Topical chlorhexidine 0.2% versus topical natamycin 5% for fungal keratitis in Nepal: rationale and design of a randomised controlled non-inferiority trial

Abstract

IntroductionFungal infections of the cornea, fungal keratitis (FK), are challenging to treat. Current topical antifungals are not always effective and are often unavailable, particularly in low-income and middle-income countries where most cases occur. Topical natamycin 5% is usually first-line treatment, however, even when treated intensively, infections may progress to perforation of the eye in around a quarter of cases. Alternative antifungal medications are needed to treat this blinding disease.Chlorhexidine is an antiseptic agent with antibacterial and antifungal properties. Previous pilot studies suggest that topical chlorhexidine 0.2% compares favourably with topical natamycin. Full-scale randomised controlled trials (RCTs) of topical chlorhexidine 0.2% are warranted to answer this question definitively.Methods and analysisWe will test the hypothesis that topical chlorhexidine 0.2% is non-inferior to topical natamycin 5% in a two-arm, single-masked RCT. Participants are adults with FK presenting to a tertiary ophthalmic hospital in Nepal. Baseline assessment includes history, examination, photography, in vivo confocal microscopy and cornea scrapes for microbiology. Participants will be randomised to alternative topical antifungal treatments (topical chlorhexidine 0.2% and topical natamycin 5%; 1:1 ratio, 2–6 random block size). Patients are reviewed at day 2, day 7 (with reculture), day 14, day 21, month 2 and month 3. The primary outcome is the best spectacle corrected visual acuity (BSCVA) at 3 months. Primary analysis (intention to treat) will be by linear regression, with treatment arm and baseline BSCVA prespecified covariates. Secondary outcomes include epithelial healing time, scar/infiltrate size, ulcer depth, hypopyon size, perforation and/or therapeutic penetrating keratoplasty (corneal transplant), positive reculture rate (day 7) and quality of life (EuroQol-5 dimensions, WHO/PBD-VF20, WHOQOL-BREF).Ethics and disseminationThe Nepal Health Research Council, the Nepal Department of Drug Administration and the London School of Hygiene and Tropical Medicine ethics committee have approved the trial. The results will be presented at local and international meetings and submitted to peer-reviewed journals for publication.Trial registration numberISRCTN14332621; pre-results.

Topical Chlorhexidine 0.2% versus Topical Natamycin 5% for the Treatment of Fungal Keratitis in Nepal

“…The trial protocol has been published. 20 The trial was registered with ISRCTN, number ISRCTN14332621.…”

Mycotic Keratitis—A Global Threat from the Filamentous Fungi

“…It is a widely used broad-spectrum biocide, killing microorganisms through cell membrane disruption. Pilot studies from the 1990s have suggested it as a potential alternative to natamycin 5% [ 23 , 25 , 191 , 195 ], and a randomised controlled trial comparing natamycin 5% to chlorhexidine 0.2% for fungal keratitis is currently underway [ 196 ].…”

“…Accessibility to the current gold standard treatment needs to be improved and the evidence-base into alternative treatments, such as chlorhexidine 0.2%, needs to be widened. Randomised controlled trials are currently underway to assess its efficacy [ 196 ].…”

Fusarium Keratitis—Review of Current Treatment Possibilities

“…The two ongoing randomized trials may bring some practical information for the clinicians. A trial conducted in Nepal aims to prove non-inferiority of topical 0.2% CHX to topical 5% NAT in fungal keratitis [ 112 ]. A study comparing treatment of fungal keratitis with topical 5% NAT alone to treatment combination of 5% NAT and 0.2% CHX is underway in East Africa [ 113 ].…”