International Journal of Infectious Diseases 78 (2019) 103–106 Contents lists available at ScienceDirect International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid Case Report High-dose benznidazole in a 62-year-old Bolivian kidney transplant recipient with Chagas central nervous system involvement M. Monteroa,* , M. Mirb , E. Sulleiroc , J.L. Avalos Esquivelb , E. García Lópeza , D. Molina-Morantd , I. López Montesinosa , L. Sorlía , G. Veliz Espinosab , E. Mounteis Olivad , M. Crespob , I. Mongee, J.P. Horcajadaa , S. Graue, J. Pascualb a Infectious Diseases Service, Hospital del Mar, Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona (UAB), CEXS-Universitat Pompeu Fabra, Barcelona, Spain b Department of Nephrology, Hospital del Mar, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona (UAB), CEXS-Universitat Pompeu Fabra, Barcelona, Spain c Microbiology Department, H. Universitari Vall dHebron. PROSICS Barcelona (International Health Program of the Catalan Health Institute), Universitat Autònoma de Barcelona, Barcelona, Spain d Tropical Medicine Unit, Infectious Diseases Department, PROSICS Barcelona (International Health Program of the Catalan Health Institute), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain e Department of Pharmacy, Hospital del Mar, Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona (UAB), CEXS-Universitat Pompeu Fabra, Barcelona, Spain A R T I C L E I N F O A B S T R A C T Article history: There is little published data on benznidazole dosing, or levels in cerebrospinal fluid. In this report, we Received 16 August 2018 describe the clinical course of an immunosuppressed patient with Chagas central nervous system Received in revised form 16 October 2018 involvement. He was treated successfully with larger benznidazole doses than are recommended, in Accepted 19 October 2018 order to reach therapeutically effective concentrations in the brain. Corresponding Editor: Eskild Petersen, Aar- hus, Denmark © 2018 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by- nc-nd/4.0/). Keywords: Chagas disease Kidney transplant recipient Chagoma Benznidazole dose Benznidazole PK/PD Introduction Case report Currently, only two effective drugs are available for the A 62-year-old man from Bolivia was admitted to hospital treatment of Chagas disease: benznidazole and nifurtimox (World because of focal neurological deficits. The patient, who had been Health Organization, 2018; Pérez-Molina and Molina, 2017). living in Spain for more than 10 years, had a medical history of Information on the pharmacokinetics of benznidazole is limited chronic kidney disease on haemodialysis treatment starting in (Molina et al., 2017). Here, we present the case of a kidney 2012. He underwent a kidney transplantation from a deceased transplant recipient with Chagas disease and central nervous donor in 2014, and was receiving long-term immunosuppression system (CNS) involvement, whose poor clinical course required with prednisone 5 mg/24 h, tacrolimus at a dose to achieve trough treatment with much higher doses of benznidazole than are levels of 6–8 ng/ml, and mycophenolic acid at 360 mg twice daily. recommended. In July 2016, he showed an increase in proteinuria and his graft was biopsied. The findings were consistent with chronic active antibody-mediated rejection, without HLA donor-specific anti- bodies. Therefore, steroid pulses at 10 mg/kg/day were adminis- * Corresponding author at: Hospital del Mar, Passeig Marítim, 25–29, 08003 tered for 5 days. Barcelona, Spain. E-mail address: 95422@parcdesalutmar.cat (M. Montero). https://doi.org/10.1016/j.ijid.2018.10.014 1201-9712/© 2018 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 104 M. Montero et al. / International Journal of Infectious Diseases 78 (2019) 103–106 Figure 1. Brain T1 Magnetic resonance imaging (MRI). In January 2017, the patient was admitted because of difficulty (CLIA) (Liaison XL Murex) (Malan et al., 2006) and immunochro- moving his left arm, headache, and loss of balance for the previous matography for serological diagnosis of Trypanosoma cruzi were 5 days. On initial examination, he showed left arm paresis and positive, as was the CLIA for Toxoplasma gondii. bradypsychia. There were no signs or symptoms of infection. Empirical treatment was started with benznidazole, sulfadia- Magnetic resonance imaging (MRI) of the brain showed a focal zine, and pyrimethamine. The initial benznidazole regimen was lesion in the corpus callosum surrounded by oedema and 100 mg/8 h, in accordance with the recommended dosage for the suggestive of lymphoma or glioblastoma (Figure 1); hence, high- treatment of T. cruzi infection (Pierrotti et al., 2018). Real-time PCR dose corticosteroid therapy was prescribed. However, during the (RT-PCR) (Molina et al., 2017; Piron et al., 2007) for the first week of admission the patient experienced clinical deteriora- determination of T. cruzi DNA was positive in both blood and tion and a decrease in level of consciousness. A brain biopsy was brain specimens, whereas RT-PCR for T. gondii was negative in performed, with findings of acute and chronic inflammation, brain; hence, sulfadiazine and pyrimethamine were discontinued. abscess formation, and histiocytes containing intracytoplasmic HIV testing was negative. The T. cruzi parasite load, estimated by microorganisms (Figure 2). Chemiluminescence immunoassays the amplification cycle threshold (Ct), was higher in the brain biopsy than in the blood sample (12.35 vs. 30.43). Approximately 2 weeks after receiving the appropriate antiparasitic treatment, the patient’s clinical and neurological status worsened and he required orotracheal intubation. Electro- encephalography ruled out non-convulsive status epilepticus, but was consistent with diffuse encephalopathy. A new brain MRI study detected an increase in the size of the Chagas lesion, although RT-PCR analyses for T. cruzi in blood samples were repeatedly negative. In view of this scenario, it was decided to progressively escalate the benznidazole dose up to 300 mg/12 h (15 mg/kg/day) at 24 days after starting this treatment, in order to reach therapeutically effective concentrations in the cerebrospinal fluid (CSF). This amount was well above the recommended dose of 5–10 mg/kg/day (Perin et al., 2017). After 2 months of treatment with the new dosing regimen (at steady state), blood benznidazole samples were taken at different time points: 1 h, 3 h, 5 h, 8 h, and 12 h after administration. The measured benznidazole concentrations were 14.6 mg/l, 14.8 mg/l, 14.1 mg/l, 10.5 mg/l, and 8.8 mg/l, respectively, all values being above the in vitro trypanosomicidal range (3–6 mg/l) (Raaflaub, 1980). The plasma area under the concentration–time curve from 0 to 12 h (AUC0–12) was 133.2 mg*h/l. In addition, CSF and blood peak (Cmax) samples (3 h after the dose) were taken 2 weeks later. The concentrations achieved were 8.3 mg/l in CSF and 17.2 mg/l in blood, which yielded a CSF/blood Cmax ratio of 48.3% (Figure 3). The Figure 2. Pathological study of brain biopsy. patient’s neurological status gradually improved and he was M. Montero et al. / International Journal of Infectious Diseases 78 (2019) 103–106 105 Figure 3. Plasma levels benznidazole (mg/dl). weaned off orotracheal intubation. A new MRI showed a 2013). This is supported by the observations in our patient, whose substantial decrease in the size of the brain mass and oedema. highest benznidazole plasma concentration was 17.2 mg/dl. Four RT-PCR T. cruzi parasitemia analyses were conducted at In conclusion, T. cruzi reactivation may occur in immunosup- different time points, with negative results; hence, after more than pressed patients; hence, this eventuality should be considered in 3 months of benznidazole at 300 mg/12 h, the antiparasitic therapy the differential diagnosis, mainly in patients from endemic areas. was discontinued. This was a challenging case because of the severe presentation and Two months after hospital discharge, the patient’s clinical the dearth of available information on benznidazole dosage and outcome was favourable with functional neurological rehabilita- the levels achieved in CSF. In conclusion, the experience described tion. His situation was nearly back to normal except for the left arm suggests that benznidazole can be safely administered in higher paresis. doses than those currently recommended for patients showing a torpid evolution, although close monitoring is advisable. Discussion Funding Information on benznidazole penetration into the CNS is No specific funding was received for this study. restricted to experimental animal studies, in which the reported mean brain/plasma benznidazole ratio varies considerably from Ethical approval 19% to 68.3%. Furthermore, the permeability of benznidazole through the blood–brain barrier of animals and humans may differ All procedures were conducted with the full cooperation and and this remains to be clarified (Perin et al., 2017; Workman et al., adequate understanding of the patient, and have therefore been 1984). The relatively high concentration measured in the CSF of the performed in accordance with the ethical standards of the patient described here suggests substantial passage of benznida- Declaration of Helsinki. zole through the blood–brain barrier. The case patient showed good tolerability without the Conflict of interest haematological and neurological side effects usually associated with the high doses of benznidazole he received. One study has The authors declare no conflicts of interest. investigated the relationship between benznidazole plasma concentrations and the development of toxicity (Pinazo et al., References 2013). Patients received a dose of 5 mg/kg/day for 60 days, which is much lower than that administered to our patient. Although Malan AK, Avelar E, Litwin SE, Hill HR, Litwin CM. Serological diagnosis of several cases of toxicity were observed, mainly changes in Trypanosoma cruzi: evaluation of three enzyme immunoassays and an indirect biochemical parameters and haematological manifestations of immunofluorescent assay. J Med Microbiol 2006;. Molina I, Salvador F, Sánchez-Montalvá A, Artaza MA, Moreno R, Perin L, et al. bone marrow depression (e.g., neutropenia, thrombocytopenia, Pharmacokinetics of benznidazole in healthy volunteers and implications in anaemia, leukopenia), which resolved after treatment discontinu- future clinical trials. Antimicrob Agents Chemother 2017;61(March (4)). ation, there were no correlations between plasma levels of the drug Pérez-Molina JA, Molina I. Chagas disease. Lancet 2017;391:82–94. Perin L, Da Silva RM, Da Silva Fonseca K, De Oliveira Cardoso JM, Mathias FAS, Reis and these adverse events. It has been reported that plasma LES, et al. Pharmacokinetics and tissue distribution of benznidazole after oral benznidazole concentrations below 20 mg/l do not seem to be administration in mice. Antimicrob Agents Chemother 2017;61(4):1–30. related to the development of serious adverse events (Pinazo et al., 106 M. Montero et al. / International Journal of Infectious Diseases 78 (2019) 103–106 Pierrotti LC, Carvalho NB, Amorin JP, Pascual J, Kotton CN, López-Vélez R. Chagas Piron M, Fisa R, Casamitjana N, López-Chejade P, Puig L, Vergés M, et al. disease recommendations for solid-organ transplant recipients and donors. Development of a real-time PCR assay for Trypanosoma cruzi detection in blood Transplantation [Internet] 2018;102(2S Suppl. 2)S1–7 Available from: http:// samples. Acta Trop 2007;103(3):195–200. www.ncbi.nlm.nih.gov/pubmed/29381572%0Ahttp://Insights.ovid.com/cross- Raaflaub J. Multiple-dose kinetics of the trypanosomicide benznidazole in man. ref?an=00007890-201802002-00001. Arzneimittelforschung [Internet] 1980;30(12)2192–4 [Cited 12 February 2018] Pinazo M-J, Guerrero L, Posada E, Rodriguez E, Soy D, Gascon J. Benznidazole- Available from: http://www.ncbi.nlm.nih.gov/pubmed/6783051. Related Adverse Drug Reactions and Their Relationship to Serum Drug Workman P, White RA, Walton MI, Owen LN, Twentyman PR. Preclinical Concentrations in Patients with Chronic Chagas Disease. Antimicrob Agents pharmacokinetics of benznidazole. Br J Cancer 1984;. Chemother [Internet] 2013;57(1)390–5 Available from: http://aac.asm.org/cgi/ World Health Organization. Chagas disease (American tripanosomiasis). 2018 doi/10.1128/AAC.01401-12. [Internet]. [Cited 20 January 2018]. Available from: http://www.who.int/ mediacentre/factsheets/fs340/en/.