Fungal keratitis is a group of corneal ulcers that cause severe visual impairment, especially in developing countries. Plant-related trauma and long-term steroid use are predisposing factors 2). Symptoms are often subtle, leading to delayed diagnosis, and treatment response is poorer compared to bacterial infections.
Natamycin (pimaricin) eye drops are the only FDA-approved topical medication for fungal keratitis. Meanwhile, in vitro studies have reported that voriconazole, a triazole agent, shows superior antifungal activity. However, randomized controlled trials comparing the two drugs were lacking.
The MUTT trial was a large-scale RCT conducted in southern India (and Nepal) with support from the National Eye Institute (NEI) to address this clinical question. It consists of two trials: MUTT 1 (published in 2013) and MUTT 2 (published in 2016).
Based on the results of MUTT 1, natamycin (pimaricin) is the first-line treatment for fungal keratitis caused by Fusarium species. Voriconazole is less effective against Fusarium and should not be used as monotherapy. On the other hand, for filamentous fungi other than Fusarium (especially Aspergillus) or cases unresponsive to pimaricin, voriconazole eye drops are recommended 2).
In the early stages, symptoms such as pain may be mild, leading to delayed diagnosis.
Clinical findings differ between filamentous fungi and yeasts. The MUTT trial targeted filamentous fungal keratitis.
In filamentous fungal keratitis, Fusarium species (especially Fusarium solani) are the most common2). Next are Aspergillus, Alternaria, and Paecilomyces species.
Definitive diagnosis requires scraping of the lesion and microbiological examination 2).
Trial Design
Design: Randomized, double-masked, controlled multicenter trial (southern India)
Subjects: 323 cases of smear-positive filamentous fungal keratitis (Fusarium spp. 128 [40%], Aspergillus spp. 54 [17%], others 141 [43%])
Intervention: 5% natamycin eye drops vs. 1% voriconazole eye drops (every hour until epithelialization, then 4 times daily for 3 weeks)
Primary outcome: Best spectacle-corrected visual acuity (BSCVA) at 3 months
Key Results
3-month BSCVA: Natamycin group was superior by 1.4 lines (regression coefficient -0.18 logMAR; P=0.06)
Fusarium subgroup: Natamycin group was superior by 4.1 lines (regression coefficient -0.41 logMAR; P<0.001)
Perforation/TPK: Significantly more frequent in the voriconazole group (34 vs 18 cases; OR 0.42; P<0.001)
Microbiological cure (day 6): Natamycin was superior (culture positivity rate 15% vs 48%)
In conclusion of MUTT 1, natamycin showed better outcomes than voriconazole for filamentous fungal keratitis, especially Fusarium species. Voriconazole should not be used as monotherapy for Fusarium keratitis.
MUTT 2 included 240 cases of advanced fungal keratitis (visual acuity worse than 20/400). All patients received topical natamycin plus topical voriconazole, and were compared between an oral voriconazole group (400 mg twice daily on day 1, then 200 mg twice daily for 20 days) and a placebo group.
| Outcome | Result |
|---|---|
| Perforation/TPK | No significant difference (HR 0.82) |
| 3-month BSCVA | No significant difference |
| Adverse events | VRC group 48.7% vs placebo group 23.1% |
In the oral voriconazole group, adverse events such as elevated liver enzymes and visual hallucinations were more frequent. In the Fusarium subgroup, a trend toward reduced perforation/TPK rate was observed (HR 0.49; P=0.03).
When analyzing only Fusarium keratitis, adding oral voriconazole to topical natamycin showed potential benefit. The hazard of perforation/TPK decreased to 0.43 times (P=0.1), and the infiltrate/scar size was 1.89 mm smaller at 3 weeks (P<0.001).
In CQ-6 of the Infectious Keratitis Clinical Practice Guidelines (3rd edition), voriconazole eye drops prepared in-house for fungal keratitis are “conditionally recommended” (strength of recommendation: weak recommendation, evidence level: B)2). For Fusarium species, pimaricin (natamycin) is recommended as the first-line polyene agent2).
In Japan, 5% pimaricin eye drops (natamycin) and 1% pimaricin ophthalmic ointment are available, equivalent to 5% natamycin ophthalmic solution overseas2). Voriconazole eye drops are an in-house preparation not covered by insurance, but should be considered for filamentous fungi other than Fusarium and for cases unresponsive to pimaricin2).
In Japan, the only topical ophthalmic antifungal drug covered by insurance is pimaricin (5% eye drops and 1% ointment). Other in-house preparations include voriconazole 1% eye drops, fluconazole 0.2% eye drops, miconazole 0.1% eye drops, and micafungin 0.1% eye drops2). Systemic options include oral voriconazole and intravenous amphotericin B, but side effects require caution.
Filamentous fungi are multicellular structures with branching filaments, inhabiting plant surfaces and soil. They invade corneal tissue following trauma and progress through the corneal stroma by extending hyphae toward deeper layers.
The mechanisms of action differ among antifungal drug classes2).
Natamycin is a suspension, so its penetration into the deep cornea is limited, but its fungicidal effect on the surface is potent. Voriconazole has good penetration into the anterior chamber with systemic administration, which was the basis for oral administration in MUTT 22).
Maniam et al. reported two cases of Candida parapsilosis keratitis after cataract surgery that were resistant to medical therapy. They performed anterior chamber irrigation and removal of endothelial plaque using a 23G vitreous cutter, achieving good visual recovery1). Anterior chamber irrigation may serve as an adjunctive treatment to avoid therapeutic penetrating keratoplasty (TPK)1).
The causative fungi vary by country and region, and the proportion of Fusarium species affects treatment outcomes2). This point must be considered when interpreting the results of the MUTT trials. Future research topics include monitoring drug resistance trends, developing new antifungal agents, and evaluating the combined effect of corneal cross-linking3).
MUTT 2 showed that adding oral voriconazole does not improve overall outcomes in advanced fungal keratitis. However, in the Fusarium subgroup, there was a trend toward reduced risk of perforation, suggesting the usefulness of combining oral voriconazole with topical natamycin. However, oral voriconazole has many adverse events (elevated liver enzymes, visual hallucinations), so careful risk-benefit assessment is necessary.
