Scientific letter
Use of isavuconazole in cryptococcal meningitis in a cirrhotic patient
Uso de isavuconazol en la meningitis criptocócica de un paciente cirrótico
Jesús Fernández Plazaa,
, Sandra Gregorio Malagónb, Manuel Poyato Borregoa,c, Rafael Luque Márqueza,d
Corresponding author
a Unidad de Enfermedades Infecciosas, Microbiología y Parasitología, Hospital Universitario Virgen del Rocío, Sevilla, Spain
b Unidad de Medicina Interna, Hospital Son Llàtzer, Palma de Mallorca, Spain
c CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain
d Infectious Diseases Research Group, Clinical Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University of Seville/CSIC/University Hospital Virgen del Rocío, Sevilla, Spain
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It is frequently associated with HIV infection in a situation of advanced immunosuppression or with other types of immunodeficiencies (solid organ transplant, cancers and patients undergoing chemotherapy or on immunosuppressive drugs). However, up to 20% of cases occur in immunocompetent patients, with the prevalent varieties being <span class="elsevierStyleItalic">C. neoformans grubii</span> and <span class="elsevierStyleItalic">C. gattii</span>.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> We present an autochthonous case of CM due to <span class="elsevierStyleItalic">C. gattii</span> resistant to fluconazole with a favourable response to isavuconazole.</p><p id="par0010" class="elsevierStylePara elsevierViewall">The subject is a 59-year-old man with a history of poly-drug addiction, ischaemic stroke with right hemiparesis and Child-Pugh B cirrhosis due to C virus with sustained viral response. He went to the Emergency Care Service with a three-week history of unsteadiness in gait, sensation of spinning objects and fever. Examination revealed upward gaze, fundus without papillary oedema, and no alterations in the rest of the physical and neurological examination.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Head CT was without findings and lumbar puncture (LP) showed cloudy cerebrospinal fluid (CSF) with normal pressure and biochemistry suggestive of bacterial meningitis (glucose 8 mg/dl, total proteins 383.7 mg/dl, leucocytes 8297 cells, 92% polymorphonuclear); yeasts compatible with <span class="elsevierStyleItalic">Cryptococcus</span> spp. were found in the Gram and India ink staining (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>), confirming the detection of DNA for <span class="elsevierStyleItalic">C. gattii/neoformans</span> using a molecular technique based on multiplex PCR nucleic acids (Biomérieux, FilmArray™). <span class="elsevierStyleItalic">C. gattii was identified in the culture.</span> Blood cultures were negative and the baseline titre of cryptococcus antigen in CSF (latex) was >1/10,000.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Brain MRI showed cerebellar cryptococcomas. Immunoglobulin subclasses, complement, lymphocyte populations and HIV serology were determined and occult neoplasms were ruled out. Splenomegaly was detected on CT without signs of portal hypertension.</p><p id="par0025" class="elsevierStylePara elsevierViewall">For the treatment of central nervous system (CNS) infection due to <span class="elsevierStyleItalic">C. gattii</span>, data on <span class="elsevierStyleItalic">C. neoformans</span> were extrapolated,<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> and it was decided to start treatment, according to WHO recommendations,<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> with liposomal amphotericin B (AmB-L) 10 mg/kg in single intravenous dose + flucytosine (5-FC) 100 mg/kg/day orally in four doses, followed by fluconazole 1200 mg orally every 24 h for two weeks.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Despite this treatment, the patient continued to show a decreased level of consciousness and the growth of the fungus persisted in successive CSF cultures. Finally, he was switched to the IDSA<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> scheme with AmB-L 3−4 mg/kg/day and 5-FC. After six weeks of treatment, yeast continued to be isolated in the CSF with antigen titres >1/10,000. We therefore decided to combine an azole with the previous regimen.</p><p id="par0035" class="elsevierStylePara elsevierViewall">At Spain's National Microbiology Centre, using the broth microdilution method, the MIC of the different azoles were: fluconazole > 4 μg/ml; voriconazole 2 μg/ml; and isavuconazole 1 μg/ml.</p><p id="par0040" class="elsevierStylePara elsevierViewall">The patient's liver disease limited the use of voriconazole so, due to its better liver profile and based on data from the literature,<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> we opted for IV isavuconazole (IVZ) at 200 mg/8 h for 48 h and 200 mg every 24 h as maintenance.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Trough levels of isavuconazole after six doses were determined by liquid chromatography with mass spectrometry, both in plasma and CSF, being 5 μg/ml and 0.66 μg/ml respectively.</p><p id="par0050" class="elsevierStylePara elsevierViewall">After two weeks with this regimen (AmB-L/5-FC/IVZ) CSF cultures were negative and the cryptococcal antigen titre dropped to 1/4000 the first week and 1/2000 the second week, associated with neurological improvement. The subject completed six weeks with this last regimen.</p><p id="par0055" class="elsevierStylePara elsevierViewall">In Spain, C. <span class="elsevierStyleItalic">gattii</span> has been isolated as a coloniser in trees on the Mediterranean coast<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> and autochthonous cases have been described in patients without HIV infection.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">In CM, in both immunosuppressed and immunocompetent patients, the CSF shows a white blood cell count of less than 50 cells/μl with mononuclear predominance, mild protein morrachia, and low or normal glucose. Therefore, our case had an atypical presentation that forced us to consider other aetiologies.</p><p id="par0065" class="elsevierStylePara elsevierViewall">Treatment of infection by <span class="elsevierStyleItalic">Cryptococcus</span> spp. is based on the use of polyenes, azoles and nucleoside analogues (pyrimidines).<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Clinical experience with azoles other than fluconazole is limited. Possible resistance to antifungals should be considered when negative CSF cultures cannot be achieved. For isolates not identified as <span class="elsevierStyleItalic">C. neoformans</span>, the Clinical and Laboratory Standards Institute (CLSI) defines the breakpoint for fluconazole as 16 μg/ml, classifying strains with MIC > 16 μg/ml as non-wild phenotype or with possible resistance mechanisms. For <span class="elsevierStyleItalic">C. gattii</span>, EUCAST has not proposed breakpoints for fluconazole, but it does establish them for amphotericin B (0.5 μg/ml) and posaconazole (1 μg/ml).<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> In our case we chose isavuconazole, as opposed to voriconazole or posaconazole, due to its lower interaction profile, lower hepatorenal toxicity and good diffusion to the CNS.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> There are trials supporting the efficacy of isavuconazole with a loading dose of 200 mg/8 h for two days, followed by 200 mg daily as maintenance for lung and meningeal disease.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Kohno et al. obtained a response rate with isavuconazole as high as 90%.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> In our case, although the plasma concentration of isavuconazole exceeds the MIC, in CSF it was lower than expected and lower than the MIC of the yeast, suggesting that the response was due to the combination of antifungals.</p><p id="par0070" class="elsevierStylePara elsevierViewall">Isavuconazole could be a safe and effective azole as part of the treatment regimen for cryptococcosis when the use of fluconazole or voriconazole is not possible.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0075" class="elsevierStylePara elsevierViewall">No funding was received.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Authorship</span><p id="par0080" class="elsevierStylePara elsevierViewall">All the authors made substantial contributions to each of the following: 1) data collection; 2) the critical review of the intellectual content; and 3) final approval of the version submitted.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Conflicts of interest</span><p id="par0085" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Funding" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Authorship" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Conflicts of interest" ] 3 => array:2 [ "identificador" => "xack779182" "titulo" => "Acknowledgements" ] 4 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 982 "Ancho" => 1000 "Tamanyo" => 153022 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Direct study of the patient's CSF using India ink technique in which yeast-like structures with a capsule are observed, some of them large (halo or clear-transparent halo, with a central element) on the dark background.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Treatment strategies for cryptococcal infection: challenges, advances and future outlook" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "K.R. 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