International Journal of Infectious Diseases 14 (2010) e348–e350
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Case Report
Voriconazole inhibition of tacrolimus metabolism in a kidney transplant recipient with fluconazole-resistant cryptococcal meningitis Hui-Hua Chang a, Nan-Yao Lee b, Wen-Chien Ko b, Hsin-Chun Lee b, Yea-Hui Kao Yang c, Chi-Jung Wu b, Chia-Ming Chang b,* a b c
Institute of Biopharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan Division of Infectious Diseases, Department of Internal Medicine, National Cheng Kung University Hospital, 138 Sheng Li Road, Tainan, 70403, Taiwan Institute of Clinical Pharmacy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 16 February 2009 Accepted 13 April 2009
Fluconazole resistance among Cryptococcus neoformans is unusual in post-transplantation patients. Voriconazole is a triazole agent with good antifungal activity but also with drug–drug interactions because of potent inhibition of the P450 enzyme system. The interaction with immunosuppressive agents, especially calcineurin inhibitors, is of concern in post-transplantation patients. We report the first case of fluconazole-resistant cryptococcal meningitis in a kidney transplant recipient successfully treated with voriconazole, but complicated with a raised serum concentration of tacrolimus and hyponatremia after co-administration. A 43-year-old man with a history of renal transplantation and on long-term immunosuppressive agents, including mycophenolate and tacrolimus, suffered from recurrent cryptococcal meningitis. He was treated with amphotericin B-liposome for 24 days because of fluconazole resistance. However, cryptococci were still found in the cerebrospinal fluid; oral voriconazole was substituted. Six days after co-administration of voriconazole and tacrolimus, the trough concentration of tacrolimus markedly increased and hyponatremia developed. A culture of the CSF did not yield growth of Cryptococcus. Conditions improved after the cessation of tacrolimus for three days followed by reducing the dosage of voriconazole and tacrolimus. When voriconazole is initially added, the dosage of tacrolimus should be reduced. Close monitoring of tacrolimus concentration and its adverse effects, including nephrotoxicity, hyperglycemia, hyperkalemia, and hyponatremia, are mandatory. ß 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Corresponding Editor: Andy I.M. Hoepelman, Utrecht, the Netherlands Keywords: Voriconazole Tacrolimus Transplant Cryptococcus Fluconazole resistance
1. Introduction Although fungal infections are not uncommon complications among post-transplantation patients on long-term immunosuppressive therapy, resistance to fluconazole among Cryptococcus neoformans is unusual in these patients. They are difficult to treat not only because of their immunocompromised status, but also because of the pharmacokinetic/pharmacodynamic properties of the antifungal agents. Voriconazole is a triazole with a broad spectrum of antifungal activity. Similar to other azoles, voriconazole is metabolized by the cytochrome P450 (CYP) enzyme system and is known to inhibit CYP 2C19, 2C9, and 3A4,1 which is also involved in the metabolism of calcineurin inhibitors, such as
* Corresponding author. Tel.: +886 6 235 3535x3596; fax: +886 6 275 2038. E-mail addresses:
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[email protected] (C.-M. Chang).
tacrolimus.2,3 We describe a patient with fluconazole-resistant cryptococcal meningitis who was successfully treated with voriconazole but complicated with a raised serum concentration of tacrolimus after co-administration. 2. Case report A 43-year-old man, weighing 47 kg, had a history of hypertension and had received a renal transplantation in India ten years earlier. Immunosuppressive agents including mycophenolate 360 mg/day, tacrolimus 2 mg/day, and methylprednisolone 4 mg/day were continued for more than five years. In the past two years, the patient had been admitted four times because of recurrent cryptococcal meningitis due to incomplete course of treatment. Several days previously, he had suffered from nausea, vomiting, fever, and neck stiffness, which revealed signs of increased intracranial pressure. Recurrent meningitis was suspected at the outpatient clinic but the patient refused admission.
1201-9712/$36.00 – see front matter ß 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2009.04.012
H.-H. Chang et al. / International Journal of Infectious Diseases 14 (2010) e348–e350
Figure 1. Concentrations of tacrolimus in a patient receiving voriconazole.
However, he was admitted a week later due to progressive dizziness with severe vomiting. On admission, his vital signs were normal. The hemogram disclosed a hemoglobin level of 11.7 g/dl (normal 13.5–17.0 g/dl) and leukocyte count of 8.7 109/l (normal 3.4–9.1 109/l), with 91% segments, 3% band forms, and 3.2% lymphocytes. Serum biochemical values were: blood urea nitrogen 31 mg/dl (normal 7– 21 mg/dl), creatinine 2.1 mg/dl (normal 0.7–1.5 mg/dl), aspartate aminotransferase 21 U/l (normal 5–40 U/l), alanine aminotransferase 19 U/l (normal 5–55 U/l), sodium 132 mmol/l (normal 135– 155 mmol/l), and potassium 4.9 mmol/l (normal 3.5–5.5 mmol/l). A lumbar puncture was performed and the initial pressure was 178 mmH2O. Analysis of the cerebrospinal fluid (CSF) revealed pleocytosis (white blood cell (WBC) count 50 106/l, 54% lymphocytes), low glucose level (17 mg/dl), high protein level (81 mg/dl), positive Indian ink, and raised titer of cryptococcal antigen (titer 1:1024). A culture of CSF yielded growth of C. neoformans. Magnetic resonance imaging of the brain did not show any abnormalities. Fluconazole 200 mg/day was administered from admission but was switched to amphotericin B-liposome (AmBisome1; Gilead) 4 mg/kg/day because of fluconazole resistance, from day 2 to day 25 of his hospitalization. By E-test diffusion (AB Biodisk, Solna, Sweden), the minimum inhibitory concentrations of fluconazole, voriconazole, and amphotericin B were >256, 0.5, and 0.123 mg/ ml, respectively. However, cryptococci were still found in the CSF. Therefore, oral voriconazole 800 mg/day was substituted for amphotericin B-liposome from day 25. Meanwhile, the tacrolimus level was within the therapeutic range (9.9 ng/ml, aimed therapeutic interval 5–15 ng/ml). Six days later, nausea and vomiting were noted and the tacrolimus level markedly increased (28.5 ng/ml). Renal functions remained at the baseline levels (blood urea nitrogen 33 mg/dl, creatinine 2.1 mg/dl). The sodium level decreased to 122 mmol/l and a low cortisol level was noted (1.22 mg/ml, normal 6–28 mg/ml). A culture of the CSF performed on day 31 did not yield growth of Cryptococcus. Voriconazole was withdrawn on day 32, and amphotericin B-liposome was resumed. Tacrolimus was completely discontinued for three days and then the daily dose was reduced to 0.5 mg. Trough levels of tacrolimus were 14.8 ng/ml and 6.5 ng/ml on days 33 and 38, respectively (Figure 1). On day 37, a decreased dosage of voriconazole 600 mg/ day was prescribed again in place of amphotericin B-liposome. Serial follow-up concentrations of tacrolimus were within the therapeutic range thereafter. The patient’s condition was stable and he was discharged on day 53. After discharge, he received oral voriconazole for additional five months and no cryptococcosis recurred during follow-up visit. 3. Discussion According to the Infectious Diseases Society of America guidelines, amphotericin B plus flucytosine for 2 weeks and then fluconazole for a minimum 10 weeks is recommended in nonHIV-infected patients.4 For our patient, culture of the CSF
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yielded growth of fluconazole-resistant C. neoformans, and response to amphotericin B liposome was unsatisfactory because cryptococci were still found in the CSF. In addition, in spite of less nephrotoxicity than conventional amphotericin B, elevations of serum creatinine have occurred in 10–30% of transplant patients treated with amphotericin B liposome.5 Voriconazole was the alternative choice for our patient, since previous studies have shown that voriconazole is effective in patients with fluconazole-resistant fungal infections and those who have failed standard antifungal therapy.6 Resistance to fluconazole among C. neoformans is unusual in HIV-negative patients.7 So far as we know, the case described here is the first case of fluconazole-resistant cryptococcal meningitis successfully treated with voriconazole after failure of amphotericin B in a post-transplantation patient. In a randomized, two-treatment, placebo-controlled pharmacokinetic study in liver transplant recipients, the tacrolimus (2 mg/ day) trough blood concentration increased 10-fold in patients who received voriconazole on day 5.8 When voriconazole is initiated, the manufacturer recommends that the concurrent tacrolimus dose be reduced by one-third.9 However, there are some case reports that have shown a requirement for an 80–90% reduction in maintenance dosage of tacrolimus.2,3,10 In our case, nausea and vomiting occurred after co-administration for six days. The tacrolimus dosage was reduced by half and voriconazole was reduced by one-fourth. Such a rapid-onset interaction is clinically important and clinicians should monitor tacrolimus levels daily when voriconazole is co-administered. The major adverse effects of tacrolimus include nephrotoxicity, hyperglycemia, and hyperkalemia.11 A previous study has reported that hyponatremia and hyperkalemia are more frequent in renal transplant recipients treated with tacrolimus than with cyclosporin for the first 90 days.11 In our case, obvious nephrotoxicity and hyperkalemia were not present, but hyponatremia was noted. Although adrenal insufficiency was also considered as one of the causes of hyponatremia, reducing levels of sodium progressed only when the tacrolimus level increased. The association between raised tacrolimus level and worsening hyponatremia was more favored. Hyponatremia caused by the syndrome of inappropriate secretion of antidiuretic hormones during administration of tacrolimus has been reported.12 Another study reported a case of sodium-losing nephropathy that was associated with tacrolimus administration, and symptoms improved after the cessation of tacrolimus.13 Whether raised tacrolimus levels lead to further loss of sodium needs to be confirmed in the future. In conclusion, fluconazole resistance should be considered among post-transplantation patients with recurrent cryptococcal meningitis. Voriconazole is an alternative choice but co-administration of tacrolimus and voriconazole may result in a significantly increased concentration of tacrolimus. When voriconazole is used, the concentration of tacrolimus should be closely monitored. Clinicians should also be alert to the adverse effects of tacrolimus, including nephrotoxicity, hyperglycemia, hyperkalemia, and hyponatremia. Conflict of interest: No conflict of interest to declare. References 1. Niwa T, Shiraga T, Takagi A. Drug–drug interaction of antifungal drugs. Yakugaku Zasshi 2005;125:795–805. 2. Pai MP, Allen S. Voriconazole inhibition of tacrolimus metabolism. Clin Infect Dis 2003;36:1089–91. 3. Tintillier M, Kirch L, Goffin E, Cuvelier C, Pochet JM. Interaction between voriconazole and tacrolimus in a kidney-transplanted patient. Nephrol Dial Transplant 2005;20:664–5. 4. Saag MS, Graybill RJ, Larsen RA, Pappas PG, Perfect JR, Powderly WG, et al. Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infect Dis 2000;30:710–8.
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5. de Marie S, Janknegt R, Bakker-Woudenberg IA, de Marie S, Janknegt R, BakkerWoudenberg IA. Clinical use of liposomal and lipid-complexed amphotericin B. J Antimicrob Chemother 1994;33:907–16. 6. Baden LR, Katz JT, Fishman JA, Koziol C, DelVecchio A, Doran M, et al. Salvage therapy with voriconazole for invasive fungal infections in patients failing or intolerant to standard antifungal therapy. Transplantation 2003;76: 1632–7. 7. Assing K, Birgens H, Arendrup M. Cryptococcus neoformans var. neoformans resistant to fluconazole in an HIV-negative patient with chronic lymphocytic leukemia. Clin Microbiol Infect 2003;9:441–4. 8. Venkataramanan R, Zang S, Gayowski T, Singh N. Voriconazole inhibition of the metabolism of tacrolimus in a liver transplant recipient and in human liver microsomes. Antimicrob Agents Chemother 2002;46:3091–3. 9. Information Package. Vfend1 IV injection, oral tablets, solution, voriconazole IV injection, oral tablets, solution. New York Pfizer, Inc., 2006.
10. Kawazoe H, Takiguchi Y, Tanaka H, Fukuoka N, Ohnishi H, Ishida T, et al. Change of the blood concentration of tacrolimus after the switch from fluconazole to voriconazole in patients receiving allogeneic hematopoietic stem cell transplantation. Biol Pharm Bull 2006;29:2528–31. 11. Higgins R, Ramaiyan K, Dasgupta T, Kanji H, Fletcher S, Lam F, et al. Hyponatraemia and hyperkalaemia are more frequent in renal transplant recipients treated with tacrolimus than with cyclosporin. Further evidence for differences between cyclosporin and tacrolimus nephrotoxicities. Nephrol Dial Transplant 2004;19:444–50. 12. Azuma T, Narumi H, Kojima K, Nawa Y, Hara M. Hyponatraemia during administration of tacrolimus in an allogeneic bone marrow transplant recipient. Int J Hematol 2003;78:268–9. 13. Sakamoto K, Yamada K, Arita S, Hamaguchi K, Kashiwabara H, Yokoyama T. Sodium-losing nephropathy and distal tubular damage of transplant kidneys with FK506 administration. Transplant Proc 1995;27:826–8.
