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Home , Endophthalmitis, Fungal keratitis, Keratitis

Cornea 19(6): 853–856, 2000. © 2000 Lippincott Williams & Wilkins, Inc., Philadelphia

Treatment of Postkeratitis Fusarium with Amphotericin B Lipid Complex

David Goldblum, M.D., Beatrice E. Frueh, M.D., Stefan Zimmerli, M.D., and Matthias Bo¨hnke, M.D.

Purpose. The authors report the first case of Fusarium solani tients treated with amphotericin B develop some degree of renal that progressed to fungal endophthalmitis and was suc- impairment. Patients who receive a cumulated dose of more than cessfully treated with amphotericin B lipid complex (ABLC). 4–5 g of the drug are particularly at risk.5 Method. The case of a 34-year-old immunocompetent woman Three new lipid formulations of amphotericin B with reduced who developed a contact -related F. solani keratitis requiring nephrotoxicity are now available for clinical use. Amphotericin B emergency penetrating keratoplasty (PKP) was analyzed. The im- lipid complex (ABLC) (Abelcet®; The Liposome Company, munocompetent patient developed fungal endophthalmitis (ante- rior chamber tap positive for F. solani three months after PKP) and Princeton, NJ, U.S.A.) is a concentration of ribbon-like structures was eventually treated with ABLC. Results. Systemic amphoteri- of a bilayered membrane formed by combining a 7:3 ratio of cin B (total, 0.42 g) and ketoconazole in addition to topical nata- dimyristoyl phosphatidylcholine and dimyristoyl phosphatidyl- mycin and amphotericin did not prove to be effective in eradicat- glycerol with amphotericin B. Amphotericin B colloidal dispersion ing the mycosis in the anterior chamber. Under ABLC treatment (Amphocil®; Sequus Pharmaceuticals, Menlo Park, CA, U.S.A.) (total, 8.79 g), the anterior chamber resolved com- is composed of disc-like structures of cholesteryl sulfate com- pletely. No recurrence was observed during an 11-month follow- plexed with amphotericin B. AmBisome® (Nextstar, San Dimas, up after treatment was discontinued. Conclusion. ABLC proved to CA, U.S.A.) consists of small unilamellar vesicles made up of be effective in treating F. solani endophthalmitis. It is an important hydrogenated soy phosphatidylcholine and distearoylphosphati- addition to the ophthalmic armamentarium, and appeared to be a dylglycerol stabilized with cholesterol in a 2:0.8:1 ratio, combined better therapeutic agent than standard amphotericin B in this pa- tient. with amphotericin B. The advantage of these new preparations Key Words: Eye——Fusarium—Keratitis—Endoph- appears to be the preferential accumulation in organs of the retic- thalmitis—Amphotericin B—Amphotericin B lipid complex uloendothelial system and the lung, as opposed to the kidney. (ABLC). Consequently, nephrotoxicity is markedly reduced. The liposomal preparations are also less commonly associated with acute infu- sional toxicity manifested as nausea, vomiting, headache, , chills, hypothermia, and hypotension that occurs in 50–90% of and endophthalmitis are sight threatening infec- patients receiving amphotericin B. Amphotericin B at a dose of up tions that often prove resistant to therapeutic approach. Antifungal to 1.25 mg/kg is usually infused over 4–6 hours to reduce side- drugs are toxic, and treatment is often prolonged. Failure to re- effects. At the commencement of therapy, a test dose of 0.25–1 mg spond may lead to confusion between the toxic effects of the drugs in 25–50 mL of 5% dextrose infused over 30–60 minutes is often and persistence of infection. recommended. Following an initial test dose of 1 mg over 15 Amphothericin B is considered the treatment of choice for sys- minutes, ABLC is commonly used at a dose 5 mg/kg/d infused temic infections caused by Candida, Aspergillus, and Fusarium. over two hours. However, the usefulness of amphotericin B is limited by poten- Two studies have demonstrated the advantages and reduced tially serious adverse effects, particularly dose-limiting nephrotox- toxic effects of ABLC in treating patients with invasive fungal icity.1,2 Renal insufficiency in association with azotemia, renal infections.6,7 In another study, seven of eight patients with life- tubular acidosis, and impaired urinary concentrating capacity re- threatening Fusarium infection and failure of prior treatment with sulting in electrolyte imbalance often lead to dose reduction or amphotericin B and other antifungal agents or with renal disease premature discontinuation of the drug.3,4 More than 80% of pa- and nephrotoxicity were successfully treated with high doses of ABLC.8 Submitted August 25, 1999. Revision received January 4, 2000. Ac- We report on a case of -related keratitis due to cepted January 7, 2000. Fusarium solani that progressed to endophthalmitis and was un- From the Department of (D.G., B.E.F., M.B.) and the Institute for Medical Microbiology (S.Z.), University of Bern, Switzerland. responsive to conventional systemic amphotericin B therapy. Un- Address correspondence and reprint requests to Dr. B.E. Frueh, Depart- der ABLC treatment, the infection completely resolved. ment of Ophthalmology, University of Bern, Inselspital, 3010 Bern, Swit- zerland. E-mail beatrice.frueh @insel.ch The authors have no financial interest in any material or device dis- CASE REPORT cussed in this report. Presented at the annual meeting of the Ocular Microbiology and Immu- A 34-year-old immunocompetent woman with a 7-year history nology Group (OMIG) on November 7 1998 in New Orleans. of rigid gas permeable contact lens wear was seen by her ophthal-

853 854 D. GOLDBLUM ET AL. mologist because of a 7-day history of and discomfort in the left eye. A central corneal ulceration was seen and a clinical di- agnosis of was made. Treatment with topical , tobramycin, acyclovir, and systemic valacyclovir was started. Twelve days later the patient was referred to our department because the condition deteriorated. On initial examination, her best corrected visual acuity was 20/20 OD and 20/50 OS. A deep central with some crystalline aspect was noted in the left eye (Fig. 1). Corneal scrapings were taken. In vivo confocal microscopy showed fine filaments in the anterior corneal stroma, consistent with fungal hyphae (Fig. 2). Infectious keratitis of fun- gal origin was suspected and amphotericin 1% (5 times/d) and ciloxan (2 times/h) were prescribed. Smears of the corneal scrap- ings revealed no microorganisms and cultures were sterile. Gram stains of the contact lens solution showed gram-positive rods. Be- FIG. 2. In vivo confocal microscopy (calibration bar = 50 µm) of the left (anterior stroma) at the first visit showing filaments cause no improvement was observed, treatment was changed to aligned in parallel planes to the anterior corneal surface. tobramycin and cephazolin hourly while amphotericin was contin- ued. This regimen initially seemed to control the infection. Seven days after the first visit to our clinic, a corneal biopsy was along the interface extending from 6–9o’clock. In addition, new taken. The biopsy tissue was processed using a mortar and a cen- deep stromal infiltrates in the host cornea were seen at 9 o’clock trifuge and then stained: gram-negative rods were detected, but (Fig. 3), while the graft remained clear. An anterior chamber tap cultures remained negative. was performed to rule out endophthalmitis. The same day, intra- A further 20 days later the keratitis had deteriorated to such an venous amphotericin B (0.5 mg/kg body weight; 30 mg/d) was extent that an emergency penetrating keratoplasty (PKP) was per- started and ketoconazole discontinued. formed. A 7.5-mm trephination encompassed the entire corneal Antifungal susceptibility testing indicated minimal inhibitory infiltrate with clear margins. Histopathology of the corneal button concentrations of 4 ␮g/mL for amphotericin B, >16 ␮g/mL for revealed acute purulent ulcerative keratitis, but no microorganisms ketoconazole, and 32 ␮g/mL for . were seen with special stains. In contrast, culture of the button Over the next 12 days, the inflammation worsened and pain grew F. solani. Local natamycin 5% (5 times/d) and systemic increased to the extent that morphine was needed. Stains from the ketoconazole 200 mg/d (later 400 mg/d) were added. Topical cor- anterior chamber tap revealed septated fungi. Because of further ticosteroids were given 6 times/d to prevent graft rejection. growth of the plaque, a complete anterior chamber washout with On the first postoperative day, the cornea appeared clear and the amphotericin B solution (50 ␮g/mL) was performed. visual acuity had improved to 20/250. One week postoperatively, The procedure did not prove to be effective because three days the graft was clear and the inflammation was subsiding. Three later the plaque continued to enlarge, and a 1-mm had weeks after PKP, the patient developed an inferior retrocorneal developed. Amphotericin B (cumulated dose, 0.42 g) was discon- plaque at the host–donor interface at the 6 o’clock position. Visual tinued and ABLC (3.3 mg/kg/d) started instead. Three days later acuity was 20/100. Ten days later, the patient returned because of the pain had decreased and the plaque as well as the hypopyon increasing conjunctival hyperemia and discomfort. Visual acuity started to regress. had decreased to 20/160 and the retrocorneal plaque had enlarged. After 45 days of ABLC treatment (total dose, 8.785 g) the The graft remained clear without evidence of infiltration. plaque had completely disappeared, the patient was free of pain, One month after the keratoplasty, the plaque continued to grow

FIG. 3. One month after PKP: Retrocorneal plaque at the host-donor FIG. 1. Central corneal ulcer with some crystalline aspects 19 days interface, and deep stromal infiltrates in the host cornea extending after symptoms were first noted. from 6 to 9 o’clock. The donor tissue is free of infiltration.

Cornea, Vol. 19, No. 6, 2000 AMPHOTERICIN B LIPID COMPLEX-TREATED ENDOPHTHALMITIS 855 and the best corrected visual acuity had recovered to 20/80. After Gram stain of the contact lens solution showed gram-positive resolution of the infection, a peripheral anterior devel- rods. Although several investigations have associated infectious oped at 6 o’clock at the host-donor interface. At the last follow-up keratitis with the use of contaminated contact lens storage cases visit 11 months after discontinuation of ABLC, the graft was clear, and solutions,30–32 Donzis et al.33 and Wilson et al.34 also dem- the anterior chamber quiet, and best corrected visual acuity was onstrated that the use of contaminated solutions by asymptomatic 20/32. contact lens wearers is not uncommon. Due to the initial limitation of the infection to the cornea and the absence of microbiological evidence for fungal infection in both DISCUSSION corneal scrapings and the corneal biopsy, no systemic antifungal Fungal keratitis in contact lens wear occurs in 4–27% of patients therapy was used from the beginning. Systemic administration of with microbial keratitis.9 ketoconazole (to which the organism was later found to be resis- Fusarium species are ubiquitous saprophytes of soil. They can tant) and amphotericin B did not improve the clinical course. The cause life-threatening infections,10,11 keratitis,12 and endophthal- infection could be controlled only after changing to systemic treat- mitis.13–15 Despite aggressive treatment with antifungal agents, ment with higher concentrated ABLC. This might be attributed such as amphotericin B, 5-flucytosine, rifampin, and the azoles, solely to the higher concentration given that, alternatively, a dif- failure rates and mortality are high. ferent pharmacokinetic with higher absorption of the drug in the Amphotericin B has remained the drug of choice for fungal eye because of the lipid complex could be possible. infections over the last 30 years, primarily due to its broad spec- To our knowledge, this is the first report showing an advantage trum of activity.16 The usefulness of this polyene is limited by its of ABLC in fungal keratitis and endophthalmitis compared to am- narrow therapeutic index. A number of adverse reactions and tox- photericin B. icity are associated with amphotericin B.17 Nephrotoxicity has been the most important limiting factor for its use. Accordingly, considerable effort has been made to reformulate amphotericin B REFERENCES to diminish its toxicity. 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Cornea, Vol. 19, No. 6, 2000