Association between in vitro susceptibility to natamycin and voriconazole and clinical outcomes in fungal keratitis

Ophthalmology. 2014 Aug;121(8):1495-500.e1. doi: 10.1016/j.ophtha.2014.03.004. Epub 2014 Apr 16.


Purpose: To assess the association between minimum inhibitory concentration (MIC) and clinical outcomes in a fungal keratitis clinical trial.

Design: Experimental study using data from a randomized comparative trial.

Participants: Of the 323 patients enrolled in the trial, we were able to obtain MIC values from 221 patients with monocular fungal keratitis.

Methods: The Mycotic Ulcer Treatment Trial I was a randomized, double-masked clinical trial comparing clinical outcomes of monotherapy with topical natamycin versus voriconazole for the treatment of fungal keratitis. Speciation and determination of MIC to natamycin and voriconazole were performed according to Clinical and Laboratory Standards Institute guidelines. The relationship between MIC and clinical outcome was assessed.

Main outcome measures: The primary outcome was 3-month best spectacle-corrected visual acuity. Secondary outcomes included 3-month infiltrate or scar size; corneal perforation and/or therapeutic penetrating keratoplasty; and time to re-epithelialization.

Results: A 2-fold increase in MIC was associated with a larger 3-month infiltrate or scar size (0.21 mm; 95% confidence interval [CI], 0.10-0.31; P < 0.001) and increased odds of perforation (odds ratio, 1.32; 95% CI, 1.04-1.69; P = 0.02). No correlation was found between MIC and 3-month visual acuity. For natamycin-treated cases, an association was found between higher natamycin MIC with larger 3-month infiltrate or scar size (0.29 mm; 95% CI, 0.15-0.43; P < 0.001) and increased perforations (odds ratio, 2.41; 95% CI, 1.46-3.97; P < 0.001). Among voriconazole-treated cases, the voriconazole MIC did not correlate with any of the measured outcomes in the study.

Conclusions: Decreased susceptibility to natamycin was associated with increased infiltrate or scar size and increased odds of perforation. There was no association between susceptibility to voriconazole and outcome.

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Topical
  • Antifungal Agents / pharmacology
  • Antifungal Agents / therapeutic use*
  • Cicatrix / pathology
  • Corneal Perforation / diagnosis
  • Corneal Ulcer / drug therapy*
  • Corneal Ulcer / microbiology
  • Double-Blind Method
  • Epithelium, Corneal / physiology
  • Eye Infections, Fungal / drug therapy*
  • Eye Infections, Fungal / microbiology
  • Fungi / drug effects*
  • Fungi / isolation & purification
  • Humans
  • Keratoplasty, Penetrating
  • Microbial Sensitivity Tests
  • Natamycin / pharmacology
  • Natamycin / therapeutic use*
  • Ophthalmic Solutions
  • Re-Epithelialization
  • Treatment Outcome
  • Visual Acuity / physiology
  • Voriconazole / pharmacology
  • Voriconazole / therapeutic use*


  • Antifungal Agents
  • Ophthalmic Solutions
  • Natamycin
  • Voriconazole