Therapeutic options for managing fungal keratitis limited

Take-home message: Natamycin was superior to voriconazole in a randomized clinical trial for outcome measures, such as visual acuity and perforations.

By Nancy Groves; Reviewed by Namperumalsamy Venkatesh Prajna, MBBS

Madurai, Tamil Nadu, India-In the Mycotic Ulcer Treatment Trial I (MUTT I), visual acuity and perforation outcomes were significantly better in patients with fungal keratitis who were randomly assigned to treatment with natamycin (Natacyn, Alcon Laboratories) than to voriconazole (Vfend, Pfizer), said principal investigator Namperumalsamy Venkatesh Prajna, MBBS.

Patients randomly assigned to voriconazole were more likely to perforate and to require therapeutic penetrating keratoplasty, said Dr. Prajna, chief, Department of Medical Education, Aravind Eye Care System, Madurai, Tamil Nadu, India.

However, the differences in efficacy in this study were primarily attributable to the high number of cases caused by Fusarium, about 50% of the positive cultures.

“It’s a well-known fact that different bacteria have different susceptibility patterns. But for fungus, it was always antifungals,” Dr. Prajna said. “We never realized that there could be a differential sensitivity to different drugs.”

In this study, Fusarium responded much better to natamycin than to voriconazole. In light of these results-where differential antifungal susceptibility has been clearly established and in light of the fact that culture is not performed for all patients with fungal keratitis-voriconazole as monotherapy for filamentous fungal keratitis is not recommended, Dr. Prajna noted.

For almost 50 years, natamycin was the only drug available for treating fungal keratitis. However, isolated case reports and small cases on the efficacy of voriconazole began to appear within the past decade. A survey whose results were published in Cornea in 2009 revealed that the majority of cornea specialists preferred voriconazole for topical treatment.

“The results were very clear that voriconazole had captured their imagination worldwide,” Dr. Prajna said. “Sixty-eight percent of the ophthalmologists would prefer voriconazole if the choice was given to them.”

Setting the stage

These findings set the stage for the MUTT I trial comparing the efficacy of natamycin, the gold standard, and the newer alternative, voriconazole in patients with fungal corneal ulcers. MUTT I, sponsored by the National Eye Institute, was a double-masked, randomized trial in which more than 300 patients from three centers in South India were enrolled.

Patients with corneal ulcers who were smear positive for fungus were screened and then randomized to receive either natamycin (5%) or voriconazole (1%). Study participants remained at the treatment centers for at least a week to ensure that the drugs were administered on schedule. Masking was conducted to the extent possible (the drugs were dispensed in similar bottles), although natamycin could be identified by its tendency to precipitate.

The primary endpoint was best-corrected visual acuity (BVCA) at 3 months compared with baseline. Secondary endpoints included treatment failure as evidenced by perforations, size of infiltrate, scarring post-treatment compared to pre-treatment, and time to resolution of epithelial defect.

After screening, 323 patients were enrolled in the study. Of the 323 ulcers, 256 (79%) had positive cultures; 128 (50%) were Fusarium, 54 (21%) were Aspergillus species, 20 (8%) were Curvularia, and 54 (21%) were other species.

Patients had significantly poor visual acuity with a median Snellen visual acuity of 20/90. The median scar size was 3.2 mm, and 35% of hypopyon were more than 1 mm.

The results-which were inconsistent with the preference of corneal specialists worldwide-showed better efficacy for the older treatment than the newer option.

“At 3 months, very clearly natamycin-treated cases had significantly better BCVA than voriconazole-treated cases,” Dr. Prajna said (95% CI, p = 0.006). In the entire study population, 52 perforations were reported, with almost twice as many in the voriconazole group (34 versus 18, p = 0.009).

Subgroup analysis

A subgroup analysis showed that patients positive for Fusarium healed significantly more rapidly with natamycin than voriconazole (p=0.005), while there was no significant difference in healing time with non-Fusarium cases.

The investigators also explored an association between in vitro susceptibility to antifungal medication and clinical outcomes.

“We found out that voriconazole was not a great drug for Fusarium,” Dr. Prajna said.

A. flavus had the highest minimum inhibitory concentration (MIC) 50 and MIC 90 among natamycin-treated organisms, and Fusarium species had the highest MIC 50 and MIC 90 among voriconazole-treated organisms.

“When we correlated MIC with the final visual outcome, we found that decreased susceptibility to natamycin correlated with increased odds of perforation, while susceptibility to voriconazole was not clearly associated with measured outcomes,” he added.

Limitations to the study included enrollment exclusively of patients in South India, exclusion of contact lens wearers, comparison only of monotherapies, and the predominance of Fusarium cases, the organism most prevalent in fungal keratitis cases in South India.

Namperumalsamy Venkatesh Prajna, MBBS

P: 91(452)4356-100

E: prajna@aravind.org

This article was adapted from Dr. Prajna’s presentation during Cornea Subspecialty Day at the 2014 meeting of the American Academy of Ophthalmology. Dr. Prajna reported no financial interests or relationships.