Randomised controlled trial of topical combination therapy chlorhexidine 0.2% and natamycin 5% versus topical natamycin 5% alone for fungal keratitis in East Africa: study protocol.

Abstract

Introduction: Fungal corneal infection (fungal keratitis [FK]) poses significant treatment challenges. The efficacy of current topical antifungals is inconsistent and often limited, especially in low and middle-income countries where the majority of FK cases occur. Topical natamycin 5% is the current primary treatment in many countries, however, a substantial proportion of cases develop progressive disease, even with intensive treatment. Given the limitations of existing antifungal treatments, there is a need for alternative treatment strategies to address this condition.Chlorhexidine, an antiseptic with both antibacterial and antifungal properties, has received attention as a potential therapeutic agent. While a recent randomized controlled trial (RCT) in Nepal demonstrated the superiority of natamycin over chlorhexidine, a pilot study in Uganda has indicated a possible role for adjunctive chlorhexidine 0.2% in FK treatment. The contrasting findings necessitate a comprehensive RCT to investigate the potential benefit of adding topical chlorhexidine 0.2% alongside natamycin 5% in the management of FK.

Methods: We will test the hypothesis that topical natamycin 5% in combination with chlorhexidine 0.2% is superior to topical natamycin 5% alone in a two-arm, single-masked RCT (ISRCTN, ISRCTN87195453, registered 27/08/2020, https://www.isrctn.com/ISRCTN87195453). Participants are adults with FK presenting to tertiary ophthalmic hospitals in Tanzania and Uganda. Baseline assessment includes history, examination, photography, in vivo confocal microscopy and corneal 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 will be reviewed at days 2, 7 (with re-culture), 14, 21, month 2, and month 3. The primary outcome is best spectacle corrected visual acuity (BSCVA) at three months. Primary analysis (intention-to-treat) will be by linear regression, with treatment arm and baseline BSCVA pre-specified covariates. Secondary outcomes include epithelial healing time, scar/infiltrate size, ulcer depth, hypopyon size, perforation and/or therapeutic penetrating keratoplasty, and positive re-culture rate.