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Year : 2022  |  Volume : 16  |  Issue : 4  |  Page : 428-430

Amphotericin B-resistant disseminated cryptococcal infection with concurrent cytomegalovirus colitis in a renal transplant recipient - A case report

1 Department of Nephrology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Radiodiagnosis and Imaging, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Date of Submission31-Mar-2021
Date of Acceptance01-Sep-2021
Date of Web Publication30-Dec-2022

Correspondence Address:
Dr. Mragank Gaur
Department of Nephrology, Post Graduate Institute of Medical Education and Research, Chandigarh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijot.ijot_31_21

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Post renal transplant opportunistic infections always pose a challenge to the clinician due to the varied nonspecific clinical manifestations and prove fatal if not diagnosed and treated early. Here, we present a case report of a patient who was 22 years post renal transplantation with amphotericin-resistant disseminated cryptococcal infection concurrent with cytomegalovirus colitis treated successfully with oral fluconazole and ganciclovir. The clinician should always take into account the antibiotic susceptibility and culture sensitivity of cryptococcosis to diagnose this rare yet emerging phenomenon of azole resistance. Furthermore, to the best of our knowledge, this is the first reported case of amphotericin-resistant cryptococcosis in posttransplant setting.

Keywords: Amphotericin resistance, cryptococcosis, cytomegalovirus, solid organ transplant

How to cite this article:
Gaur M, Sethi J, Prakash M. Amphotericin B-resistant disseminated cryptococcal infection with concurrent cytomegalovirus colitis in a renal transplant recipient - A case report. Indian J Transplant 2022;16:428-30

How to cite this URL:
Gaur M, Sethi J, Prakash M. Amphotericin B-resistant disseminated cryptococcal infection with concurrent cytomegalovirus colitis in a renal transplant recipient - A case report. Indian J Transplant [serial online] 2022 [cited 2023 Feb 3];16:428-30. Available from: https://www.ijtonline.in/text.asp?2022/16/4/428/364619

  Introduction Top

Cryptococcal infection is a common opportunistic infection in renal transplant recipients and is associated with substantial morbidity and mortality. We hereby present this case of amphotericin B-resistant disseminated Cryptococcus neoformans infection in a renal transplant recipient. To the best of our knowledge, this is the first reported case of amphotericin-resistant cryptococcal infection in post renal transplant setting. This is important as it will sensitize the clinicians toward the emerging amphotericin-resistant cryptococcal infection and to look for culture sensitivity and antibiotic susceptibility early in the course of illness. Early institution of appropriate antifungal is important to avoid lethal outcome in this infection.

  Case Report Top

We describe here a 50-year-old man, 22 years post renal transplantation with mother as a donor (basic disease unknown). Immunosuppression included no induction therapy and maintenance with tacrolimus, mycophenolate mofetil (MMF), and prednisolone. Allograft biopsy was done 6 years posttransplant in view of serum creatinine of 1.7 mg/dl that showed evidence of chronic calcineurin inhibitor nephrotoxicity. Hence, tacrolimus was substituted with sirolimus that was also stopped 2 years later in view of significant proteinuria, and the patient was thereafter continued on double immunosuppression with MMF (1 g BD) and prednisolone (5 mg OD). His baseline creatinine was stable between 2.5 and 3 mg/dl for the last 6–7 years. Significant events posttransplant included pulmonary tuberculosis in 2012 (received antitubercular therapy for 12 months). The patient was initially admitted under our unit in February 2021, i.e., 22 years posttransplant, with complaints of fever, headache, and productive cough for 4 months. He was diagnosed as disseminated cryptococcal infection (cerebrospinal fluid (CSF) showed growth of C. neoformans with magnetic resonance (MR) brain that was suggestive of bilateral frontoparietal parenchymal nodules and T2 hyperintensities) [Figure 1]. The patient also had growth of C. neoformans on two serial blood cultures, and computed tomography chest also showed evidence of bilateral consolidation. Hence, for disseminated cryptococcal infection, the patient was started on liposomal amphotericin (5 mg/kg/day) with flucytosine (25 mg/kg/day). MMF was stopped, and the dose of prednisolone was increased to 7.5 mg/day. His creatinine during this admission was stable in the range of 2.5–3.0 mg/dL. The patient again presented 3 weeks after the first admission with complaints of two episodes of generalized tonic-clonic seizures and diarrhea. He had received a total amphotericin cumulative dose of 3.15 g by this time. His laboratory parameters revealed hemoglobin (Hb) of 4 g/dl, total leukocyte count (TLC) of 6.5 × 109/L, platelet count of 22 × 109/L, and serum creatinine of 2.8 mg/dL. Bone marrow examination done in view of bicytopenia showed evidence of hemophagocytosis with high serum ferritin of 6640 ng/ml, low fibrinogen of 1.9 g/L, and high triglyceride of 333 mg/dL. Repeat evaluation for seizures revealed raised CSF protein (160 mg/dl) with mononuclear leukocytosis and budding yeast cells on India ink and CSF Cryptococcus antigen positive. Repeat MR brain during this admission showed similar lesions as previous MR with no resolution/decrease in size of lesions. CSF samples for culture and in vitro antibiotic susceptibility were found to be positive for C. neoformans var. grubii but resistant to amphotericin B and sensitive to itraconazole, voriconazole, and fluconazole. Cytomegalovirus (CMV) viral copies were 6500 IU/ml, and colonic biopsy was also suggestive of CMV colitis, for which he was started on intravenous ganciclovir. The patient was started on oral fluconazole (800 mg/day) along with flucytosine after stopping amphotericin B and intravenous immunoglobulin for secondary hemophagocytic histiocytosis. After 5 days of IVIG therapy (400 mg/kg/day × 5 days), cytopenia improved to Hb of 7 g/dL, TLC of 4.3 × 109/L, and platelet of 96 × 109/L and diarrhea subsided. One month after fluconazole therapy, the patient was shifted to consolidation phase of therapy with fluconazole (400 mg/day). CMV polymerase chain reaction became undetectable, and he was shifted to valganciclovir oral secondary prophylaxis. His serum creatinine had remained stable at 2.6 mg/dL with stable total white count and platelets. Repeat MR brain showed partial resolution of lesions. Plan is to continue lifelong fluconazole therapy at a dose of 200 mg/day. We also plan to do an allograft biopsy after completion of consolidation phase to decide on immunosuppression based on the biopsy findings.
Figure 1: T2-weighted axial (a) and fluid-attenuated inversion recovery (b) shows multiple variable size hyperintense focal lesions in periventricular white matter in bilateral frontoparietal lobes (arrows)

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  Discussion Top

Cryptococcosis is the thirst most common infection in solid organ transplant (SOT) recipients following candidiasis and aspergillosis accounting for 8% of all fungal infections.[1] In SOT recipients, cryptococcosis usually leads to disseminated disease or meningoencephalitis. Incidence rates of 0.3%–5.3% have been reported.[2] The most common mode of transmission is through inhalation of fungal spores from the environment which likely happened in our patient. Cryptococcal meningoencephalitis should be considered in renal transplant recipients who present with nonspecific signs and symptoms of fever, seizures, and headache, as was in our case. Other commonly associated symptoms include altered sensorium and visual disturbances. Patients with CNS disease are more likely to have fungemia. Radiological imaging includes meningoencephalitis and granulomas typically seen in the basal ganglia. The gold standard for microbiological diagnosis is blood fungal culture and serum cryptococcal antigen test. Negative staining by India ink and radiology is also used for diagnosis. Positive serum cryptococcal antigen has been reported in 88%–91% of the SOT recipients with cryptococcal meningitis.[2]

Preferred induction therapy for disseminated disease (at least two noncontiguous sites involvement) consists of lipid formulation of amphotericin B and flucytosine for at least 2 weeks followed by a consolidation phase with fluconazole (400–800 mg/day) for 8 weeks and finally maintenance phase with fluconazole (200–400 mg/day) for a minimum period of 6 months. In the case of amphotericin B-resistant cryptococcosis, fluconazole (800–1200 mg/day) plus flucytosine (100 mg/kg/day) can be administered for induction period.[3],[4],[5] Another important issue is the management of immunosuppression that should be gradually reduced during therapy as rapid tapering can lead to untoward side effects.[3]

Our patient also had concurrent CMV viremia which has been associated with increased death rates among patients with acquired immunodeficiency syndrome. However, the impact of concurrent CMV and opportunistic fungal infections is not well understood in the posttransplant setting. CMV potentially blunts the cytokine responses to comorbid fungal infections, thus leading to immunomodulatory effects. There has been a shift in the antibiotic susceptibility pattern of C. neoformans with increased incidence of polyene resistance. Despite the widespread use, mechanism conferring resistance of Cryptococcus to polyenes is not well understood. Alteration in sterol content in fungal cell membrane has been proposed as one of the mechanisms.[6] One of the first proposed mechanisms suggested mutations in sterol 8–7 isomerase, an enzyme involved in ergosterol biosynthesis. The widespread use of antifungal agents in medicine and agriculture promotes the evolution of resistant strains.[7] We report the first case of amphotericin-resistant Cryptococcus in posttransplant setting and highlight this important and rapidly emerging issue of polyene-resistant cryptococcosis that should be looked for early in the disease course.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Singh N, Dromer F, Perfect JR, Lortholary O. Cryptococcosis in solid organ transplant recipients: Current state of the science. Clin Infect Dis 2008;47:1321-7.  Back to cited text no. 1
Husain S, Wagener MM, Singh N. Cryptococcus neoformans infection in organ transplant recipients: Variables influencing clinical characteristics and outcome. Emerg Infect Dis 2001;7:375-81.  Back to cited text no. 2
Vilchez RA, Fung J, Kusne S. Cryptococcosis in organ transplant recipients: An overview. Am J Transplant 2002;2:575-80.  Back to cited text no. 3
Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis 2010;50:291-322.  Back to cited text no. 4
Day JN, Chau TT, Wolbers M, Mai PP, Dung NT, Mai NH, et al. Combination antifungal therapy for cryptococcal meningitis. N Engl J Med 2013;368:1291-302.  Back to cited text no. 5
Lozano-Chiu M, Paetznick VL, Ghannoum MA, Rex JH. Detection of resistance to amphotericin B among Cryptococcus neoformans clinical isolates: Performances of three different media assessed by using E-test and National Committee for Clinical Laboratory Standards M27-A methodologies. J Clin Microbiol 1998;36:2817-22.  Back to cited text no. 6
Bermas A, Geddes-McAlister J. Combatting the evolution of antifungal resistance in Cryptococcus neoformans. Mol Microbiol 2020;114:721-34.  Back to cited text no. 7


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