Skip to main content
NCBI home page
Transactions of the American Ophthalmological Society logoLink to Transactions of the American Ophthalmological Society
. 2003;101:183–189.

Safety of intravitreal voriconazole: electroretinographic and histopathologic studies.

Gao Hua 1, Mark Pennesi 1, Kekul Shah 1, Xiaoxi Qiao 1, Seenu M Hariprasad 1, William F Mieler 1, Samuel M Wu 1, Eric R Holz 1
PMCID: PMC1358987  PMID: 14971576

Abstract

PURPOSE: Voriconazole, a novel triazole antifungal agent, presents potent activity against a broad spectrum of yeast and molds. To determine whether it could be safely used as an intravitreal agent in the treatment of fungal endophthalmitis, retinal toxicity of voriconazole was examined in a rodent animal model. METHODS: Voriconazole solutions were serially diluted and injected intravitreally into eyes of normal adult Sprague-Dawley rats so that the final intravitreal concentrations were 5 microg, 10 microg, 25 microg, 50 microg, and 500 microg/mL (N = 3 for each concentration group). Saline was injected into the fellow eyes of each animal as controls. Three weeks after injections, electroretinograms (ERGs) were measured, and eyes were subsequently enucleated for histologic examination. RESULTS: In ERG studies, maximum scotopic b-wave, bmax intensity needed for half saturation, I0.5, and saturated a-wave amplitude were measured. There was no statistically significant difference in these parameters recorded between control eyes and voriconazole-injected eyes in any concentration groups. Histologic examination with light microscopy did not reveal any retinal abnormality in the eyes with 5 to 25 microg/mL intravitreal voriconazole. In the eyes with 50 microg/mL and 500 microg/mL voriconazole, small foci of retinal necrosis were occasionally observed in the outer retina, especially in the eyes with 500 mg/mL voriconazole. CONCLUSION: Our results demonstrate that intravitreal voriconazole of up to 25 mg/mL causes no ERG change or histologic abnormality in rat retina. This indicates that voriconazole is a safe antifungal agent that may be employed by intravitreal injection in the treatment of fungal endophthalmitis.

Full Text

The Full Text of this article is available as a PDF (197.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abraham O. C., Manavathu E. K., Cutright J. L., Chandrasekar P. H. In vitro susceptibilities of Aspergillus species to voriconazole, itraconazole, and amphotericin B. Diagn Microbiol Infect Dis. 1999 Jan;33(1):7–11. doi: 10.1016/s0732-8893(98)00102-3. [DOI] [PubMed] [Google Scholar]
  2. Axelrod A. J., Peyman G. A., Apple D. J. Toxicity of intravitreal injection of amphotericin B. Am J Ophthalmol. 1973 Oct;76(4):578–583. doi: 10.1016/0002-9394(73)90753-8. [DOI] [PubMed] [Google Scholar]
  3. Baldinger J., Doft B. H., Burns S. A., Johnson B. Retinal toxicity of amphotericin B in vitrectomised versus non-vitrectomised eyes. Br J Ophthalmol. 1986 Sep;70(9):657–661. doi: 10.1136/bjo.70.9.657. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Berkowitz B. A., Lukaszew R. A., Mullins C. M., Penn J. S. Impaired hyaloidal circulation function and uncoordinated ocular growth patterns in experimental retinopathy of prematurity. Invest Ophthalmol Vis Sci. 1998 Feb;39(2):391–396. [PubMed] [Google Scholar]
  5. Christmas N. J., Smiddy W. E. Vitrectomy and systemic fluconazole for treatment of endogenous fungal endophthalmitis. Ophthalmic Surg Lasers. 1996 Dec;27(12):1012–1018. [PubMed] [Google Scholar]
  6. Dunlap W. A., Karaçorlu M., Peyman G. A., Nair M. G., Rahimy M., Pedroza L. Retinal toxicity of intravitreally injected faeriefungin. Ophthalmic Surg. 1994 May;25(5):303–306. [PubMed] [Google Scholar]
  7. Espinel-Ingroff A., Boyle K., Sheehan D. J. In vitro antifungal activities of voriconazole and reference agents as determined by NCCLS methods: review of the literature. Mycopathologia. 2001;150(3):101–115. doi: 10.1023/a:1010954803886. [DOI] [PubMed] [Google Scholar]
  8. Gallis H. A., Drew R. H., Pickard W. W. Amphotericin B: 30 years of clinical experience. Rev Infect Dis. 1990 Mar-Apr;12(2):308–329. doi: 10.1093/clinids/12.2.308. [DOI] [PubMed] [Google Scholar]
  9. Ghannoum M. A., Rice L. B. Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance. Clin Microbiol Rev. 1999 Oct;12(4):501–517. doi: 10.1128/cmr.12.4.501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ghannoum Mahmoud A., Kuhn D. M. Voriconazole -- better chances for patients with invasive mycoses. Eur J Med Res. 2002 May 31;7(5):242–256. [PubMed] [Google Scholar]
  11. Howes Kim A., Pennesi Mark E., Sokal Izabela, Church-Kopish Jill, Schmidt Ben, Margolis David, Frederick Jeanne M., Rieke Fred, Palczewski Krzysztof, Wu Samuel M. GCAP1 rescues rod photoreceptor response in GCAP1/GCAP2 knockout mice. EMBO J. 2002 Apr 2;21(7):1545–1554. doi: 10.1093/emboj/21.7.1545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kappe R. Antifungal activity of the new azole UK-109, 496 (voriconazole). Mycoses. 1999;42 (Suppl 2):83–86. [PubMed] [Google Scholar]
  13. Lazar M., Ganor E., Nemet P., Godel V. The effect of experimental glaucoma on vitreous volume. Metab Pediatr Syst Ophthalmol. 1982;6(3-4):347–348. [PubMed] [Google Scholar]
  14. Lyubarsky A. L., Pugh E. N., Jr Recovery phase of the murine rod photoresponse reconstructed from electroretinographic recordings. J Neurosci. 1996 Jan 15;16(2):563–571. doi: 10.1523/JNEUROSCI.16-02-00563.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Maesaki S., Iwakawa J., Higashiyama Y., Miyazaki Y., Yanagihara K., Tomono K., Tashiro T., Kohno S. Antifungal activity of a new triazole, voriconazole (UK-109496), against clinical isolates of Aspergillus spp. J Infect Chemother. 2000 Jun;6(2):101–103. doi: 10.1007/pl00012145. [DOI] [PubMed] [Google Scholar]
  16. Marco F., Pfaller M. A., Messer S. A., Jones R. N. Antifungal activity of a new triazole, voriconazole (UK-109,496), compared with three other antifungal agents tested against clinical isolates of filamentous fungi. Med Mycol. 1998 Dec;36(6):433–436. [PubMed] [Google Scholar]
  17. O'Day D. M., Foulds G., Williams T. E., Robinson R. D., Allen R. H., Head W. S. Ocular uptake of fluconazole following oral administration. Arch Ophthalmol. 1990 Jul;108(7):1006–1008. doi: 10.1001/archopht.1990.01070090108050. [DOI] [PubMed] [Google Scholar]
  18. Pfaller M. A., Messer S. A., Hollis R. J., Jones R. N., Diekema D. J. In vitro activities of ravuconazole and voriconazole compared with those of four approved systemic antifungal agents against 6,970 clinical isolates of Candida spp. Antimicrob Agents Chemother. 2002 Jun;46(6):1723–1727. doi: 10.1128/AAC.46.6.1723-1727.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Pfaller M. A., Messer S. A., Hollis R. J., Jones R. N., Doern G. V., Brandt M. E., Hajjeh R. A. In vitro susceptibilities of Candida bloodstream isolates to the new triazole antifungal agents BMS-207147, Sch 56592, and voriconazole. Antimicrob Agents Chemother. 1998 Dec;42(12):3242–3244. doi: 10.1128/aac.42.12.3242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Reis A., Sundmacher R., Tintelnot K., Agostini H., Jensen H. E., Althaus C. Successful treatment of ocular invasive mould infection (fusariosis) with the new antifungal agent voriconazole. Br J Ophthalmol. 2000 Aug;84(8):932–933. doi: 10.1136/bjo.84.8.928d. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Sabo J. A., Abdel-Rahman S. M. Voriconazole: a new triazole antifungal. Ann Pharmacother. 2000 Sep;34(9):1032–1043. doi: 10.1345/aph.19237. [DOI] [PubMed] [Google Scholar]
  22. Sanati H., Belanger P., Fratti R., Ghannoum M. A new triazole, voriconazole (UK-109,496), blocks sterol biosynthesis in Candida albicans and Candida krusei. Antimicrob Agents Chemother. 1997 Nov;41(11):2492–2496. doi: 10.1128/aac.41.11.2492. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Serracarbassa P. D., Peyman G. A., Liang C., Calixto N., Jr, Nair M. G. Toxicity and efficacy of intravitreal injection of spartanamicin B in the treatment of Candida endophthalmitis. Int Ophthalmol. 1998;22(1):53–58. doi: 10.1023/a:1006191629625. [DOI] [PubMed] [Google Scholar]
  24. Shah Kekul B., Wu Tzu G., Wilhelmus Kirk R., Jones Dan B. Activity of voriconazole against corneal isolates of Scedosporium apiospermum. Cornea. 2003 Jan;22(1):33–36. doi: 10.1097/00003226-200301000-00008. [DOI] [PubMed] [Google Scholar]
  25. Shahsavari M., Peyman G. A., Niesman M. R. Retinal toxicity and in vitro efficacy study of cilofungin (LY121019). Ophthalmic Surg. 1990 Oct;21(10):726–728. [PubMed] [Google Scholar]
  26. Sutton D. A., Sanche S. E., Revankar S. G., Fothergill A. W., Rinaldi M. G. In vitro amphotericin B resistance in clinical isolates of Aspergillus terreus, with a head-to-head comparison to voriconazole. J Clin Microbiol. 1999 Jul;37(7):2343–2345. doi: 10.1128/jcm.37.7.2343-2345.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Wellington M., Gigliotti F. Update on antifungal agents. Pediatr Infect Dis J. 2001 Oct;20(10):993–995. doi: 10.1097/00006454-200110000-00014. [DOI] [PubMed] [Google Scholar]
  28. White T. C., Marr K. A., Bowden R. A. Clinical, cellular, and molecular factors that contribute to antifungal drug resistance. Clin Microbiol Rev. 1998 Apr;11(2):382–402. doi: 10.1128/cmr.11.2.382. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Transactions of the American Ophthalmological Society are provided here courtesy of American Ophthalmological Society

RESOURCES