Voriconazole in Fungal Keratitis Caused by Scedosporium apiospermum

Case Report

A 19-year-old man was admitted to our hospital with an incisive horizontal wound of his left eye and the cornea totally sectioned. The trauma took place accidentally with a cutter used habitually in gardening. The patient did not report any other predisposing factors (contact lens use, prior keratitis, or immunosuppression status) to invasive fungal infection. Emergency cleaning of the ocular camera, from which vegetable matter was removed, and corneal suture were performed. After surgery, the patient was empirically treated with intravenous vancomycin 1 g every 12 hours, gentamicin 80 mg every 8 hours, methylprednisolone 40 mg once daily, and metoclopramide 10 mg once daily. Mild analgesia was prescribed with intravenous metamizole 2 g every 8 hours and oral ibuprofen 600 mg every 8 hours. Tobramycin 0.3% and dexamethasone eyedrops 4 times a day were used, together with mydriatic agents including atropine 1% and cyclopentolate 3 times a day.

The wound was healing well for the first week after surgery. The patient then reported severe ocular pain, acute headaches, nausea, and photophobia. Ocular examination showed conjunctival congestion, edematous cornea, and a corneal abscess with hypopyon, although the suture was firm. Antibiotic treatment was changed to oral ciprofloxacin 750 mg every 12 hours, and topical treatment was instituted using hourly vancomycin, ceftazidime 5%, and dexamethasone eyedrops 3 times a day. Suspecting an ocular infection, the physicians obtained corneal material for direct microscopic evaluation and bacterial and fungal cultures. No other material was cultured. Microscopic examination of the corneal scraping stained with Giemsa revealed fungal micelle. The micelle were composed of septate hyphae. The sample was therefore sent to a reference center to identify the fungus and perform susceptibility studies. With this initial result, a decision was made to add topical amphotericin B 0.2% administered every 2 hours while the patient was awake to the treatment.

A month after admission, while the patient was still being treated at the hospital, the result of the culture on Sabouraud dextrose agar was received and was positive for ScA; there was no evidence of ScA growing from other sites. The minimum inhibitory concentrations (MICs) reported were amphotericin B 16 mg/L, itraconazole 8 mg/L, and voriconazole 1 mg/L. In view of these results, the previous treatment was discontinued, intravenous voriconazole 200 mg every 12 hours was initiated, and the Pharmacy Service was requested to study the formulation of topical voriconazole, as well as intracameral irrigations or voriconazole drops.

After a thorough review of the literature, an ophthalmic formulation of voriconazole 1% drops was prepared daily. From the lyophilized powder intended for parenteral administration (Vfend 200 mg IV, Pfizer), a dilution with 19 mL of NaCl 0.9% was made in a horizontal laminar flow cabinet. This solution was transferred to sterile droppers through a 0.22-μm filter. We sent samples to the Microbiology Department, and no evidence of microbiologic growth was reported after 7 days of culture. For the formulation prepared in this manner and stored between 2 and 8 °C, we estimated the length of stability to be 24 hours because the manufacturer listed this time for the reconstituted vial in these conditions. The recommended dosage was one drop each 30 minutes while the patient was awake during the first month and a minimum duration of treatment for 8 weeks. During this time, the interval was eventually modified to one drop every 2 hours. Approximately 15 days after beginning this treatment, and as a result of the patient's favorable clinical course, he was discharged and the treatment was shifted to voriconazole 200 mg twice daily by mouth while maintaining topical treatment with voriconazole 1%.

There were no local or systemic adverse effects during this therapeutic regimen except for blurred vision at the beginning of the intravenous treatment (first dose). This effect was transient and fully reversible and disappeared with the following doses. There was no hepatotoxicity. The total treatment duration was 4 months for the systemic route and 3 months for topical voriconazole.

Once the patient had recovered from the infection, a penetrating keratoplasty, extraction of traumatic cataract, and intraocular lens implantation was performed. Histopathologic evaluation of the corneal button revealed friable necrotic tissue with no microorganisms or inflammatory cellular infiltration. Stained sections of the tissue with Groccott stain also failed to detect fungi. Bacterial and fungal cultures were negative. Since it was necessary to use topical corticosteroids after surgery, topical voriconazole 6 times a day for one week and systemic voriconazole for 4 weeks were added to the treatment to prevent relapse.

Discussion

The incidence of ocular fungal infections has increased in the last few years as a consequence of the introduction of new therapeutic measures such as the wide use of broad-spectrum antibiotics, immunosuppressive drugs, corticosteroids, and the improvement of microbiologic diagnostic techniques.^1,2.

ScA is the anamorph or asexual state of the ascomycete Pseudallescheria boydii (PsB). Corneal biopsy isolates grown on Sabouraud's agar usually are the asexual form of the fungus (ScA), whereas nutritionally poor media facilitate formation of the sexual state (PsB). ³ Although ScA is a microorganism with a low inherent virulence, it has been identified as the causal agent of a wide variety of infections in humans (keratomycosis, endophthalmitis, meningitis, brain abscesses, endocarditis, pulmonary infections, peritonitis, localized skin infections) whose severity and prognosis depends on the patient's immune status. ⁴ .

ScA is an uncommon cause of keratitis. A large series of 68 mycotic keratitis cases described only one caused by ScA. ⁵ A review of 125 cases of fungal keratitis in Florida found only one (0.8%) caused by this fungus. ⁶ Among 730 cases of corneal ulcers in northern India, 61 (8.3%) were due to fungi, and only one (0.14%) was attributed to ScA. ⁷ Recently, Wu et al. ³ described 2 new cases of keratitis caused by ScA and reviewed 26 other cases. The outcomes of patients with ocular infections caused by ScA are variable: enu-cleation, evisceration, saved, or unknown. ³ .

A review of 13 cases of keratitis due to this fungus reported that most developed after corneal trauma by objects contaminated by vegetable matter. ⁸ It is likely that even minimal injury is enough for the infection to take place. ⁹ The identification of ScA cannot be done by histopatholo-gy alone due to the similarities between ScA, Aspergillus spp., and other hyaline hyphomycetes, such as Fusarium spp. Definitive diagnosis depends, therefore, on fungal culture in selective media. Aspergillus spp. or Scedosporium spp. grows on routine mycologic media such as Sabouraud dextrose agar or potato dextrose agar, and ScA also has the ability to grow on media containing cycloheximide, which is inhibitory for some Aspergillus spp. Growth is rapid, with a maximum temperature near 37 °C. Colonies of ScA on potato dextrose agar are initially white, becoming light to dark gray with the production of conidia within a few days. New molecular diagnostic methods, such as polymerase chain reaction, are being developed and may be helpful in distinguishing ScA and Scedosporium prolificans.

There are 3 main classes of drugs available for use in fungal eye infections: polyenes, azoles as derivatives of imidazoles, and fluorocytosine. Of the polyenes, amphotericin B, natamycin, and nystatin are of clinical ophthalmic use. Based on better pharmacokinetic profiles and spectra of antifungal activity, the triazoles are therapies consisting of topically applied antifungal agents, since topical administration most likely provides the best opportunity for achieving therapeutic corneal levels.

The success rate for the treatment of ScA keratitis is poor because of its intrinsic resistance to conventional antifungals. ScA is relatively resistant to amphotericin B in vitro. ² Against clinical isolates of ScA, MICs of amphotericin B, fluconazole, and miconazole were 4 mg/L, >16 mg/L, and 0.5 mg/L, respectively. ¹⁰ On the other hand, there is evidence that ScA infection resolved with amphotericin B treatment alone despite resistance in vitro. It is therefore important not to choose the suitable treatment only on the basis of in vitro susceptibility data.^11,12 Another important factor is that the initial empirical regimens target only viruses or bacteria—not fungus—and the treatment with antifungal therapy starts when there is evidence of fungal infection.

Topical natamycin (natamycin as ophthalmic suspension available in the US) has been recommended as the first-line treatment for filamentous fungal keratitis and, as an alternative, topical miconazole. ¹³ Miconazole shows excellent activity against ScA and penetrates the cornea better than natamycin or amphotericin B. ¹⁰ The molecular weight of the various antifungal agents is important, since it influences their ability to penetrate the corneal epithelium. Even intravenous miconazole alone can be successful against keratitis caused by some fungi. Intravenous miconazole is available in Mexico, Belgium, and Australia, but not in the US.

There are also some references to the effectiveness of amphotericin B in the treatment of keratitis by ScA. ¹⁴ Since topical ocular application is limited because of ocular irritation and poor penetration, amphotericin B encapsulated in unilamellar liposomes (L-AmB) has been studied. The results suggest that topically delivered L-AmB provides stable corneal drug concentrations and has the potential benefit of lowered ocular toxicity. ¹⁵ Toxicity of the amphotericin B ophthalmic preparation is related to the type of formulation employed. Significantly more eyes treated with amphotericin B lipid complex (ABLC) showed development of vitreal opacities than developed in eyes treated with amphotericin B deoxycholate or L-AmB. Vitreal band formation was significantly higher in ABLC-treated eyes than in those treated with L-AmB. Vitreal inflammation was greater in eyes treated with L-AmB, amphotericin B deoxycholate, and ABLC than with the control. Retinal ganglion cell loss was greater in eyes treated with amphotericin B deoxycholate, L-AmB, and ABLC than with the control. Based on histologic data, increasing doses of all 3 agents appear to be associated with increasing toxicity. However, based on ophthalmologic data, L-AmB appears to be less toxic than either amphotericin B deoxycholate or ABLC. ¹⁶ .

A recent study on the activity of amphotericin B, natamycin, ketoconazole, itraconazole, and voriconazole against corneal isolates of ScA shows that the lowest MIC occurs with voriconazole (0.5 mg/L), concluding that it has promising activity in fungal keratitis. ¹⁷ However, it is also important to note that sensitivities in vitro cannot correlate with in vivo clinical efficacy. In the treatment of serious disseminated fungal infections by ScA, the use of voriconazole is suitable since it has a much lower MIC than the rest of the azoles, amphotericin B, or nystatin. These infections are relatively frequent in populations that have undergone organ transplantation or in patients receiving high doses of corticosteroids because the immunosuppression degree could be an important risk factor. There are reports of successful outcome of ScA-disseminated infections treated with voriconazole.^18,19.

We have found 2 previous papers in which voriconazole had been used topically. In the first, the case of a patient with keratitis by Fusarium spp., not improving in spite of receiving fluconazole 200 mg/day intravenously, hourly topical amphotericin B 0.3%, and itraconazole 200 mg twice daily by mouth, was described. ²⁰ Due to the lack of response to conventional therapy, the clinicians decided to change the antifungal treatment to intravenous voriconazole. There was significant clinical improvement; however, because of the possibility of suboptimal penetration to the infection site using the intravenous route, voriconazole therapy was changed to intracameral injections at a dosage of 10 μg/0.1 mL and hourly topical voriconazole 1%. The patient recovered from the infection and voriconazole treatment was well tolerated, with only a transient elevation of hepatic enzyme levels that returned to their normal values when the antifungal was discontinued.

In the second paper, 2 cases of keratitis refractory to treatment with amphotericin B and subsequently treated with systemic and topical voriconazole are described. ²¹ The first infection, caused by Fusarium spp., was solved in a positive way, whereas the second, caused by Aspergillus spp., did not have a satisfactory outcome. Topical preparations consisted of 3-μg/mL intracameral irrigations and hourly voriconazole 1% drops. Neither of the above reports had enough information to establish the formulation of the topical preparation.

Voriconazole is a triazole antifungal agent with high activity in vitro against several species of pathogenic molds including ScA. Voriconazole is well absorbed after oral administration, and an intravenous formulation is also available. The use of voriconazole showed good oral and topical tolerance. The most commonly reported adverse events were visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, peripheral edema, and abdominal pain. The severity of the adverse events was generally mild to moderate. In our patient, a transient visual disturbance was related to voriconazole use. In clinical trials, approximately 30% of subjects experienced altered or enhanced visual perception, blurred vision, color vision change, or photophobia. The visual undesirable effects are reversible, with the majority spontaneously resolving within 60 minutes. There is evidence of attenuation with repeated doses of voriconazole. Visual disturbances may be associated with higher plasma concentrations. The mechanism of action is unknown, although the site of action is most likely to be within the retina.^22,23.

Summary

Since it is difficult to predict how keratitis will respond to treatment, we think that it must be managed in an aggressive manner, especially if there is a history of ocular trauma with contaminated objects by vegetable matter, contact lens wear, and long-term corticosteroid use. In these cases, we recommend that a broad-spectrum antimicrobial regimen must be initiated including antibacterials and antifungals. When the culture is diagnostic of ScA keratitis, antifungal therapy could be changed to voriconazole if in vitro susceptibility tests show a low MIC for this drug.

The case reported here is the first in which keratitis caused by ScA is treated with systemic and topical voriconazole. In our opinion, the use of voriconazole is a good alternative against fungi resistant to conventional antifungal therapy, showing good oral and topical tolerance. In addition, this drug allows the shift from the intravenous route to the oral one, which means a great advantage in the treatment of these lengthy infections.