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Retrospective studies have suggested that, compared with bacterial keratitis, fungal keratitis has particularly poor outcomes.1 An unbiased analysis would ideally be performed in a prospective, standardized fashion. Herein, we compare clinical outcomes in ulcers due to bacteria and fungus using data collected from 2 similarly structured prospective clinical trials.2,3
The National Eye Institute–funded Steroids for Corneal Ulcers Trial3,4 (SCUT) and the pilot study for the National Eye Institute–funded Mycotic Ulcer Treatment Trial2 (MUTT pilot) were concurrent, randomized controlled trials comparing outcomes in patients with bacterial (SCUT) and fungal (MUTT pilot) keratitis. Detailed methods have been previously reported.2,3 Outcomes for both trials included best spectacle-corrected visual acuity and infiltrate or scar size at 3 months from enrollment, time to re-epithelialization, and corneal perforation. The 2 trials were conducted at the Aravind Eye Care System (Madurai, Pondicherry, Tirunelveli, and Coimbatore, India) by the same investigators; all measurements were made by the same graders according to identical protocols. Patients were enrolled during overlapping periods (September 2006 through February 2010 for SCUT; December 2007 through May 2008 for MUTT pilot). Institutional review board approval was obtained by the University of California, San Francisco Committee on Human Research and the Aravind Institutional Review Board, and written informed consent was obtained from each participant.
All culture-positive bacterial and fungal cases enrolled in India were included in the analysis. Three-month best spectacle-corrected visual acuity and infiltrate or scar size between fungus and bacteria were analyzed by linear regression controlling for baseline characteristics (enrollment best spectacle-corrected visual acuity or infiltrate or scar size). In patients who had undergone corneal transplantation prior to their 3-month visit, last observation carried forward or an assigned visual acuity of 1.7 was used, whichever was worse. For infiltrate or scar size, last observation carried forward was used in these patients. Time to re-epithelialization was analyzed with a Cox proportional hazards model controlling for baseline epithelial defect size. Perforation was assessed using Fisher exact test.
Of 500 cases enrolled in SCUT and 120 cases enrolled in MUTT pilot, 485 cases in SCUT and 101 cases in MUTT pilot were culture positive, enrolled in India, and included in the analysis. Fungal keratitis cases were associated with approximately a 0.32-mm larger infiltrate or scar size compared with bacterial keratitis cases at 3 months, correcting for enrollment infiltrate size (P < .001) (Table). There was no difference in best spectacle-corrected visual acuity at 3 months in patients with fungal and bacterial keratitis (P = .12) (Table). Fungal keratitis cases re-epithelialized significantly more slowly than bacterial keratitis cases (median, 15 vs 7.5 days, respectively; P < .001). There were more perforations in the fungal keratitis group than in the bacterial keratitis group (16 of 101 [16%] vs 15 of 485 [3%], respectively; P < .001). Sensitivity analyses restricting the bacterial cases to only those enrolled during the same period as the fungal cases did not change the results.
Fungal keratitis is frequently considered more difficult to treat than bacterial keratitis and is thought to have worse prognoses.1,5 Here, fungal keratitis cases had nearly 5 times as many corneal perforations, some of which led to therapeutic penetrating keratoplasty, and longer healing times. They also had larger scars, although a difference of 0.32 mm may not be clinically significant. However, there was no significant difference in visual acuity in the bacterial and fungal keratitis groups, including patients with presumably the most severe ulcers, some of whom underwent sight-improving keratoplasty.
While there are inherent challenges in combining data from multiple clinical studies, these trials are a special case. The trials were conducted concurrently by the same investigators, outcomes were measured according to identical protocols, and the inclusion and exclusion criteria were nearly identical for both trials. For fungal ulcers, the epithelium was removed to enhance drug penetration, and approximately half of the cases received repeated scraping at 7 and 14 days because one of the primary aims of the trial was to assess whether repeated scraping improved outcomes. The result of longer healing times in fungal ulcers may be influenced by this. Re-epithelialization is a difficult end point to measure, particularly in fungal keratitis, so this result should be interpreted with some caution. Other factors associated with fungal and bacterial keratitis cases, such as geographic location of the patients, could act as confounders in this study. Selection bias could occur because use of topical antibiotics prior to presentation is more common than antifungal use, and culture-negative bacterial ulcers may be milder. However, the results of this study suggest that fungal keratitis has a higher risk of perforation and may have worse overall outcomes compared with bacterial keratitis.
Funding/Support: The Steroids for Corneal Ulcers Trial was supported by grant U10 EY015114 from the National Eye Institute. Acharya is supported by grant K23EY017897 from the National Eye Institute and a Research to Prevent Blindness Award. The Department of Ophthalmology, University of California, San Francisco is supported by core grant EY02162 from the National Eye Institute, by an unrestricted grant from Research to Prevent Blindness, and by That Man May See, Inc. Alcon provided moxifloxacin (Vigamox) for the Steroids for Corneal Ulcers Trial. Alcon donated natamycin and Pfizer donated voriconazole for the Mycotic Ulcer Treatment Trial pilot study.
Role of the Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.
Author Contributions: All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Prajna, Srinivasan, Oldenburg, McLeod, Acharya, Lietman.
Acquisition of data: Prajna, Lalitha, Krishnan, Rajaraman, Ravindran, Mascarenhas, Oldenburg, Ray, McLeod.
Analysis and interpretation of data: Prajna, Srinivasan, Mascarenhas, Oldenburg, Ray, McLeod, Acharya, Lietman.
Drafting of the manuscript: Ravindran, Oldenburg.
Critical revision of the manuscript for important intellectual content: Prajna, Srinivasan, Lalitha, Krishnan, Rajaraman, Mascarenhas, Ray, McLeod, Acharya, Lietman.
Statistical analysis: Srinivasan, Oldenburg, Ray.
Obtained funding: Lietman.
Administrative, technical, and material support: Prajna, Lalitha, Krishnan, Rajaraman, Ravindran, Mascarenhas, Oldenburg, McLeod, Acharya.
Study supervision: Prajna, Srinivasan, Lalitha, Oldenburg, McLeod, Acharya, Lietman.
Conflict of Interest Disclosures: None reported.
N. Venkatesh Prajna, Aravind Eye Care System, Madurai, Tamil Nadu, India.
Muthiah Srinivasan, Aravind Eye Care System, Madurai, Tamil Nadu, India.
Prajna Lalitha, Aravind Eye Care System, Madurai, Tamil Nadu, India.
Tiruvengada Krishnan, Aravind Eye Care System, Pondicherry, India.
Revathi Rajaraman, Aravind Eye Care System, Coimbatore, Tamil Nadu, India.
Meenakshi Ravindran, Aravind Eye Care System, Tirunelveli, Tamil Nadu, India.
Jeena Mascarenhas, Aravind Eye Care System, Madurai, Tamil Nadu, India.
Catherine E. Oldenburg, Francis I. Proctor Foundation, University of California, San Francisco.
Kathryn J. Ray, Francis I. Proctor Foundation, University of California, San Francisco.
Stephen D. McLeod, Francis I. Proctor Foundation, University of California, San Francisco.
Nisha R. Acharya, Francis I. Proctor Foundation, University of California, San Francisco.
Thomas M. Lietman, Francis I. Proctor Foundation, University of California, San Francisco.