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. Author manuscript; available in PMC: 2018 Apr 1.
Published in final edited form as: Transpl Infect Dis. 2017 Mar 6;19(2):10.1111/tid.12661. doi: 10.1111/tid.12661

Disseminated Acanthamoeba infection in a heart transplant recipient treated successfully with a miltefosine-containing regimen: case report and review of the literature

MN Brondfield 1, MR Reid 2, RL Rutishauser 2, JR Cope 3, J Tang 4, JM Ritter 5, A Matanock 6, I Ali 3, SB Doernberg 2, A Hilts-Horeczko 7, T DeMarco 8, L Klein 8, JM Babik 2
PMCID: PMC5510642  NIHMSID: NIHMS871234  PMID: 28067969

Abstract

Disseminated acanthamoebiasis is a rare, often fatal, infection most commonly affecting immunocompromised patients. We report a case involving sinuses, skin, and bone in a 60-year-old woman five months after a heart transplant. She improved with a combination of flucytosine, fluconazole, miltefosine, and decreased immunosuppression. To our knowledge this is the first case of successfully treated disseminated acanthamoebiasis in a heart transplant recipient and only the second successful use of miltefosine for this infection among solid organ transplant recipients. Acanthamoeba infection should be considered in transplant recipients with evidence of skin, central nervous system, and sinus infections that are unresponsive to antibiotics. Miltefosine may represent an effective component of a multi-drug therapeutic regimen for the treatment of this amoebic infection.

Case Presentation

A 60-year-old Pacific Islander presented to her primary care physician with rhinorrhea and sinus pressure five months after orthotopic heart transplantation.

Her past medical history was notable for non-ischemic cardiomyopathy requiring heart transplantation, gout, and chronic kidney disease. She had received thymoglobulin induction at the time of transplant and had been doing well on a maintenance immunosuppressive regimen of mycophenolate (1,000mg BID), tacrolimus (1.5mg BID), and prednisone (2.5mg daily). She was also on trimethoprim-sulfamethoxazole (800mg-160mg) three times weekly for Pneumocystis pneumonia (PCP) prophylaxis and had not experienced any episodes of rejection or opportunistic infections.

She was initially treated by her primary care physician for these sinus symptoms with a 10-day course of cephalexin and nasal fluticasone for presumed bacterial sinusitis. When her symptoms failed to improve, she received an additional 10 days of amoxicillin-clavulanate with guaifenesin and pseudoephedrine. During this time, she had several episodes of epistaxis and was referred for evaluation by an otolaryngologist. In the six-week period between antibiotic treatment and being evaluated by her otolaryngologist, she performed a tap water lavage of her sinuses on several occasions, as she had done in the past for nasal congestion, with minimal improvement of her symptoms. She had no fevers, chills or night sweats. She had not traveled outside of Northern California in several years and did not endorse any recent history of freshwater exposure or dust inhalation. Trained as an esthetician, she had not worked since before her transplant.

The patient was seen by an outpatient otolaryngologist two months after the onset of symptoms (seven months after transplant), and was noted on exam to have a friable and raised right nasal septal mass, with magnetic resonance imaging (MRI) of the sinuses showing right frontal, maxillary, and ethmoid opacification (Figure 1a). A nasal endoscopy was performed and biopsy was taken. Histopathological review was notable for an acutely inflamed atypical squamoproliferative lesion, raising concern for squamous cell carcinoma. Given the concern for malignancy, she was admitted for surgical resection of the mass. On admission, she was hemodynamically stable and afebrile. Labs showed a white blood cell count of 6200 cells/μL, hemoglobin of 8.5 g/dL, and creatinine of 2.81 mg/dL (baseline 2–3 mg/dL). Surgical resection was aborted when intraoperative frozen section revealed the presence of amoeba, and the patient was started on metronidazole and amphotericin B on the first post-operative day. Tissue sections were sent to the Centers for Disease Control and Prevention (CDC) for specific pathogen identification. Histopathologic examination and subsequent immunohistochemical testing revealed necrotizing granulomatous inflammation with intralesional Acanthamoeba healyi.

Fig. 1.

Fig. 1

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A) MRI of sinuses before debridement showed opacification consistent with observed mass (red arrows). B) MRI of sinuses 6 months after discharge demonstrated clearance of previous opacifications.

After consulting with local infectious disease specialists and the CDC, the patient was switched to fluconazole, flucytosine, and miltefosine on hospital day four. Miltefosine is not currently approved to treat acanthamoebiasis, but is available through the CDC’s expanded access investigational new drug (IND) protocol. In this case, the drug was obtained through the IND protocol following patient consent and institutional review board approval. A second surgical debridement of the right nasal septum, including right total ethmoidectomy and right frontal sinusotomy, was performed on hospital day seven. Histopathological evaluation and immunohistochemical testing of specimens obtained during this procedure again demonstrated the presence of Acanthamoeba healyi. The CDC also performed serologic testing for Acanthamoeba, which was negative.

Between hospital days one and four (before initiation of miltefosine therapy), the patient developed several subcutaneous nodules on her left flank and bilateral upper and lower extremities (Figure 2a). Skin biopsy of one of these lesions demonstrated Acanthamoeba by histopathological examination and immunohistochemistry (Figure 3a) performed at the California Department of Public Health, further confirmed by polymerase chain reaction (PCR) at CDC. Topical ketoconazole was added. A lesion over the right 3rd metacarpal started to drain in the next 48 hours, and imaging showed a lytic lesion of the right 3rd metacarpal (Figure 4a and 4b). The patient underwent incision and drainage of the digit by orthopedic surgery on hospital day nine, and the surgeon noted that the shaft was hollow and contained small exophytic growths, which were sent for pathologic evaluation. Amoebae were seen with Periodic acid–Schiff–diastase (PAS-D) and Grocott’s methamine silver (GMS) stains, and Acanthamoeba was identified by PCR at the CDC.

Fig. 2.

Fig. 2

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A) Cutaneous lesion of the right forearm photographed 8 days after initial eruption. B) Photograph of the right forearm at 8-month follow up visit demonstrated resolution.

Fig. 3.

Fig. 3

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A) Immunohistochemical stain of skin biopsy showed Acanthamoeba cysts by immunofluorescence (performed at the CDC). B) Biopsy sample from repeat sinus debridement showed cysts consistent with Acanthamoeba spp. 12 days after the patient’s initial surgery.

Fig. 4.

Fig. 4

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a) Radiograph of the right hand revealed a lytic lesion of the third metacarpal. b) MRI of the hand following debridement showed hollow cavity due to bone destruction.

The patient was then transferred to the tertiary care center where she had received her transplant for further management of antimicrobials and immunosuppression. In consultation with the CDC, the regimen of fluconazole, flucytosine, miltefosine, and topical ketoconazole was continued. Her immunosuppressive regimen was also altered: tacrolimus dosing was reduced from 1.5mg BID to 1mg BID with a target trough of 8–10 μg/L, and mycophenolate was reduced from 1,000mg BID to 750mg BID. Repeat brain MRI showed persistent severe pansinusitis but no evidence of bony destruction or central nervous system (CNS) extension of disease. The patient underwent a third superficial debridement of the right sinuses 12 days after her initial surgery and pathologic evaluation again demonstrated amoeba (Figure 3b). More extensive debridement was avoided to mitigate potential translocation of amoeba from the sinuses into the CNS.

Despite persistent demonstration of amoeba in the sinuses, the patient showed clinical improvement during her hospitalization: skin lesions visibly regressed in size and her sinus complaints diminished. Her C-reactive protein (CRP) levels, 76.6 mg/L at the time of transfer, also decreased substantially, dropping to 19.3 mg/L 10 days later. The patient was discharged after 25 days in the hospital, with the plan to maintain her decreased immunosuppressive regimen and the triple-drug therapy of fluconazole, flucytosine, and miltefosine for at least six months. At follow-up visits, she reported continued clinical improvement while on this triple therapy, although the patient did endorse significant nausea from the miltefosine. Liver function tests four months after discharge showed mildly elevated alkaline phosphatase (143–147 U/L) and an elevated gamma-glutamyl transferase (211 U/L), but no other laboratory abnormalities were observed. At six-months after discharge, her CRP was 1.5 mg/L, brain MRI showed resolution of sinus opacities, and her skin lesions had resolved completely. (Figure 2b). Her immunosuppressive regimen was increased to pre-infection levels at this time.

Although no cases of donor-derived Acanthamoeba infection have ever been reported, the California Transplant Donor Network was contacted because transplant-related transmission of another amoeba, Balamuthia, has been reported (1–3). The donor network concluded that no other infection or illness consistent with free-living amoeba infection had been reported in other organ recipients, and archived donor serum was negative for Acanthamoeba serology.

Discussion

Acanthamoeba are free-living amoebae found in soil, air, and numerous aquatic environments, including drinking water, seawater, and swimming pools (3). Human infection is most common in immunocompromised hosts and is transmitted by inhalation of Acanthamoeba cysts or inoculation by direct contact with skin or mucosal surfaces. This protozoan has been reported to cause cutaneous lesions, nasopharyngeal infections, pneumonia, pyelonephritis, and granulomatous amoebic encephalitis (GAE), which is fatal in 90% of cases (3–6). Acanthamoeba osteomyelitis is extremely rare, and has only been reported in one other solid organ transplant (SOT) patient (7).

All 22 reported cases of acanthamoebiasis in SOT patients (including the present case) are described in Table 1. Given that exposure is common but diagnosis is difficult to establish, these reported cases may underrepresent the true disease burden in SOT recipients. To our knowledge this is only the second reported case of Acanthamoeba infection in a heart transplant recipient and the first report of successful treatment (8). Other cases have been reported in kidney (n=8), lung (n=8), liver (n=2), and multi-organ (n=2) recipients. The mean age of patients for these cases was 50 (range 31–64), and mean time to infection following transplant was 18 months (range three months-six years). Immunosuppressive regimens have most commonly included tacrolimus, cyclosporine, mycophenolate and/or prednisone. In three cases (including this case), the patient received thymoglobulin as part of his or her post-transplant immunosuppression regimen. Our patient’s use of tap water for nasal lavage was initially regarded as a possible source of amoeba, particularly given her history of repeated tap water irrigations in the past. However, upper respiratory symptoms pre-dated her use of nasal irrigation in the acute setting, and this mechanism of amoebic infection has only been reported in two cases of Naegleria fowleri infection in the United States (9). Immunocompromised patients should nonetheless avoid the use of non-sterile water for nasal irrigation given the potential for amoebic infection.

Table 1.

Reported cases and outcomes of Acanthamoeba infection in solid organ transplant (SOT) patients

Year Patient
Age/Gender		 Location Organ Time to
infection
(months)		 Immunosuppresive
regimen		 Type of
Infection		 Treatment
Regimen		 Diagnosis
confirmation		 Outcome Reference
1982 38/M Pennsylvania Kidney 30 Azathioprine, methylprednisolone Skin, lung, brain Broad-spectrum antibiotics Histopathologic staining – biopsy specimen Died 23
1994 31/M Texas Kidney 10 Azathioprine, cyclosporine, prednisone Skin Pentamidine, topical chlorhexidine/ketoconazole IF staining of biopsy tissue section Cured 13
1999 39/F South Carolina Lung 72 Azathioprine, prednisone, tacrolimus Skin 5-fluorocytosine, itraconazole, pentamidine, topical chlorhexidine/ketoconazole Histopathologic staining of abscess fluid* Cured 14
2001 38/M France Bilateral lung 36 Methylprednisolone, tacrolimus Skin Itraconazole pentamidine, topical chlorhexidine/ketoconazole IF staining of tissue at autopsy Died 24
2002 61/F Maryland Kidney 12 Mycophenolate mofetil, prednisone, tacrolimus Skin, bone Amikacin, amphotericin B, azithromycin, imipenem Culture of tissue at autopsy Died (postmortem dx) 7
2005 49/F Florida Bilateral lung 7 Mycophenolate mofetil, prednisone, tacrolimus Sinus Amphotericin B, caspofungin, voriconazole IF staining of biopsy tissue section Cured 15
2006 60/M Texas Bilateral lung 9 Mycophenolate mofetil, prednisone, Tacrolimus Skin, lung, brain Amphotericin B, ciprofloxacin, imipenem, itraconazole, vancomycin Histopathologic staining at autopsy* Died (postmortem dx) 25
2006 60/M Texas Lung Not reported Azathioprine, prednisone, tacrolimus Skin, lung, brain Broad-spectrum antibiotics IF staining and PCR analysis of brain biopsy specimen Died 26
2006 51/M Utah Kidney 3 Mycophenolate mofetil, prednisolone, tacrolimus Skin, brain Amphotericin B, azithromycin, flucytosine, metronidazole, pentamidine, rifampin, sulfadiazine IF staining of tissue at autopsy Died (post-mortem dx) 27
2006 40/M Pennsylvania Multiple organs 9 Thymoglobulin, tacrolimus Brain Not reported IF staining of tissue at autopsy Died (postmortem dx) 28
2007 40/M Spain Multiple organs 9 Tacrolimus Brain Not reported Histopathologic staining at autopsy Died (postmortem dx) 29
2007 52/F Florida Lung 36 Mycophenolate mofetil, prednisone, tacrolimus Skin Amphotericin B, voriconazole IF staining of biopsy tissue section Cured 16
2007 39/M France Heart 22 Cyclosporine, mycophenolate mofetil, prednisone Skin, lungs, kidneys 5-fluorocytosine, itraconazole, pentamidine IF staining of biopsy tissue section, confirmed by culture and PCR Died 8
2007 36/F India Kidney 48 Not reported Brain, lungs, pancreas Broad-spectrum antibiotics IF staining of biopsy tissue section Died (postmortem dx) 30
2008 41/M United Kingdom Liver 14 Azathioprine, cyclosporine, prednisone Brain co-trimoxazole, rifampicin, surgical resection IF staining of biopsy tissue section Cured 31
2010 63/M New York Liver 12 Alemtuzumab, Cyclophosphamide, Daclizumab, Doxorubicin, Etoposide, mycophenolate mofetil, Prednisone, Rituximab, Tacrolimus, Vincristine Skin, lung, brain Amphotericin B, caspofungin, flucytosine, miltefosine, pentamidine, voriconazole, topical ketoconazole IF staining of biopsy tissue section Died 18
2013 62/M California Bilateral lung 6 Mycophenolate mofetil, prednisolone, tacrolimus Skin, brain Amikacin, flucytosine, pentamidine, intrathecal amphotericin B Light microscopy and PCR of CSF fluid Died 32
2013 58/M New York Kidney 24 Methylprednisolone, mycophenolate mofetil, prednisone, rituximab, tacrolimus, thymoglobulin Brain Broad-spectrum antibiotics, ganciclovir, pyrimethamine, sulfadiazine, voriconazole IF staining of tissue at autopsy Died (postmortem dx) 3
2014 63/M Mississippi Kidney 6 Mycophenolate mofetil, tacrolimus Brain Azithromycin, fluconazole, flucytosine, miltefosine, sulfadiazine Histopathologic staining – brain biopsy specimen* Died 19
2015 64/F Arizona Kidney 7 Mycophenolate mofetil, prednisone, tacrolimus Brain Azithromycin, fluconazole, flucytosine, miltefosine, pentamidine, sulfadiazine IF staining of brain biopsy section Died 20
2015 59/F California Lung 10 Not reported Skin, sinus Inpatient: 5-flucytosine, azithromycin, bactrim, intranasal pentamidine; Discharge: azithromycin, bactrim, miltefosine, voriconazole IF staining of biopsy tissue section Cured 22
2015 60/F California Heart 5 Mycophenolate mofetil, prednisone, tacrolimus, thymoglobulin Skin, sinus, bone Fluconazole, flucytosine, miltefosine IF staining of biopsy tissue section Cured 24
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IF: immunofluorescence; PCR –polymerase chain reaction; CSF –cerebrospinal fluid

*

Histochemical staining not specified

Diagnosis of Acanthamoeba infection can be challenging. The majority of cases listed in Table 1 relied on histopathologic or immunofluorescence staining of involved tissue or fluid, and most cases (including ours) confirmed the diagnosis by sending samples to the CDC for immunofluorescence testing to detect Acanthamoeba trophozoites and cysts. Additionally, diagnosis can be made by culture or PCR from tissue or fluid specimens. Serologic testing is available, however the sensitivity and specificity of this assay is not well described.

Optimal treatment for acanthamoebiasis is not well established. Lack of susceptibility data for Acanthamoeba makes choice of antibiotic particularly challenging. Thus, a ‘kitchen sink’ approach relying on multiple pharmacologic mechanisms of action is often employed (10). There are six previous case reports of successfully treated Acanthamoeba infection in SOT patients, as noted in Table 1. Effective regimens have included sterol-targeting azoles (fluconazole, itraconazole, ketoconazole), pentamidine isethionate, trimethoprim-sulfamethoxazole, sulfadiazine, 5-fluorocytosine, azithromycin, amphotericin B, and miltefosine (10–16). Miltefosine, an aklylphosphocholine drug initially approved by the United States Food and Drug Administration (FDA) for the treatment of visceral leishmaniasis, also has in vitro activity against free living amoeba, including N. fowleri, Balamuthia mandrillaris, and Acanthamoeba spp. (12). It has been available in the United States (from CDC) under an expanded access IND protocol for use in the treatment of free-living ameba infections since 2013. There are five case reports of its use in treatment of Acanthamoeba, only two of which resulted in successful treatment (17–22). Topical chlorhexidine or ketoconazole has also been used for cutaneous lesions. Overall prognosis for this infection remains poor: only six of 21 previous SOT cases were reported as cured, and no therapeutic regimen has shown consistent efficacy. Of those that survived, only one had CNS involvement, and only two had disease involving more than one organ. This would suggest that the absence of encephalitis and/or disseminated disease may be important prognostic factors.

Our patient developed disseminated infection, which included the sinuses, skin, and bone but fortunately without evidence of CNS disease. Dissemination appeared to progress despite initial therapy with amphotericin B and metronidazole for four days and subsequent conversion to fluconazole, flucytosine, and miltefosine. Continued use of this triple-drug therapy and concurrent reduction in immunosuppression were followed by steady improvement in the second and third weeks of hospitalization. We speculate that improvement of the patient’s skin lesions and absence of new bone invasion resulted from this combination of anti-amoebic therapy and prompt decrease in the patient’s immunosuppressive regimen. Following discharge, the patient missed numerous appointments but did report adhering to her drug regimen, making it difficult to assess the progress of her improvement. Given a lack of interval imaging and evaluation, adequate duration of triple-drug therapy to resolve the infection was unclear, and a prolonged course was maintained. After six months of therapy, sinus symptoms and MRI lesions had completely resolved, and cutaneous lesions were not visible. Given this improvement and the patient’s ongoing nausea, miltefosine was discontinued eight months after discharge. Shortly after discontinuation of miltefosine, the patient’s absolute neutrophil count (ANC) began to drop; this was attributed to bone marrow suppression from flucytosine. Her ANC reached a nadir of 1660 cells/μL and she was switched to a regimen of fluconazole and trimethoprim-sulfamethoxazole, which she has been on for four months. Her ANC returned to baseline (> 4000 cells/μL) and she has remained clinically stable at 16 months after discharge.

Summary

Acanthamoebiasis is a rare, potentially fatal infection in SOT patients. Here we describe the second reported occurrence of disseminated acanthamoebiasis in a heart transplant recipient. This is also the first instance of successful treatment with a miltefosine-containing regimen for such a patient with disseminated disease, albeit without amebic encephalitis. Our patient demonstrated an extremely rare lytic lesion of bone, along with more typical sinus and skin involvement. Miltefosine appears to show some promise in the treatment of free-living amoebic infection, although it should be noted that regimens including this investigational drug have only led to cure in three out of six Acanthamoeba SOT case reports where it was used. Furthermore, miltefosine had limited effect in individuals with granulomatous amebic encephalitis, where infection was uniformly fatal. This ubiquitous protozoan should be considered as a cause of disseminated infection in immunosuppressed individuals who do not respond initially to antibiotics. Although reported outcomes are poor, and the optimal anti-amoebic regimen is not well defined, prompt diagnosis of Acanthamoeba infection, reduction of immunosuppression, and initiation of multi-drug therapy may provide the best chance for successful treatment.

Acknowledgments

The authors wish to thank Jessica Finn MD, from University of California San Francisco Department of Pathology, Kristina Hsieh DrPH, Shigeo Yagi PhD, Thelma Dunnebacke-Dixon PhD, Diana Singh BS, BA, and Anna Clayton MPH from the California Department of Public Health Viral & Rickettsial Disease Laboratory, as well as Sharon Roy MD, MPH and Pallavi D. Annambhotla, DrPH from the Centers for Disease Control and Prevention.

Abbreviations

CDC

Centers for Disease Control and Prevention

IND

investigational new drug

CNS

central nervous system

CRP

C-reactive protein

SOT

solid organ transplant

MRI

magnetic resonance imaging

ANC

absolute neutrophil count

Footnotes

Disclaimer: The findings and conclusions herein are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

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