with recalcitrant fungal keratitis not resolving after 2 weeks of natamycin therapy. The mean duration of symptoms was longer in both the groups compared with that from studies reported in the literature.5,6,12,23 The mean sizes of ulcers in the 2 groups in this study were 5.051.33 mm and 5.51.9 mm, which was larger as opposed to smaller in the MUTT study, where it ranged from 3.8 to 4.1 mm in the various groups.12 Likewise, the baseline BSCVA in logMAR units also was better in this study compared with that reported in the MUTT study: 1.640.3 in the topical voriconazole group and 1.70.23 in the intrastromal group, in contrast to the MUTT study, where it varied from 0.87 to 0.96.12 Twelve of 20 patients (60%) in the topical voriconazole group and 15 of 20 patients (75%) in the intrastromal voriconazole group had a baseline visual acuity of counting ngers or worse. That is, fungal ulcers recruited in this study were more severe than those published in various randomized and comparative trials in the literature. This may be because corneal ulcers larger than 0.5 mm were recruited in the MUTT study,12 as opposed to corneal ulcers larger than 2 mm in the present study. Also, topical natamycin and voriconazole were started as primary drug therapy in the MUTT study12 because voriconazole has good ocular penetration. However, in the present study, patients not responding to topical natamycin therapy were enrolled. Debridement was not performed in any of the current patients, unlike the MUTT study, where debridement was performed in some patients. Topical ciprooxacin 0.3% was chosen as the antibiotic for prevention of superadded bacterial infection in the presence of epithelial defect. It is known to crystallize in the cornea at an acidic pH.24 Corneal deposits resulting from ciprooxacin,24 ooxacin,25 and gatioxacin26 have been reported in some studies. However, in the frequency used in our study (that is, 4 times daily), none of the patients had any evidence of corneal deposits. The most common organism in this study was Aspergillus species, followed by Fusarium species. Aspergillus species are more common in North India, whereas Fusarium species are more common in South India.1,2 Hence, in this study, topical voriconazole seemed to be effective in combination with natamycin in recalcitrant cases. The results of this study cannot be extrapolated to all patients with fungal keratitis for whom natamycin remains the drug of choice. Moreover, the MIC90 of voriconazole for Aspergillus species is 0.25 to 0.5 g/ml, which is much lower than the MIC90 of natamycin for Aspergillus species, 3.12 to 25 g/ml.11 In comparison, the MIC90 of voriconazole for Fusarium species is 1 to 4 g/ml, which is comparable with 1.56 to 6.25 g/ml for natamycin.9 Thus, Aspergillus species are extremely sensitive to voriconazole, whereas Fusarium species are not signicantly sensitive to voriconazole. Therefore, the greater percentage of Aspergillus species cultured in this study has to be taken into consideration when extrapolating the results of this study, especially in geographical areas where Fus-

References
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9. Marangon FB, Miller D, Giaconi JA, Alfonso EC. In vitro investigation of voriconazole susceptibility for keratitis and endophthalmitis fungal pathogens. Am J Ophthalmol 2004; 137:820 5. 10. Hariprasad SM, Mieler WF, Lin TK, et al. Voriconazole in the treatment of fungal eye infections: a review of current literature. Br J Ophthalmol 2008;92:871 8. 11. OShaughnessy EM, Meletiadis J, Stergiopoulou T, et al. Antifungal interactions within the triple combination of amphotericin B, caspofungin and voriconazole against Aspergillus species. J Antimicrob Chemother 2006;58:1168 76. 12. Prajna NV, Mascarenhas J, Krishnan JT, et al. Comparison of natamycin and voriconazole for the treatment of fungal keratitis. Arch Ophthalmol 2010;128:672 8. 13. Al-Badriyeh D, Leung L, Davies GE, et al. Successful salvage treatment of Scedosporium apiospermum keratitis with topical voriconazole after failure of natamycin. Ann Pharmacother 2009;43:1139 42. 14. Klont RR, Eggink CA, Rijs AJ, et al. Successful treatment of Fusarium keratitis with cornea transplantation and topical and systemic voriconazole [report online]. Clin Infect Dis 2005;40:e110 2. 15. Thiel MA, Zinkernagel AS, Burhenne J, et al. Voriconazole concentration in human aqueous humor and plasma during topical or combined topical and systemic administration for fungal keratitis. Antimicrob Agents Chemother 2007;51:239 44. 16. Jhanji V, Sharma N, Mannan R, et al. Management of tunnel fungal infection with voriconazole. J Cataract Refract Surg 2007;33:9157. 17. Garcia-Valenzuela E, Song CD. Intracorneal injection of amphotericin B for recurrent fungal keratitis and endophthalmitis. Arch Ophthalmol 2005;123:17213. 18. Tu EY. Alternaria keratitis: clinical presentation and resolution with topical uconazole or intrastromal voriconazole and topical caspofungin. Cornea 2009;28:116 9. 19. Neoh CF, Leung L, Vajpayee RB, et al. Treatment of Alternaria keratitis with intrastromal and topical caspofungin in combination with intrastromal, topical, and oral voriconazole. Ann Pharmacother 2011;45:e24. 20. Siatiri H, Daneshgar F, Siatiri N, Khodabande A. The effects of intrastromal voriconazole injection and topical voriconazole in the treatment of recalcitrant Fusarium keratitis. Cornea 2011;30:8725. 21. Prakash G, Sharma N, Goel M, et al. Evaluation of intrastromal injection of voriconazole as a therapeutic adjunctive for the management of deep recalcitrant fungal keratitis. Am J Ophthalmol 2008;146:56 9. 22. Sharma N, Agarwal P, Sinha R, et al. Evaluation of intrastromal voriconazole injection in recalcitrant deep fungal keratitis: case series. Br J Ophthalmol 2011;95:17357. 23. Bharathi MJ, Ramakrishnan R, Meenakshi R, et al. Microbial keratitis in South India: inuence of risk factors, climate, and geographical variation. Ophthalmic Epidemiol 2007;14:619. 24. Tanhehco TY, Chiavetta SV III, Lee PP, et al. Cracked-mud ciprooxacin precipitates on a corneal graft. Ophthalmic Surg Lasers Imaging 2005;36:2523. 25. Mitra A, Tsesmetzoglou E, McElvanney A. Corneal deposits and topical ooxacinthe effect of polypharmacy in the management of microbial keratitis. Eye (Lond) 2007;21: 410 2. 26. Awwad ST, Wang MX, Cavanagh HD. A case of gatioxacin crystal deposits in the corneal graft of an 85-year-old man [letter]. Eye Contact Lens 2006;32:157.

Footnotes and Financial Disclosures

Originally received: January 22, 2012. Final revision: September 12, 2012. Accepted: September 12, 2012. Available online: December 12, 2012.
1

Presented at: American Academy of Ophthalmology Annual Meeting, October 2011, Orlando, Florida. Manuscript no. 2012-95. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Funding for the drugs was obtained from the Dr. Rajendra Prasad Centre for Ophthalmic Sciences, New Delhi, India. Correspondence: Namrata Sharma, MD, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi 110029, India. E-mail: namrata.sharma@gmail.com.

Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India. Ocular Pharmacology Services, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India. Ocular Microbiology Services, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India. Centre for Eye Research, Melbourne, Australia.

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