Synergy, Indifference, or Antagonism? In vitro Susceptibility of Fusarium spp and Aspergillus spp Isolated From Keratitis in South India Against Amphotericin B and Natamycin Combination Therapy

Abstract

Purpose: : A limited number of antimicrobial agents are available for the treatment of fungal keratitis. The non-ocular infectious disease literature suggests susceptibility testing of fungal isolates provides clinically relevant information. Nevertheless, physicians often combine drugs empirically rather than based on laboratory or clinical evidence. One of the more common combinations used by U.S. ophthalmologists is amphotericin B and natamycin. Here, we investigate whether amphotericin B and natamycin interact synergistically in vitro against Fusarium sppand Aspergillus spp isolated from keratitis.

Methods: : Twenty isolates of Fusarium spp and Aspergillus spp were randomly selected from cases of fungal keratitis treated at Aravind Eye Hospital. Each isolate was tested for susceptibility to amphotericin B and natamycin alone. Synergy was determined using the checkerboard microdilution method and by calculating the Fractional Inhibitory Concentration Index (FICI). Synergy is defined as FICI ≤ 0.5, indifference is FICI > 0.5 and ≤ 4, and antagonism is FICI > 4.

Results: : The susceptibility pattern for all twenty isolates showed indifference to combinations of amphotericin B and natamycin. For Fusarium spp the mean FICI was 1.022, and for Aspergillus spp the mean FICI was 0.934.

Conclusions: : None of the twenty isolates demonstrated synergism between amphotericin B and natamycin. These results suggest there may not be additional benefit to treating fungal ulcers with amphotericin and natamycin simultaneously. Future studies are necessary to assess whether other combinations, such as natamycin and voriconazole, demonstrate synergy, and how in vitro susceptibilities correlate with in vivo clinical results.

Keywords: fungal disease • keratitis • cornea: basic science