Intraocular penetration of voriconazole and caspofungin in a patient with fungal endophthalmitis

Sir, Fungal infections of the eye are important causes of morbidity and loss of vision. Therapeutic options include intravitreally administered antifungals, ocular surgery and systemic antifungals. Until recently, intravitreal amphotericin B was the most common treatment option, along with vitrectomy. Only limited data are available describing voriconazole and caspofungin intraocular penetration, despite their increasing use in patients with fungal endophthalmitis.1–3 We report on the use of voriconazole and caspofungin in a patient with fungal endophthalmitis with measurement of plasma and intraocular concentrations of both drugs. A 51-year-old monophthalmic man, was admitted with ulcerative keratitis of his left eye. Briefly, he had a complex ophthalmological history with recurrent corneal ulcerations treated with several penetrating keratoplasties, two limbal stem cell transplantations and finally loss of his right eye. As the patient only partially responded after 2 weeks with topical and systemic antibiotics, a keratolimbal transplantation was performed. Azathioprine and methylprednisolone were used to prevent rejection. Microscopy of the removed cornea showed fungi and itraconazole was started. However, after 1 week, inflammation persisted with development of hypopyon and visual acuity dropped to hand movements. The anterior chamber (AC) was flushed and amphotericin B (5 µg in 0.1 mL) was injected twice intracamerally. Microscopy of the AC taps showed fungal filaments. Cultures of aqueous humour on Sabouraud dextrose agar produced no growth. The infection spread from the AC into the vitreous, resulting in endophthalmitis. A pars plana vitrectomy was subsequently performed with intravitreal injections of voriconazole (50 µg in 0.1 mL). A few days later, the hypopyon recurred, with a new white feathery mass appearing in the AC. A second vitrectomy and explantation of the lens was performed to clear the dense debris, followed by a repeat intravitreal voriconazole injection (50 µg in 0.1 mL). Microscopy of the second vitreous sample showed septated hyphae of filamentous fungi with neutrophils. During the following weeks, rinsing of the AC and intravitreal injection of voriconazole was repeated another five times. However, endophthalmitis persisted with visual acuity decreasing to light perception. Systemic voriconazole (orally, loading dose 400 mg, maintenance dose 300 mg both twice daily) was started on day 36, as invasive aspergillosis was suspected in this immunocompromised patient; all immunosuppressants were stopped. Six days later, caspofungin (loading dose 70 mg, maintenance dose 50 mg intravenously) was added as it has been shown to act synergistically with voriconazole against Aspergillus, also in the ocular setting.3 After 3 days of combination therapy, the AC was rinsed again. Concentrations of both antifungals were determined in the ocular fluid, and in a concomitantly taken plasma sample. Caspofungin concentration in the aqueous was 0.28 mg/L, with a simultaneous plasma concentration of 4.70 mg/L. Voriconazole levels were 3.47 mg/L and 7.45 mg/L; in the aqueous and in plasma, respectively. Combination therapy was continued, until finally, on day 52, Fusarium oxysporum was cultured. As caspofungin is not active against Fusarium spp. and the infection did not respond well to voriconazole, treatment was switched to posaconazole (orally, 4 × 200 mg). The plasma concentration of posaconazole on day 56 was 1.26 mg/L. After that, the infection did not recur. The patient's vision improved to hand motions. Susceptibility of F. oxysporum to caspofungin, voriconazole and posaconazole was determined using Sensititre YeastOne plates (Trek Diagnostic Systems, East Grinstead, UK). MICs were >16, 2 and 2 mg/L, respectively. Numerous reports demonstrate successful use of systemic voriconazole with therapeutic intraocular concentrations in fungal endophthalmitis.2 Our results match with literature results, i.e. a concentration up to 46% of the plasma level penetrated into the ocular fluid.2 The concentration that we found was high and exceeds the MIC90 for a wide spectrum of yeasts and moulds. Clinical reports on the use of caspofungin for ocular infections are scarce. Successful treatment has been reported in a patient with Candida glabrata endophthalmitis.4 However, another case described a patient with more advanced endogenous Candida albicans endophthalmitis not responding to caspofungin; the intravitreal caspofungin level was undetectable. Owing to its high molecular weight (1213 kDa), caspofungin may not cross the uninflamed blood–eye barrier, which is thought to be impermeable for molecules exceeding 500 kDa.5 In our patient, however, we found an intraocular concentration of 0.28 mg/L, which is 6% of the simultaneously determined plasma level, and exceeds the values reported in the literature. Severe inflammation causing breakdown of the blood–ocular barrier, as expected in our patient, may explain this unexpected intraocular disposition.5 Despite good voriconazole penetration in our patient, we decided to switch to posaconazole as the infection was clinically unresponsive to therapy. Previously, Fusarium cases have been reported in which voriconazole therapy was not effective.6 Although in vitro studies indicate variable activity against Fusarium spp., posaconazole has been found to retain activity against isolates resistant to voriconazole and to have greater clinical efficacy, along with good ocular penetration.6 The quantification of voriconazole, caspofungin and posaconazole concentrations was supported by an independent grant from Merck Sharp & Dohme, Pfizer Inc. and Schering Plough, Belgium. None to declare. We would like to acknowledge Professor Dr J. de Hoon (Centre for Clinical Pharmacology), Professor Dr P. Augustijns and Pharm. J. Walravens (Laboratory for Biopharmacy and Pharmacotechnology) for the quantification of the antifungals. We would like to express our thanks to Professor Dr B. Foets and Professor Dr P. Stalmans (Ophthalmology Department) for their valuable contribution in the discussion of the management in this case.