Background and review question
Fungal infection of the cornea occurs rarely in higher income countries but is relatively common in lower income countries. If left untreated the cornea may develop a hole and this may lead to blindness. Although there are a number of medications available, it is not clear which is the most effective and cost-effective. Our review question was: which is the best treatment for fungal infection of the cornea (fungal keratitis)?
We identified 12 randomised controlled trials that included 981 people; the evidence is current up to March 2015. The trials were mainly conducted in India.
Key results and quality of the evidence
The studies were small and many of them were at risk of bias. They also looked at different treatments. This meant that for most treatments we could not draw any conclusions as to which was better. There was one exception. Three trials (434 participants) compared topical natamycin and topical voriconazole. In these trials there was low quality evidence that people receiving topical natamycin were more likely to be cured and were more likely to have better vision three months after treatment started. There was high quality evidence that people receiving natamycin were less likely to develop a hole in the cornea and need a transplant. We did not find any evidence on quality of life. One trial found evidence that natamycin was particularly good when treating a particular type of fungal infection (Fusarium species).
The trials included in this review were of variable quality and were generally underpowered. There is evidence that natamycin is more effective than voriconazole in the treatment of fungal ulcers. Future research should evaluate treatment effects according to fungus species.
Fungal keratitis is a fungal infection of the cornea. It is common in lower income countries, particularly in agricultural areas but relatively uncommon in higher income countries. Although there are medications available, their effectiveness is unclear.
To assess the effects of different antifungal drugs in the management of fungal keratitis.
We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2015, Issue 2), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to March 2015), EMBASE (January 1980 to March 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to March 2015), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 16 March 2015.
We included randomised controlled trials of medical therapy for fungal keratitis.
Two review authors selected studies for inclusion in the review, assessed trials for risk of bias and extracted data. The primary outcome was clinical cure at two to three months. Secondary outcomes included best-corrected visual acuity, time to clinical cure, compliance with treatment, adverse outcomes and quality of life.
We included 12 trials in this review; 10 trials were conducted in India, one in Bangladesh and one in Egypt. Seven of these trials were at high risk of bias in one or more domains, two of these studies were at low risk of bias in all domains. Participants were randomised to the following comparisons: topical 5% natamycin compared to topical 1% voriconazole; topical 5% natamycin compared to topical 2% econazole; topical 5% natamycin compared to topical chlorhexidine gluconate (0.05%, 0.1% and 0.2%); topical 1% voriconazole compared to intrastromal voriconazole 50 g/0.1 mL (both treatments combined with topical 5% natamycin); topical 1% voriconazole combined with oral voriconazole compared to both oral voriconazole and oral itraconazole (both combined with topical 5% natamycin); topical 1% itraconazole compared to topical 1% itraconazole combined with oral itraconazole; topical amphotericin B compared to topical amphotericin B combined with subconjunctival injection of fluconazole; intracameral injection of amphotericin B with conventional treatment compared to conventional treatment alone (severe fungal ulcers); topical 0.5% and 1% silver sulphadiazine compared to topical 1% miconazole. Overall the results were inconclusive because for most comparisons only one small trial was available. The exception was the comparison of topical natamycin and topical voriconazole for which three trials were available. In one of these trials clinical cure (healed ulcer) was reported in all 15 people allocated to natamycin and in 14/15 people allocated to voriconazole (risk ratio (RR) 1.07; 95% confidence interval (CI) 0.89 to 1.28, low quality evidence). In one trial people randomised to natamycin were more likely to have a microbiological cure at six days (RR 1.64; 95% CI 1.38 to 1.94, 299 participants). On average, people randomised to natamycin had better spectacle-corrected visual acuity at two to three months compared to people randomised to voriconazole but the estimate was uncertain and the 95% confidence intervals included 0 (no difference) (mean difference -0.12 logMAR, 95% CI -0.31 to 0.06, 434 participants; 3 studies, low quality evidence) and a decreased risk of corneal perforation or therapeutic penetrating keratoplasty, or both (RR 0.61; 95% CI 0.40 to 0.94, 434 participants, high quality evidence). There was inconclusive evidence on time to clinical cure. Compliance with treatment and quality of life were not reported. One trial comparing natamycin and voriconazole found the effect of treatment greater in Fusarium species, but this subgroup analysis was not prespecified by this review.