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

Abstract

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 (MUTT 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/scar size, corneal perforation and/or therapeutic penetrating keratoplasty (TPK), and time to re-epithelialization. Results A 2-fold increase in MIC was associated with a larger 3-month infiltrate/scar size (0.21 mm, 95% confidence interval [CI] 0.10–0.31, P <0.001) and increased odds of perforation (odds ratio [OR] 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/scar size (0.29 mm, 95% CI 0.15–0.43, P<0.001) and increased perforations (OR 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. Conclusion Decreased susceptibility to natamycin was associated with increased infiltrate/scar size and increased odds of perforation. There was no association between susceptibility to voriconazole and outcome.

Natamycin and Voriconazole Exhibit Synergistic Interactions with Nonantifungal Ophthalmic Agents against Fusarium Species Ocular Isolates

“…In addition, because the selected nonantifungal agents have already demonstrated safety when applied to the ocular surface, combined formulations could be developed and deployed quickly. A potential limitation of the present study is that it involves exclusively in vitro experiments, and it has been shown with Fusarium species that in vitro susceptibility does not necessarily correlate with the in vivo clinical response (33). Therefore, future work should evaluate the translation of these preliminary in vitro findings to in vivo animal or human trials.…”

Changing Azole Resistance

“…3 Reduced success in the treatment of corneal ulcers has also been associated with increasing MICs to voriconazole. 1 Treatment with azoles before presentation and enrollment in MUTT I was not shown to increase voriconazole MICs. 11 This finding suggests that the increased resistance patterns observed in this study are not owing to treatment of disease with antifungals.…”

“…1 The mechanism for azole resistance in filamentous fungi may be a mutation in the CYP51 gene responsible for producing the lanosterol-14α-demethylase enzyme, which is the drug target. 2 Development of resistance has been documented in patients with chronic fungal infections such as pulmonary aspergillosis after prolonged use of triazole antifungals.…”

“…7 Secondary analyses collected from MUTT I data showed that a 2-fold increase in minimum inhibitory concentration (MIC) was associated with increased odds of perforation and increased 3-month scar size, but not decreased visual acuity. 1 In this non–prespecified subgroup analysis, we investigate how azole resistance patterns changed during MUTT I.…”

In vitro synergy of natamycin and voriconazole against clinical isolates of Fusarium, Candida, Aspergillus and Curvularia spp

“…Therefore, testing of drug susceptibility of fungal species seems important for the final treatment outcome. However, the guidelines for antifungal susceptibility testing in treatment of fungal keratitis have not been well established,9 and the clinical trials are very few in numbers.…”