Purpose

To determine if there is a benefit to adjuvant corneal crosslinking (CXL) and to compare natamycin versus amphotericin B for filamentous fungal keratitis.

Design

Outcome-masked, 2×2 factorial design, randomized controlled clinical trial.

Participants

Consecutive patients presenting with moderate vision loss from a smear-positive fungal ulcer at Aravind Eye Hospital, Madurai, India.

Methods

Study eyes were randomized to 1 of 4 treatment combinations using an adaptive randomization protocol. The treatment arms included (1) topical natamycin 5% alone, (2) topical natamycin 5% plus CXL, (3) topical amphotericin B 0.15% alone, and (4) topical amphotericin 0.15% plus CXL.

Main outcome measures

The primary outcome of the trial was microbiological cure at 24 hours on repeat culture. Secondary outcomes included best spectacle-corrected visual acuity (BSCVA) at 3 weeks and 3 months, percentage of study participants with epithelial healing at 3 days, 3 weeks, and 3 months, infiltrate or scar size at 3 weeks and 3 months, 3-day smear and culture, and adverse events.

Results

Those randomized to CXL regardless of medication (topical natamycin or amphotericin) had 1.32-fold increased odds of 24-hour culture positivity, although this was not statistically significant (95% confidence interval [CI], 0.57-3.06; P = 0.51). We were also unable to find a difference in 24-hour culture positivity between those randomized to amphotericin and those randomized to natamycin when evaluating as a group regardless of whether or not they received CXL (coefficient 1.10; 95% CI, 0.47-2.54; P = 0.84). The BSCVA was approximately 0.22 logarithm of the minimum angle of resolution (logMAR) (2.2 Snellen lines) worse on average at 3 weeks among those receiving CXL regardless of medication (95% CI, -0.04 to 0.40; P = 0.04) and 0.32 logMAR (3.2 Snellen lines) worse visual acuity at 3 months after controlling for baseline visual acuity (95% CI, 0.03-0.54; P = 0.02). There was no difference in infiltrate or scar size, percentage of epithelialized or adverse events when comparing CXL with no CXL or the 2 topical medications.

Conclusions

There appears to be no benefit of adjuvant CXL in the primary treatment of moderate filamentous fungal ulcers, and it may result in decreased visual acuity.

Introduction

Although antibiotics are successful at achieving microbiological cure in infectious keratitis, outcomes are often poor due to corneal scarring. Ideal treatment of corneal ulcers would address both the infection and the inflammation. Adjunctive topical steroid treatment may improve outcomes by reducing inflammation. Corneal cross-linking (CXL) is a novel prospective therapy that may simultaneously reduce both inflammatory cells and bacterial pathogens. The purpose of this study is to determine differences in 6-month visual acuity between standard medical therapy with antibiotics versus antibiotics with adjunctive early topical steroid therapy versus antibiotic treatment plus CXL and early topical steroids.

Methods and analysis

This international, randomised, sham and placebo-controlled, three-arm clinical trial randomises patients with smear positive bacterial ulcers in a 1:1:1 fashion to one of three treatment arms: (1) topical 0.5% moxifloxacin plus topical placebo plus sham CXL; (2) topical 0.5% moxifloxacin plus difluprednate 0.05% plus sham CXL; or (3) the CXL group: topical 0.5% moxifloxacin plus difluprednate 0.05% plus CXL.

Ethics and dissemination

We anticipate that both adjunctive topical steroids and CXL will improved best spectacle corrected visual acuity and also reduce complications such as corneal perforation and the need for therapeutic penetrating keratoplasty. This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. Our results will be disseminated via ClinicalTrials.gov website, meetings and journal publications. Our data will also be available on reasonable request.

Trial registration number

NCT04097730.