We found mean voriconazole concentrations in aqueous and vitreous were 6.492 ± 3.042 and 0.156 ± 0.082 g/ml, respectively. Aqueous concentrations exceeded inhibitory MIC90 levels for a wide spectrum of fungi and mold, including Aspergillus, Fusarium, and Candida species. Vitreous levels of voriconazole exceeded the MIC90 for Candida albicans. Topically administered voriconazole achieves therapeutic levels in the aqueous of the noninflamed human eye for many fungi and molds, and achieves therapeutic levels in the vitreous for Candida. Because of its broad-spectrum coverage, high potency against organisms of concern, good tolerability, and intraocular penetration with topical administration, topical voriconazole may be a useful agent for the management of fungal keratitis and prophylaxis against the development of fungal endophthalmitis.

Orally and topically administered voriconazole achieves therapeutic aqueous and vitreous levels in the noninflamed human eye and the activity spectrum appears to encompass appropriately the most frequently encountered fungal species involved in the various causes of exogenous and endogenous fungal endophthalmitis. In addition, oral or intravitreal voriconazole may present an alternative management technique for fungal endophthalmitis by which the risk of retinal toxicity associated with intravitreal amphotericin B injection can be avoided.37 Because of its broad spectrum of coverage, low MIC90 levels for the organisms of concern, good tolerability, and excellent bioavailability, voriconazole through various routes of admini­ stration may be useful to the ophthalmologist in the primary treatment of, or as an adjunct in, the current management of ocular fungal infections.38

CONCLUSION

In the past 20 years, numerous significant advances and the availability of new-generation anti-infectives have undoubtedly paved the way for improved outcomes in our management of ocular infections. The EVS provided us with excellent evidence-based data; however, numerous questions remain.

The fourth-generation fluoroquinolones are already playing a key role in the management of ocular infection, as well as in prophylaxis against infection. Additionally, advances in antifungal therapy, specifically the new-generation triazoles, will help improve outcomes through various routes of administration for patients with ocular fungal infection.

We need to rethink the applicability of the EVS data given the availability of these “new weapons in the arsenal of ophthalmic antibiotics.”10 So, while we do have evidence-based data from the EVS, with time the data may have lost some significance, due to the new developments noted above. Our next step is to develop new strategies for the management of ocular infection utilizing these new fluoroquinolone and triazole agents, with a goal of limiting the impact of proven infection, or ideally eliminating the development of endophthalmitis in a cost-effective manner.

Even with the advancements over the past decade, unparalleled opportunities for prevention and/or reduction of morbidity from intraocular infection continue to exist. While we truly would like to base all of our therapeutic decisions on evidence-based data, we will still be forced to rely on data from a variety of clinical sources.

REFERENCES

1.Endophthalmitis Vitrectomy Study Group. Results of the Endophthalmitis Vitrectomy Study: A randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Arch Ophthalmol 1995;113:1479–1496.

2.el-Massry A, Meredith TA, Aguilar HE, et al. Aminoglycoside levels in the rabbit vitreous cavity after intravenous administration. Am J Ophthalmol 1996;122:684–689.

3.Aguilar HE, Meredith TA, Shaarawy A, et al. Vitreous cavity penetration of ceftazidime after intravenous administration. Retina 1995; 15:154–159.

4.Doft BH. The Endophthalmitis Vitrectomy Study. Arch Ophthalmol 1991;109:487–489.

5.Han DP, Wisniewski SR, Wilson LA, et al. Spectrum and susceptibilities of microbiologic isolates in the EVS. Am J Ophthalmol 1996;122:1–17.

6.Endophthalmitis Vitrectomy Study Group. Microbiologic factors and visual outcomes in the Endophthalmitis Vitrectomy Study. Am J Ophthalmol 1996;122:830–846.

7.Johnson MW, Doft BH, Kelsey SF, et al. The Endophthalmitis Vitrectomy Study. Relationship between clinical presentation and microbiologic spectrum. Ophthalmology 1997;104:261–272.

8.Miller D, Flynn PM, Scott IU, et al. In vitro fluoroquinolone resistance in staphylococcal endophthalmitis isolates. Arch Ophthalmol 2006;124: 479–483.

9.Bannerman TL, Rhoden DL, McAllister SK, et al. The source of coagulase-

negative staphylococci in the Endophthalmitis Vitrectomy Study: A comparison of eyelid and intraocular isolates using pulsed-field gel electrophoresis. Arch Ophthalmol 1997;115:357–361.

10.Mather R, Karanchak LM, Romanowski EG, et al. Fourth generation fluoroquinolones: new weapons in the arsenal of ophthalmic antibiotics. Am J Ophthalmol 2002;133:463–466.

11.Fiscella RG, Shapiro MJ, Solomon MJ, et al. Ofloxacin penetration into the eye after intravenous and topical administration. Retina 1997;17: 535–539.

12.Hariprasad SM, Blinder KJ, Shah GK, et al. Penetration pharmacokinetics of topically administered 0.5% moxifloxacin ophthalmic solution in human aqueous and vitreous. Arch Ophthalmol 2005;123:39–44.

13.Hariprasad SM, Shah GK, Chi J, et al. Determination of aqueous and vitreous concentration of moxifloxacin 0.5% in humans after delivery via a dissolvable corneal collagen shield device. J Cataract and Refractive Surg 2005;31(11):2142–2146.

14.Hariprasad SM, Mieler WF, Holz ER. Vitreous and aqueous penetration of orally administered Gatifloxacin in humans. Arch Ophthalmol 2003;121: 345–350.

15.Hariprasad SM, Mieler WF, Holz ER. Vitreous penetration of orally administered Gatifloxacin in humans. Tr Am Ophth Soc 2002;100: 153–160.

16.Fiscella RG, Nguyen TK, Cwik MJ, et al. Aqueous and vitreous penetration of levofloxacin after oral administration. Ophthalmol 1999;106:2286–2290.

17.Garcia-Saenz MC, Arias-Puente A, Fresnadillo-Martinez MJ, et al. Human aqueous humor levels of oral ciprofloxacin, levofloxacin, and moxifloxacin. J Cataract Refract Surg 2001;27:1969–1974.

18.Hariprasad SM, Shah GK, Mieler WF, et al. Vitreous and aqueous penetration of orally administered moxifloxacin in humans. Arch Ophthalmol 2006;124:178–182.

19.Keren G, Alhalel A, Bartov E, et al. The intravitreal penetration of orally administered ciprofloxacin in humans. Invest Ophthalmol Vis Sci 1991;32:2388–2392.

20.Aras C, Ozdamar A, Ozturk R, et al. Intravitreal penetration of Cefepime after systemic administration to humans. Ophthalmologica 2002;216: 261–264.

21.Hariprasad SM, Mieler WF, Orengo-Nania S, et al. The use of oral Gatifloxacin in the treatment of localized filtering bleb infections. Eye 2009 (in press).

22.Speaker MG, Milch FA, Shah MK, et al. Role of external bacterial flora in the pathogenesis of acute postoperative endophthalmitis. Ophthalmology 1991;98:639–649; discussion 650.

23.Kluytmans JA, Wertheim HF. Nasal carriage of Staphylococcus aureus and prevention of nosocomial infections. Infection 2005;33:3–8.

24.Doebbeling BN, Breneman DL, Neu HC, the Mupirocin Collaborative Study Group. Elimination of Staphylococcus aureus nasal carriage in health care workers: analysis of six clinical trials with calcium mupirocin ointment. The Mupirocin Collaborative Study Group. Clin Infect Dis 1993;17:466–474.

25.von Eiff C, Becker K, Machka K, et al. Nasal carriage as a source of Staphylococcus aureus bacteremia. N Engl J Med 2001;344:11–16.

26.Kluytmans JA, Mouton JW, VandenBergh MF, et al. Reduction of surgicalsite infections in cardiothoracic surgery by elimination of nasal carriage of Staphylococcus aureus. Infect Control Hosp Epidemiol 1996;17:780–785.

27.The Mupirocin Study Group. Nasal mupirocin prevents Staphylococcus aureus exit-site infection during peritoneal dialysis. J Am Soc Nephrol 1996;7:2403–2408.

28.Alexandrou TJ, Hariprasad SM, Benevento J, et al. Reduction of preoperative conjunctival bacterial flora with the use of mupirocin nasal ointment. Trans Am Ophth Soc 2006;104:196–201.

29.Ghannoum MA, Kuhn DM. Voriconazole – better chances for patients with invasive mycoses. Eur J Med Res 2002;7:242–256.

30.Sabo JA, Abdel-Rahman SM. Voriconazole: A new triazole antifungal. Ann Pharmacother 2000;34:1032–1043.

31.Hariprasad SM, Mieler WF, Holz ER, et al. Determination of vitreous, aqueous, and plasma concentration of orally administered voriconazole in humans. Arch Ophthalmol 2004;122:42–47.

32.Gao H, Pennesi M, Shah K, et al. Safety of intravitreal voriconazole – histopathologic and electroretinographic study. Tr Am Ophth Soc 2003;101:183–189.

33.Breit SM, Hariprasad SM, Mieler WF, et al. Management of endogenous fungal endophthalmitis with voriconazole and caspofungin. Am J Ophthalmol 2005;139:135–140.

34.Lin RC, Sanduja N, Hariprasad SM. Successful treatment of postoperative

Diseases Retinal in Mechanisms and Drugs • 4 section

• 45 chapter Antibiotics

fungal endophthalmitis using intravitreal and intracameral voriconazole. J Ocul Pharmacol Ther 2008;24(2):245–248.

35.Gorscak JJ, Ayres BD, Bhagat N, et al. An outbreak of Fusarium keratitis associated with contact lens use in the northeastern United States. Cornea 2007;26:1187–1194.

36.Vemulakonda GA, Hariprasad SM, Mieler WF, et al. Aqueous and vitreous concentrations following topical administration of 1% voriconazole in humans. Arch Ophthalmol 2008;126(1):18–22.

37.Axelrod AJ, Peyman GA, Apple DJ. Toxicity of intravitreal injection of

amphotericin B. Am J Ophthalmol 1973;76:578–583.

38.Hariprasad SM, Mieler WF, Lin TK, et al. Voriconazole in the treatment of fungal eye infections: a review of current literature. Br J Ophthalmol 2008;92:871–878.