Broad-spectrum activity of antifungals needs further study

Key Points

San Francisco-Findings of a study evaluating in vitro susceptibility of clinical fungal keratitis isolates suggest that use of newer antifungal medications may afford better outcomes in these potentially sight-threatening infections, according to the investigators of a paper published earlier this year (Arch Ophthalmol. 2007;125:789-793).

Prajna Lalitha, MD, conducted the study at Aravind Eye Hospital, South India, in conjunction with Brett Shapiro, MD, and other researchers from the University of California, San Francisco (UCSF), and the University of Texas Health Sciences Center, San Antonio. In it, the susceptibility of a total of 90 fungal isolates was tested to six different antifungal medications using macro-dilution assays. Aspergillus species (n = 41) and Fusarium (n = 38) accounted for the majority of the isolates. The antifungals tested were amphotericin B, natamycin, caspofungin acetate, itraconazole, voriconazole, and posaconazole.

The minimum inhibitory concentration (MIC) data showed that no single antifungal was consistently the most effective against all species. Voriconazole and posaconazole had the broadest spectrum, but natamycin had the lowest MICs against Aspergillus and Fusarium species when the MICs were adjusted for concentrations used topically.

"Considering the relatively poor efficacy of traditional approaches to treatment, and based on the results of this study, it appears we should be using more voriconazole to treat fungal keratitis. Ideally, further clinical studies should be done to investigate the relative efficacy of different agents in the management of these challenging infections and also the relationship between in vitro susceptibility and clinical outcomes," he said.

Dr. Lietman is associate professor in residence, Francis I. Proctor Foundation for Research in Ophthalmology, UCSF. Dr. Shapiro, who did much of the project work, was a medical student at UCSF and will return in 2008 to begin a residency in ophthalmology.

The results of the study showed that against Aspergillus isolates, posaconazole, voriconazole, itraconazole, and caspofungin offered the lowest MIC₉₀ values (0.125 to 0.5 μg/ml), whereas voriconazole and amphotericin B had the most potent activity against Fusarium isolates (MIC₉₀ = 4 μg/ml for both). All Fusarium species were resistant to highest tested concentrations of itraconazole (8 μg/ml) and caspofungin acetate (16 μg/ml).

"Itraconazole is commercially available as a topical preparation in India, but we and others in the United States have been using oral itraconazole empirically in patients with fungal corneal ulcers. This study shows it's not a good drug for Fusarium and should not be used," Dr. Lietman said.

In a separate analysis, the MIC values were corrected to account for the varying concentrations of the different antifungals that are used clinically.

"Although amphotericin B had significantly lower MICs than natamycin against Aspergillus and Fusarium species, once we adjusted for the fact that amphotericin B is usually administered in a concentration of 0.15% and natamycin is available as a 5% solution, relative MICs against these fungal species were lower for natamycin," Dr. Lietman said.

Bioavailability differences

The study does not consider the possible influence of differences in bioavailability between antifungal agents. As the investigators noted, amphotericin B and natamycin have poor penetration through intact corneal epithelium, whereas voriconazole appears to penetrate well. In addition, it is unknown whether geographic variability exists in antifungal susceptibility because the relative infrequency of fungal keratitis in most areas precludes large-scale susceptibility studies in different regions worldwide.