Natamycin still the best bet for fungal keratitis

Reviewed by Jennifer R. Rose-Nussbaumer, MD

A recent study sponsored by the National Eye Institute (NEI) of the optimal treatments for fungal keratitis showed that topical natamycin is still the mainstay of treatment. Adding oral voriconazole to the treatment regimen also may be beneficial to treat patients with Fusarium species.

In tropical areas, fungal infections are responsible for more than 50% of corneal ulcers and they carry a worse prognosis compared with bacterial keratitis–with higher rates of corneal perforations and the need for penetrating keratoplasty (PK), according to Jennifer Rose-Nussbaumer, MD.

With this serious clinical picture, it has been more than 50 years since a treatment for fungal keratitis was introduced. The last treatment introduced for corneal keratitis was natamycin.

While microbiology with Giemsa gram staining and culture plates continues to be the primary methods of establishing a clinical diagnosis for fungal keratitis, Dr. Rose-Nussbaumer, assistant professor of ophthalmology, Proctor Foundation, University of California, San Francisco (UCSF), considers confocal microscopy to be a fast and excellent way to diagnose filaments.

“We can diagnose the patient in the office in just a few minutes and prescribe the appropriate therapy at that time,” Dr. Rose-Nussbaumer emphasized.

She depends on anterior-segment optical coherence tomography to follow up on patients with fungal keratitis by evaluating infiltrates, scar sizes, and corneal thinning over time.

Treatment trial

Regarding the rationale the use of natamycin for treating fungal ulcers, Dr. Rose-Nussbaumer cited the results of the Mycotic Ulcer Treatment Trial, which was a randomized, double-masked, non-placebo-controlled collaborative study (JAMA Ophthalmol 2013; 131:422-9) between UCSF and the NEI and N. Venkatesh Prajna, MD, Aravind Eye Hospital, Madurai, India.

In this study, smear-positive fungal ulcers were randomized to treatment with either topical natamycin or topical voriconazole. The primary outcome measure was the best spectacle-corrected visual acuity (BSCVA) at 3 months after the start of treatment.

The results indicated that in the 323 patients enrolled at the Aravind Eye Hospital, the eyes treated with natamycin improved more than those treated with voriconazole in the BSCVA (P = 0.006), the 6-day microbiologic cure rate (P <0.001), the infiltrate and scar size (P = 0.05), and the corneal perforation rate (P = 0.009).

“These results were especially applicable to patients with Fusarium ulcers who had a mean improvement of 4 lines of visual acuity in the group that was randomized to treatment with natamycin,” Dr. Rose-Nussbaumer reported.

Oral voriconazole trial

Oral voriconazole trial

Topical natamycin, however, is not as effective as might be desired. The major limitation of the drug is its shallow penetration into the cornea.

This shortcoming prodded the investigators to take a look at treatment with oral voriconazole for fungal ulcers because of its ability to penetrate the eye and the possibility that it might be more beneficial for deeper infections, Dr. Rose-Nussbaumer explained.

However, the results of the Mycotic Ulcer Treatment Trial II, released in the last quarter of 2016 and published in JAMA Ophthalmol (2016; online), were mixed.

This study was a randomized, double-masked, placebo-controlled study that looked at 240 smear-positive, severe fungal corneal ulcers in eyes with a visual acuity of 20/400 that were randomized to treatment with oral voriconazole or placebo. All patients received a topical anti-fungal treatment.

The primary outcomes were the rates of perforation and the need for therapeutic PK at 3 months after the start of treatment. The baseline median BCVA was counting fingers, and the median infiltrate/scar size was 5.4 mm².

The Fusarium species was the most occurring pathogen, followed by the Aspergillus species (30% and 26.3%, respectively) in this patient population.

The results indicated that a significantly (P = 0.003) higher rate of adverse events was associated with the use of oral voriconazole that included elevated liver function tests and visual disturbances, among others.

No marked improvement

No marked improvement

In the first Mycotic Ulcer Treatment Trial, the investigators found that the organism subtypes present in an ulcer are predictive of the therapeutic response. Among the patients with a Fusarium infection in the second Mycotic Ulcer Treatment Trial, the investigators found no marked improvement in the patients treated with placebo at 3 weeks after the start of treatment.

In contrast, the patients treated with oral voriconazole showed marked improvement in their corneal ulcers. The same findings were true at the 3-month time point.

“Overall, in the subgroup of patients with Fusarium infections and randomized to oral voriconazole, the rate of corneal perforation or the need for a therapeutic PK deceased (hazard ratio, 0.43; 95% confidence interval, 0.22-0.84; P = 0.01), Dr. Rose-Nussbaumer said.

Among the secondary outcomes, the BSCVA and the 3-month infiltrate/scar size in the patients treated with voriconazole were superior to those who received placebo (P =0.05 and P =0.001, respectively). The BSCVA improved by about 3 lines and the infiltrate/scar size was almost 1 mm smaller. The times to re-epithelialization did not differ between the groups.

“Topical natamycin remains the mainstay of treatment of fungal keratitis,” Dr. Rose-Nussbaumer outlined. “However, Fusarium corneal ulcers might benefit from the addition of oral voriconazole to the treatment regimen. It is important to note that oral voriconazole is associated with more adverse events and higher costs.”

Jennifer Rose-Nussbaumer, MD

E: Jennifer.Rose-Nussbaumer@ucsf.edu

This article was adapted from a presentation Dr. Rose-Nussbaumer delivered at the Cornea Subspecialty Day prior to the 2016 American Academy of Ophthalmology meeting. Dr. Rose-Nussbaumer has no financial interest in any aspect of this report.