Elsevier

Ophthalmology

Volume 121, Issue 8, August 2014, Pages 1495-1500.e1
Ophthalmology

Original article
Association between In Vitro Susceptibility to Natamycin and Voriconazole and Clinical Outcomes in Fungal Keratitis

Presented at: American Academy of Ophthalmology Annual Meeting, November 2013, New Orleans, Louisiana.
https://doi.org/10.1016/j.ophtha.2014.03.004Get rights and content

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.

Section snippets

Methods

The MUTT I was a multicenter, randomized, double-masked clinical trial investigating the optimal antimicrobial treatment of filamentous fungal keratitis. Detailed methods for MUTT I have been reported previously.16 In brief, 323 smear-positive fungal ulcer cases with enrollment visual acuity of 20/40 (0.3 logarithm of the minimum angle of resolution [logMAR]) to 20/400 (1.3 logMAR) seeking treatment at the Aravind Eye Care System (Madurai, Pondicherry, and Coimbatore) in India were randomized

Results

Of the 323 patients enrolled in the trial, 256 (79%) had ulcers with positive fungal culture results, and 221 (68%) had MIC results available and were included in the analysis. The 35 isolates that demonstrated positive fungal culture results but had missing MIC values had no growth during susceptibility testing. In Table 1, we report the MICs of natamycin or voriconazole for genus and species based on which treatment arm they were assigned. For natamycin-treated organisms, A. flavus had the

Discussion

In this study, we investigated the relationship between organism, in vitro susceptibility, and clinical outcome. We found that decreased susceptibility to natamycin correlated with larger 3-month infiltrate or scar size and increased odds of perforation. However, susceptibility to voriconazole was not associated significantly with any of the measured outcomes in the study.

Our findings are similar to previous studies of systemic fungal infection8, 12, 13 and fungal keratitis10, 11 that

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  • Cited by (0)

    Financial Disclosure(s): The author(s) have made the following disclosure(s): Nisha R. Acharya: Consultant—Xoma and Santan.

    Supported by the National Eye Institute, National Institutes of Health, Bethesda, Maryland (grant nos.: U10EY018573 [T.M.L.] and K23 EY017897 [N.R.A.]; That Man May See, San Francisco, CA (N.R.A., S.D.M., T.M.L.); Harper/Inglis Trust (T.M.L.); South Asia Research Fund (T.M.L.); Research to Prevent Blindness, Inc, New York, New York (N.R.A., T.M.L.); and the UCSF Academic Senate Committee on Research, San Francisco, California (C.Q.S.). Natamycin and voriconazole were donated by Alcon, Fort Worth, TX, and Pfizer, New York, NY, respectively. The sponsor or funding organization had no role in the design or conduct of this research.

    Supplemental material is available at www.aaojournal.org.

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