Mycotic Ulcer Treatment Trial 1 & 2

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Mycotic (Fungal) keratitis is a major group of corneal ulcers with significant morbidity particularly in the developing world. Long- term steroids, diabetes, and trauma with vegetative matter predispose to this condition. Most of these conditions are diagnosed late owing to the lack of disabling symptoms like pain. The MUTT trials were undertaken to study the outcomes of various treatment regimens for filamentous mycotic keratitis.

Mycotic Ulcer Treatment Trial 1[1]

Rationale

Topical Natamycin is the only topical drug approved by the FDA for use in mycotic keratitis. However, in vitro studies showed a superior response of isolated fungal groups to voriconazole. These findings were further supported by anecdotal instances of topical voriconazole usage. A randomized controlled trial comparing topical natamycin to voriconzole was lacking.

Study design

A National Eye Institute supported randomized, double-masked, controlled multi-center trial was conducted in southern India to determine if the use of natamycin or voriconazole resulted in better outcomes for fungal corneal ulcers.

Inclusion criteria and intervention

323 cases of fungal corneal ulcers (smear- positive) with presenting visual acuity worse than 20/40 (logMAR 0.3) but better than 20/400 (logMAR 1.3) were included in the study. 128 patients (40%) had Fusarium, 54 patients (17%) had Asperigillus, and 141 patient (43%) had other filamentous fungi. The cases were randomized into two groups with the first group receiving topical natamycin 5% and the other receiving topical voriconazole 1% (one drop hourly while until reepithelialization, followed by four times daily for the next three weeks). Further continuation of the medication was at the discretion of the treating physician.

Outcome measures

Patients were assessed at enrollment, every 3 days until reepithelialization, and additionally at 3 weeks and 3 months from enrollment.

Primary outcome:

Best spectacle- corrected visual acuity (BSCVA) 3 months from enrollment

Secondary outcomes:

  • BSCVA at 3 weeks
  • Infiltrate or scar size at 3 weeks & 3 months
    • Depth was assess as more than 0% to 33%, more than 33% to 67%, and more than 67% to 100%.
  • Time to reepithelialization
  • Microbiological cure at 6 days
  • Corneal perforation and/or therapeutic penetrating keratoplasty (TPK)

Results

  • BSCVA was better (1.4 lines) at 3 months in patients who received topical natamycin compared to those that received topical voriconazole (regression coefficient= -0.18 logMAR, 95% CI, -0.30 to -0.05; P=0.06).
    • Subgroup analysis: Those with smear-positive Fusarium, the BSCVA was 4.1 lines better compared to those treated with voriconazole (regression coefficient= -0.41 logMAR; 95% CI, -0.61 to -0.20; P=< 0.001).
    • There was no difference between non-Fusarium cases (regression coefficient= -0.02 logMAR; 95% CI, -0.17 to 0.13; P=0.81).
  • BSCVA was better (1.1 lines) at 3 weeks in patient who received topical natamycin compared to those that received topical voricozole (regression coefficient= -0.11 logMAR; 95% CI , -0.21 to -0.01, P=0.03).
  • Corneal perforation and/or the need for TPK was more likely in patients who received voriconazole (34 patients vs. 18 patients) (OR= 0.42, 95% CI, 0.22 to 0.80; P< 0.001).
  • Reepithelialization time and 3- month infiltrate or scar size were not significantly different between the two groups.
  • Natamycin was more effective in clearing culture positivity after 6 days compared to voriconzole (15% vs. 48%).
    • This difference was detected when comparing Fusarium-only subgroups and non- Fusarium cases.

Conclusion

In fungal corneal ulcer cases with filamentous fungal keratitis, particularly the Fusarium species, patients treated with natamycin had a better outcome than those treated with voriconazole. The difference in outcome in other species were not significant. Voriconazole should not be used as mono- therapy in the treatment of Fusarium keratitis.

Mycotic Ulcer Treatment Trial 2[2]

MUTT 2 was designed to study the benefit of oral voriconazole in addition to topical anti fungals in advanced mycotic keratitis cases. Compared to topical voriconazole, systemic voriconazole has good ocular penetration.

Study design

Randomized, double-masked, placebo controlled trial conducted in India and Nepal to determine if the use oral voriconazole in addition to topical anti fungal agents had any therapeutic benefit.

Inclusion criteria and intervention

240 cases (2133 patients were screened) of advanced fungal keratitis with presenting vision less than 20/400 (logMAR 1.3) were included in this study. The study participants were randomised into two group. The first group (n=119) received oral tablet voriconazole 400mg twice daily for one day followed by 200mg twice daily for 20days. The second group received a placebo with a similar schedule. Both groups received topical voriconazole 1% and topical natamycin 5% in addition to the oral drug.

Outcome measures

Primary outcome:

The rate of corneal perforation or the need for TPK within 3 months

Secondary outcomes:

  • Culture negativity at 6 days
  • Rate of reepithelialization
  • BSCVA at 3 weeks & 3 months
  • Infiltrate and/or scar size at 3 weeks & 3 months
  • Complication rate associated with PO voriconazole

Results

  • No significant difference in the rate of corneal perforation or the need for TPK was found between the two groups (hazard ratio, 0.82, 95% CI, 0.57-1.18, P=0.29).
  • No significant difference in BSCVA at 3 months between the groups.
  • Subgroup analysis looking at only Fusarium species found a trend towards decreased rate of perforation or TPK in the PO voriconzole group (effect coefficient, 0.49; 95% CI, 0.26-0.92, P= 0.03).
  • A total of 58 adverse events (48.7%) were recorded in the PO voriconzole arm vs. 28 adverse events (23.1%) in the placebo group. Adverse events in the PO voriconzole group included increased liver enzymes and visual hallucinations.

Conclusions

The addition of oral voriconazole to topical antifungals does not provide any therapeutic benefit for advanced filamentous fungal ulcer cases.

Secondary analysis[3]

Analysis of only Fusarium keratitis cases, the authors found that PO voriconazole in addition to topical natamycin may be beneficial.

  • Patients that received PO voriconzole had a 0.43- fold decreased hazard of perforation or TPK compared with placebo (95% CI, 0.22- fold to 0.84- fold; P=0.1).
  • Multiple linear repression showed a 1.89mm smaller infiltrate and/or scar size at 3 weeks (95% CI, -2.69 to -1.09mm; P<0.001) and 0.83m decreased infiltrate and/or scar size at 3 months (95% CI, -1.33 to -0.32mm; P=0.001) in patients treated with PO voriconazole vs. placebo, respectively.
  • No statistical difference was found in BSCVA at 3 months between the two groups (though there was a tendency for better vision in the PO voriconazole arm).

References

  1. Prajna NV, Mascarenhas J, Krishnan T, et al. Comparison of natamycin and voriconazole for the treatment of fungal keratitis. Arch Ophthalmol 2010;128:672-8.
  2. Prajna NV, Krishnan T, Rajaraman R, et al. Effect of Oral Voriconazole on Fungal Keratitis in the Mycotic Ulcer Treatment Trial II (MUTT II): A Randomized Clinical Trial. JAMA Ophthalmol 2016;134:1365-72.
  3. Prajna NV, Krishnan T, Rajaraman R, et al. Adjunctive Oral Voriconazole Treatment of Fusarium Keratitis: A Secondary Analysis From the Mycotic Ulcer Treatment Trial II. JAMA Ophthalmol 2017;135:520-5.