Original Article
Brief Report
Successful Treatment of Disseminated Acanthamoeba Infection in an Immunocompromised Patient
N Engl J Med 1994; 331:85-87July 14, 1994
- Article
Disseminated acanthamoeba infection, an amebic infection characterized by granulomatous infiltrates in the brain and skin, usually occurs in immunocompromised or debilitated patients and generally progresses to death. There has been no effective therapy. We report on a patient who had undergone renal transplantation and was receiving triple immunosuppressive therapy when widespread granulomatous skin lesions caused by Acanthamoeba rhysodes developed. Antimicrobial therapy was initiated with a four-week course of intravenous pentamidine isethionate, topical chlorhexidine gluconate, and 2 percent ketoconazole cream. The result was a dramatic improvement in the skin lesions. Cyclosporine levels remained stable, but therapy was complicated by signs of nephrotoxicity. The patient's condition was maintained by oral itraconazole therapy, with healing of all skin lesions. The success of the treatment was attributed to its initiation before the infection entered the central nervous system.
Case Report
A 31-year-old man with Down's syndrome underwent cadaveric renal transplantation in September 1991 for end-stage renal disease caused by congenital deformities of the kidney. In July 1992, a tender nodule developed on the left thigh, ruptured into a draining pustule, and eventually ulcerated. Medications being administered at that time included prednisone (20 mg per day), cyclosporine (250 mg per day), and azathioprine (150 mg per day). By October 1992, four more cutaneous ulcers had developed, ranging in size from 2 to 5 cm. Specimens from two separate skin biopsies showed nonspecific inflammation and granulomatous changes suggestive of pyoderma gangrenosum. The stains and cultures were negative for bacteria, fungi, and mycobacteria.
The patient was referred to our institution in December 1992. Two new skin-biopsy specimens revealed extensive necrotizing granulomatous inflammation affecting the entire dermal thickness and subcutis. Stains and cultures were negative for fungi and mycobacteria. Cytochemical stains for cytomegalovirus were negative, and there was no evidence of herpes simplex infection. On further review of the histologic specimens, scattered round-to-ovoid amebic forms, measuring up to 20 micrometers in diameter, were identified at all levels of the skin-biopsy specimen, including trophozoites migrating through the epidermis. The morphologic diagnosis of cutaneous acanthamoeba was made (Figure 1Figure 1
Biopsy Specimen of a Skin Ulcer from the Patient's Left Thigh.). A retrospective review of the skin-biopsy specimens obtained in October 1992 revealed amebic organisms that had been overlooked, probably because they had been obscured by inflammation and necrotic debris.The patient was admitted for evaluation of systemic infection. He reported no headache, nausea, vomiting, fever, nuchal rigidity, or changes in mental status. Medications he was receiving on admission were prednisone (7.5 mg per day), cyclosporine (125 mg per day), and azathioprine (50 mg per day). His medical history included an IgA deficiency (8.2 mg per deciliter), anemia, and mild non-insulin-dependent diabetes.
A complete neurologic examination showed no evidence of focal deficits. A skin examination revealed 10 necrotic ulcers with purulent drainage and black eschars, measuring 2 to 6 cm and located on the upper thighs, lower abdomen, and arms. Also present on the extremities, back, neck, and tongue were eight tender, firm, pink nodules, approximately 1 cm in diameter, some of which were beginning to produce purulent drainage. The rest of the physical examination was unremarkable.
The hemoglobin level was 9.2 g per deciliter (5.7 mmol per liter), and the leukocyte count was 6300 per cubic millimeter, with 77 percent neutrophils, 19 percent lymphocytes, and 4 percent monocytes. A serologic assay for infection with the human immunodeficiency virus was negative. The serum urea nitrogen level was 22 mg per deciliter (7.9 mmol per liter), and the serum creatinine concentration was 1.5 mg per deciliter (130 μmol per liter). The serum electrolyte levels were within normal limits. No focal mass lesions were identified by computed tomographic scanning of the head without contrast medium or by cerebral magnetic resonance imaging with contrast medium.
A fresh skin-biopsy specimen was obtained for culture and immediately plated on non-nutrient agar overlaid with Escherichia coli; amebic organisms did not grow. Tissue was preserved in Karnovsky's fixative for evaluation by electron microscopy; a study of the ultrastructures confirmed the presence of acanthamoeba.
Skin tissue fixed in formalin and embedded in paraffin was sent to the Centers for Disease Control and Prevention. An indirect immunofluorescence test using rabbit antiserum against 14 species of acanthamoeba, as well as the leptomyxid ameba, was performed on sections cut from the paraffin block, as described elsewhere1. Amebae in the sections were identified as A. rhysodes.
Antimicrobial therapy was initiated with pentamidine isethionate administered intravenously at a dose of 4 mg per kilogram of body weight (330 mg) per 24 hours. Topical therapy consisted of morning and evening cleansing of all skin lesions with chlorhexidine gluconate, followed by 2 percent ketoconazole cream. Within one week after the start of treatment, there was notable improvement in the cutaneous lesions. Therapy was complicated by a rise in the serum creatinine concentration, which reached a peak of 3.8 mg per deciliter (340 μmol per liter) and necessitated a reduction in the dose of pentamidine. A four-week course of pentamidine therapy was completed, with a total dose of 2700 mg administered. Whole-blood monoclonal and polyclonal antibody measurements of cyclosporine (by a fluorescent polarization immunoassay, as described elsewhere2), obtained daily during pentamidine therapy, showed stable cyclosporine levels. Because of the marked improvement in the patient's cutaneous lesions and the risk of further renal compromise, pentamidine was discontinued, and oral itraconazole therapy was begun at a dose of 200 mg per day for maintenance outpatient treatment.
Eight months after the start of treatment, all skin lesions were fully healed (Figure 2Figure 2
Representative Skin Lesion before Treatment (A) and after Three Months of Treatment (B).), and there was continued improvement in the patient's stamina and well-being. As of March 1994, the patient was still receiving oral itraconazole, at a tapered dose of 200 mg administered on alternate days, and he remained free of any signs or symptoms of acanthamoeba infection.During treatment, serial antibody titers were assayed by an indirect immunofluorescence assay on an acanthamoeba cytospin preparation, with culture-derived A. rhysodes used as the antigen, as described elsewhere3. The pretreatment antibody titer was 1:256; one month and three months after the start of antimicrobial therapy, the titer was 1:128; at five months, the antibody titer was 1:64, and it remained unchanged at seven and nine months.
Discussion
Acanthamoebae are ubiquitous free-living amebae capable of causing serious opportunistic infections4. Among those at risk for disseminated infection with acanthamoeba are patients with diabetes mellitus, leukemia, lymphoma, cancer, malnutrition, the acquired immunodeficiency syndrome (AIDS), renal transplants, or chronic alcoholism5,6. An IgA deficiency in our patient, in addition to immunosuppressive drugs, may have played a part in his susceptibility to this infection.
Invasive acanthamoeba infections appear to be transmitted by hematogenous spread, probably originating at a primary focus in the skin or respiratory tract. The infection then disseminates, producing multiple skin lesions and involving the central nervous system, a condition termed granulomatous amebic encephalitis7. Although most reported cases of disseminated acanthamoeba infection have progressed to granulomatous amebic encephalitis, there have been four other reports of infections limited to the skin, all of which occurred in patients with AIDS8-11. Three of the patients died from other AIDS-related complications, making it difficult to evaluate the treatment for acanthamoeba infection. Treatment was discontinued in one patient and never instituted in another; in a third patient acanthamoeba was present in cutaneous lesions at autopsy despite four months of therapy with rifampin and ketoconazole. In the fourth patient there was improvement of cutaneous acanthamoeba infection after two weeks of treatment with flucytosine; the long-term outcome was not reported. All other reported cases of disseminated acanthamoeba infection have progressed to granulomatous amebic encephalitis. Only three patients with this condition have survived, and all three were immunocompetent12-14.
We describe an immunocompromised patient with disseminated cutaneous acanthamoeba infection that was diagnosed and successfully treated before the infection spread to the central nervous system. The exact incubation period of granulomatous amebic encephalitis due to acanthamoeba is unknown but has been reported to be weeks to months7. One explanation for the long incubation in our patient may be that acanthamoeba species differ in virulence15. Nevertheless, it is known that A. rhysodes is capable of producing granulomatous amebic encephalitis without obvious cutaneous involvement13,16.
Therapy for disseminated acanthamoeba infection has not been established. Our choice of intravenous pentamidine therapy was based on previous in vitro evidence of the susceptibility of acanthamoeba to pentamidine17-19. Limited data from studies of patients with AIDS indicate that pentamidine may enter the central nervous system in some patients, but only in very low concentrations and after prolonged therapy (a month or longer)20. Therefore, pentamidine is most suitable for the treatment of acanthamoeba infection at a stage before the central nervous system is involved. Intravenous pentamidine therapy resulted in dramatic improvement in our patient's cutaneous ulcers; however, the therapy was discontinued because of signs of nephrotoxicity. Subsequent outpatient treatment with oral itraconazole resulted in slower improvement, but all skin lesions healed during the following eight months.
In vitro studies have documented the sensitivity of acanthamoeba to other antibacterial, antifungal, and antiprotozoal agents, including chlorhexidine, sulfadiazine, ketoconazole, flucytosine, itraconazole, and amphotericin17-19,21. These data were our rationale for the use of topical therapy consisting of twice-daily cleansing of the skin ulcers with chlorhexidine, followed by topical ketoconazole.
With the large number of patients requiring immunosuppressive therapy for organ transplants, as well as the ever-increasing number of patients with AIDS, acanthamoeba is a life-threatening opportunistic infection that is important to recognize and diagnose. Clinicians and pathologists should consider free-living amebae as possible etiologic agents in the differential diagnosis of purulent cutaneous ulcers, with or without central nervous system involvement, whenever bacteria, fungi, and mycobacteria are not found in smears or cultures. If the diagnosis is made early, particularly before the infection enters the central nervous system, death may be averted. Further studies are needed to establish the optimal choice of therapy. In our patient intravenous pentamidine followed by oral itraconazole led to healing of the lesions.
Supported by grants from the National Institutes of Health (R01 29 AR40933), the T. Franklin Williams Foundation (the Pepper Center Award for the Study of Diseases of Aging), and the Center for Alternatives to Animal Testing (93038).
We are indebted to A. Julio Martinez for his advice on diagnosis, to Karen Jensen for electron-microscopical studies, to Sara Wallace for the indirect immunofluorescence assay, and to Douglas Wear and Ronald Neafie at the Armed Forces Institute of Pathology for their review of the pathological studies.
Source Information
From the Departments of Dermatology (C.A.S., A.A.G.), Pathology (J.Z.S.), and Medicine, Nephrology Unit (R.C.P.), University of Rochester Medical Center, Rochester, N.Y.; and the Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta (G.S.V.).
Address reprint requests to Dr. Gaspari at the University of Rochester Medical Center, 601 Elmwood Ave., Box 697, Rochester, NY 14642.
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