Comparison of Natamycin vs. Voriconazole for Treating Fungal Keratitis: MUTT-I Trial

Background

Fungal corneal ulcers are more difficult to treat as compared to bacterial corneal ulcers. The existing treatment options for fungal keratitis seem to be only moderately effective. In fact, corneal specialists believe that voriconazole, if available, could be the choice of drug for treating filamentous fungal keratitis.

Aim

The Mycotic Ulcer Topical Treatment (MUTT) Trial I aimed at comparing the efficacy of topical natamycin as against voriconazole for the treatment of filamentous fungal keratitis.

Patient Profile

• Patients (age >16 years) with smear positive filamentous fungal ulcer and baseline visual acuity of 20/40 to 20/400 (n=368)

Methods

Study Design

• Phase 3, randomized, active comparator–controlled, double-masked, multicenter (including hospitals in India and California) trial

Treatment Strategy

• Patients were randomized to receive:

Primary Outcome

• The best spectacle-corrected visual acuity (BSVA) at 3 months

Secondary Outcomes

• BSVA at 3 weeks
• Infiltrate or scar size at 3 weeks and 3 months
• Time to re-epithelialization
• Microbiological cure at day 6
• Corneal perforation and/or therapeutic penetrating keratoplasty

Assessments

• Patients were assessed at baseline, every 3 days until re-epithelialization, and at 3 weeks and 3 months after enrolment

Results

• The most commonly isolated causative organisms included:
  • Fusarium species: 40% (n=128)
  • Aspergillus species: 17% (n=54)
  • Other filamentous fungi:  43% (n=141 patients)
• The median duration of treatment was 31 days in the natamycin treatment arm and 39 days in the voriconazole treatment arm (P =0.006).
• At 3 weeks, patients treated with voriconazole had BSCVA poorer by 1.1 lines as compared to those treated with natamycin (regression coefficient = −0.11 logMAR; P = 0.03)
• Similarly, at 3 months voriconazole-treated patients had BSCVA poorer by 1.8 lines as compared to the patients treated with natamycin (regression coefficient=−0.18 logMAR; P=0.006).
• Natamycin treatment rather than voriconazole treatment was more effective in patients infected with fusarium (regression coefficient=−0.41 logMAR; P<0.001; OR for perforation=0.06; P<0.001)
• Both the treatments had similar impact on non-fusarium cases (regression coefficient=−0.02 logMAR; P=0.81; odds ratio for perforation=1.08; P=0.86).
• Greater proportion of voriconazole-treated patients tested culture positive at day 6 vs. the natamycin-treated patients (48% vs. 15%; P < 0.001). The findings were similar between the fusarium and non-fusarium cases.
• As per a Cox proportional regression analysis, natamycin-treated cases had a 1.25-fold higher hazard ratio ([HR]; p=0.11) for re-epithelialization with fusarium cases having a rapid healing with natamycin (HR; 1.89, p=0.005). Such rapid healing was not evident in non-fusarium cases treated with natamycin (HR; 1.00, p>0.99).
• The scar size at 3 months was significantly smaller in the fusarium cases treated with natamycin vs. those treated with voriconazole (regression coefficient = −1.02 mm; P < .001). The findings did not differ significantly for the non-fusarium cases.
• Greater proportion of patients treated with voriconazole had a perforation and/or required a therapeutic penetrating keratoplasty (TPK) vs. those treated with natamycin (34 vs. 18 patients; OR, 0.42, p=0.009). The OR for perforation in the fusarium cases was 0.06 (p<0.001) and that for non-fusarium cases was 1.08 (p=0.86).
• More number of patients treated with voriconazole had an increase of at least 2 mm in hypopyon size as compared to natamycin treated patients (12 vs. 5 patients; p=0.09)

Conclusions

• Natamycin treatment was associated with a significantly better visual acuity at 3 months vs. voriconazole treatment in patients with fungal keratitis.
• Voriconazole-treated patients were more likely to have a perforation and/or receive a therapeutic corneal transplant as compared to natamycin treatment.
• The superiority of natamycin over voriconazole was more prominent in fusarium cases rather than the non-fusarium cases.
• Overall, topical natamycin yielded superior clinical and microbiological outcomes over voriconazole for smear-positive filamentous fungal keratitis, particularly in fusarium cases.
• Voriconazole should therefore not be used as monotherapy for treating filamentous keratitis.

JAMA Ophthalmol. 2013; 131 (4): 422–29.