CASE REPORT

Refractory keratitis from Beauveria bassiana—Successful treatment with intrastromal amphotericin B and micafungin

de la Presa, Martin MD; McCafferty, Brandon MD; Page, Michael A. MD

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doi: 10.1097/j.jcro.0000000000000017
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Beauveria bassiana is a filamentous fungus that is ubiquitous in soil and is often used as a biological alternative to chemical insecticides. It is rarely pathogenic with only a few reports describing the clinical course of fungal keratitis caused by Beauveria. It is characterized by slow growth and the development of non-necrotic keratitis.1 The previously reported risk factors for Beauveria keratitis include contact lens wear, previous keratoplasty, immunosuppression, and history of topical corticosteroids and broad-spectrum antibiotic use.2 The following retrospective case report describes the clinical course of a patient with refractory fungal keratitis from B. bassiana. The patient was treated with multiple topical and oral antifungal agents without success before eventually responding to intrastromal injections of amphotericin B and micafungin.

CASE REPORT

A 65-year-old man without a significant medical history was referred to a tertiary referral center for management of a marginal corneal ulcer. He initially presented 1 month earlier with injection and irritation in the right eye, with examination revealing a corneal infiltrate without an epithelial defect. Despite treatment with tobramycin and vancomycin, the infiltrate progressed and he developed a worsening epithelial defect. He was referred for a concern of fungal keratitis because of his worsening clinical course and failure of multiple topical antibiotics.

On initial evaluation, the patient reported blurry vision, light sensitivity, and a persistent foreign-body sensation in the right eye. He denied any previous problems with the right eye, recurrent conjunctivitis, or symptoms of dry eyes. There was no history of contact lens wear, ocular surgery, or significant ocular trauma. The patient recalled that he was stacking hay at his farm around the time when the eye irritation began. Examination revealed a visual acuity of 20/80 and 20/15 in the right and left eye, respectively. The intraocular pressures were normal, and there was a normal pupillary response in both eyes. Slitlamp biomicroscopy of the right eye revealed mild blepharitis and meibomian gland dysfunction along with associated conjunctival-ciliary injection. There were no anterior chamber cells or flare, and the iris was normal. Examination of the cornea demonstrated a superior-nasal C-shaped fluffy corneal infiltrate with a small overlying epithelial defect and a small area of surrounding microcystic edema extending centrally (Figure 1, A).

Figure 1.
Figure 1.:
Slitlamp photographs demonstrating the clinical course of keratitis from Beauveria bassiana. A: Photographs show a fluffy corneal infiltrate with a small overlying C-shaped epithelial defect highlighted with fluorescein staining. B: After 2 months of topical antifungal therapy, the patient had developed worsening ulceration, a dense infiltrate, and progressive corneal thinning. C: One month after intrastromal injections, residual stromal haze and thinning is apparent, but the infiltrate and epithelial defect had resolved.

Confocal microscopy of the right eye was performed, which revealed numerous branching and interlocking filamentous structures consistent with fungal keratitis (Figure 2). Corneal cultures were obtained aseptically at the slitlamp using an eyelid speculum and sterile stainless steel spatulas. The corneal scrapings were obtained from the leading edge of the ulcer. Preliminary results did not demonstrate growth on blood, chocolate, Sabouraud, or thioglycolate culture media under standard laboratory conditions. Gram stain did not reveal any bacterial or fungal elements. He was empirically started on topical natamycin 5.0% every 2 hours while awake and ofloxacin 0.3% 4 times a day and continued on topical prednisolone 1.0% 4 times a day.

Figure 2.
Figure 2.:
Confocal microscopy revealed numerous filamentous structures indicative of fungal elements.

There was initial symptomatic improvement at 1-week follow-up, and examination revealed regression of the epithelial defect and underlying stromal infiltrate. Updated microbiology cultures reported light growth of B. bassiana on Sabouraud dextrose agar after 15 days of incubation at 30°C. It was determined that this growth was not from a culture contaminate because this genus is not a component of the normal human skin flora, and the corneal scraping were collected under aseptic conditions. He was continued on the same antifungal regimen and began a prednisolone taper. One week later, the clinical examination had not improved, so topical voriconazole 1.0% was started every 2 hours while awaiting the antifungal sensitivities. Over the next 2 weeks, the corneal infiltrate became denser without change to the overlying epithelial defect, and mild peripheral corneal thinning was noted. With antimicrobial sensitivities still pending, oral voriconazole 200 mg a day and topical amphotericin B 0.15% every 2 hours while awake were started because of his worsening clinical picture. Prednisolone was tapered to once a day, natamycin was stopped, and ofloxacin was reduced to 3 times a day to help promote epithelial healing and limit corneal toxicity from medication burden.

Over the following 2 weeks, the patient's clinical picture continued to worsen with decreasing visual acuity and a denser infiltrate. Susceptibilities returned demonstrating a high sensitivity to micafungin (minimum inhibitory concentration [MIC] 0.25 μg/mL) and a moderate sensitivity to voriconazole (MIC 1 μg/mL) and amphotericin B (MIC 4 μg/mL). The fungus was also found to be mildly sensitive to natamycin (MIC 8 μg/mL). Topical micafungin 0.1% at a frequency of every 2 hours was added to the treatment regimen. Despite the broad antifungal coverage, the dense corneal infiltrate only marginally improved and the patient developed worsening corneal ulceration and progressive thinning (Figure 1, B). Two months after the initial referral, the patient had been on topical voriconazole for 6 weeks, topical amphotericin B for 4 weeks, oral voriconazole for 4 weeks, and topical micafungin for 2 weeks.

At this time, it was decided to proceed with intrastromal injections of amphotericin B and micafungin to provide more focally directed therapy of medications in line with the sensitivity profiles. The intrastromal injections were performed aseptically at the slitlamp with an eyelid speculum placed. Local anesthesia was achieved with a 1 cm ribbon of lidocaine gel 2%, and the eye was prepped with povidone–iodine 5%. A 32-gauge needle on a 1 mL tuberculin syringe was inserted obliquely at the uninvolved clear cornea and advanced along the margin of the infiltrate at the deep stromal level. A total of 0.05 mL of 1.5 mg/mL amphotericin B and 0.05 mL of 1 mg/mL micafungin were injected along the supratemporal and inferior-nasal margin of the lesion, respectively. After the injection, the patient reported significant discomfort.

Examination 2 weeks later revealed marked improvement of the stromal infiltrate and epithelial defect. The frequency of topical amphotericin B and micafungin was slowly tapered over the next month until the epithelial defect and stromal infiltrate completely resolved. Four months after the onset of symptoms, the infection was resolved with a sequela including prominent residual corneal haze and mild peripheral stromal thinning without neovascularization (Figure 1, C).

DISCUSSION

There is no established consensus on management of Beauveria keratitis due to the paucity of published reports. The clinical course is often unpredictable because many case reports describe variable responses to the antifungal agents with the highest sensitivity profiles.1,3 However, other case studies have reported resolution of Beauveria keratitis with the use of topical triazole monotherapy and with natamycin.4–7 In other patients, penetrating keratoplasty or deep lamellar dissection proved necessary to achieve clinical resolution.8,9

In their in-depth analysis of drug and sensitivity profiles of B. bassiana, Mitania et al. assessed that the fungus is extremely slow-growing and typically causes a non-necrotic keratitis.1 They postulate that initial treatments aimed at impairment of fungal cell wall production, such as voriconazole, may only appear to be ineffective because of the inherently slow clinical course of the disease in terms of both onset and offset. In practice, however, a prolonged clinical course is more likely to result in increased residual corneal haze, thinning, endothelial failure, and scarring.

One method of applying more focally directed therapy that may hasten clinical recovery is with the use of intrastromal injection of antifungal agents. These have previously been shown to be effective in cases of recalcitrant filamentous fungal keratitis.10–13 However, there are no reports in the literature describing the use of intrastromal micafungin in cases of fungal keratitis. Micafungin is an echinocandin antifungal agent with a mechanism of action that inhibits the production of beta-1,3-d-glucan. This results in the destabilization of the cell wall, which leads to cellular lysis and death.14 By contrast, amphotericin B works by binding to ergosterols in fungal cell membranes with the same result of cellular lysis.15 In our patient, it is possible that the simultaneous use of amphotericin B and micafungin may have proved synergistic in leading to clinical resolution.

Our patient did report significant discomfort for 3 days after the dual intrastromal injections. When evaluated 1 week after the procedure, he did not demonstrate any signs of corneal toxicity or anterior chamber inflammation. It is possible that he may have initially developed an anterior chamber reaction to the injections that subsequently resolved. This would be consistent with the previous reported responses to intrastromal antifungals.14,16

As amphotericin B and micafungin were simultaneously injected intrastromally in this patient, we cannot definitively infer that micafungin played the greater role in hastening his clinical course. However, the patient had been receiving topical amphotericin B for a longer period than topical micafungin, and culture sensitivities revealed only moderate sensitivity to amphotericin B. We believe that intrastromal micafungin played a key role in successfully treating this case of recalcitrant keratitis from B. bassiana. This case report has important implications for the future treatment of Beauveria-related keratitis and other forms of fungal corneal infections. This case demonstrates that intrastromal micafungin and amphotericin B can be used as potential adjunctive treatments when the initial conservative methods are ineffective.

WHAT WAS KNOWN

  • Beauveria bassiana often has an unpredictable course and appears resistant to the typical ophthalmic regimens of topical natamycin, voriconazole, or amphotericin B, despite high-sensitivity profiles.
  • Intrastromal injections of antifungal agents are effective in cases of recalcitrant filamentous fungal keratitis.

WHAT THIS PAPER ADDS

  • Intrastromal micafungin can be used as an adjunctive treatment for refractory Beauveria keratitis.

REFERENCES

1. Mitania A, Shiraishi A, Miyamoto H, Sunada A, Ueda A, Asari S, Zheng X, Yamamoto Y, Hara Y, Ohashi Y. Fungal keratitis caused by Beauveria bassiana: drug and temperature sensitivity profiles: a case report. BMC Res Notes 2014;7:677
2. Oya L, Hurtado M, Martin R, Aguilera Pérez A, Alastruey-Izquierdo A, Miranda Casas C, Rubio Prats M, Medialdea Marcos S, Navarro Marí JM. Fungal keratitis due to Beauveria bassiana in a contact lenses wearer and review of published reports. Mycopathologia 2016;181:745–752
3. Tu E, Park A. Recalcitrant bassiana keratitis; confocal microscopy findings and treatment with posaconazole (Noxafil). Cornea 2007;26:1008–1010
4. Sonoyama H, Araki-Sasaki K, Kazama S, Kawasaki T, Ideta H, Sunada A, Asari S, Inoue Y, Hayashi K. The characteristics of keratomycosis by Beauveria bassiana and its successful treatment with antimycotic agents. Clin Ophthalmol 2008;2:675–678
5. Ogawa A, Matsumoto Y, Yaguchi T, Shimmura S, Tsubota K. Successful treatment of Beauveria bassiana fungal keratitis with topical voriconazole. J Infect Chemother 2016;22:257–260
6. Figueira L, Pinheiro D, Moreira R, Pinto E, Simões J, Camisa E, Torrão L, Palmares J, Falcão-Reis F. Beauveria bassiana keratitis in bullous keratopathy: antifungal sensitivity testing and management. Eur J Ophthalmol 2012;22:814–818
7. Kisla T, Cu-Unjieng A, Sigler L, Suger J. Medical management of Beauveria bassiana keratitis. Cornea 2000;19:405–406
8. Ligozzi M, Maccacaro L, Passilongo M. A case of Beauveria bassiana keratitis confirmed by internal transcribed spacer and LSU rDNA D1-D2 sequencing. New Microbes New Infect 2014;2:84–87
9. Low C, Badenoch P, Coster D. Beauveria bassiana keratitis cured by deep lamellar dissection. Cornea 1997;16:698-699
10. Guber I, Bergin C, Majo F. Repeated intrastromal injections of voriconazole in combination with corneal debridement for recalcitrant fungal keratitis- a case series. Klin Monbl Augenheilkd 2016;233:369–372
11. You X, Li J, Li S, Shi W. Effects of lamellar keratectomy and intrastromal injection of 0.2% fluconazole on fungal keratitis. J Ophthalmol 2015;656027:10
12. Kalaiselvi G, Narayana S, Krishan T, Sengupta S. Intrastromal voriconazole for deep recalcitrant fungal keratitis: a case series. Br J Ophthalmol 2015;99:195–198
13. Hu J, Zhang J, Li Y, Han X, Zheng W, Yang J, Xu G. A combination of intrastromal and intracameral injections of amphotericin B in the treatment of severe fungal keratitis. J Ophthalmol 2016;2016:3436415
14. Pappas P, Rotstein C, Betts R. Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. Clin Infect Dis 2007;45:883–893
15. Stone N, Bicanic T, Salim R, Hope W. Liposomal amphotericin B (AmBisome): a review of the pharmacokinetics, pharmacodynamics, clinical experience and future directions. Drugs 2016;76:485–500
16. Garcia-Valenzuela E, Song D. Intracorneal injection of amphotericin B for recurrent fungal keratitis and endophthalmitis. Arch Ophthalmol 2015;123:1721–1723
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