Cryptococcal meningoencephalitis (CM) is a serious disease that causes 181,100 deaths worldwide each year.1 The main causative species are Cryptococcus neoformans and Cryptococcus gattii. 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 C. neoformans grubii and C. gattii.2 We present an autochthonous case of CM due to C. gattii resistant to fluconazole with a favourable response to isavuconazole.
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.
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 Cryptococcus spp. were found in the Gram and India ink staining (Fig. 1), confirming the detection of DNA for C. gattii/neoformans using a molecular technique based on multiplex PCR nucleic acids (Biomérieux, FilmArray™). C. gattii was identified in the culture. Blood cultures were negative and the baseline titre of cryptococcus antigen in CSF (latex) was >1/10,000.
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.
For the treatment of central nervous system (CNS) infection due to C. gattii, data on C. neoformans were extrapolated,2 and it was decided to start treatment, according to WHO recommendations,3 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.
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 IDSA4 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.
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.
The patient's liver disease limited the use of voriconazole so, due to its better liver profile and based on data from the literature,5 we opted for IV isavuconazole (IVZ) at 200 mg/8 h for 48 h and 200 mg every 24 h as maintenance.
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.
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.
In Spain, C. gattii has been isolated as a coloniser in trees on the Mediterranean coast6 and autochthonous cases have been described in patients without HIV infection.7
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.
Treatment of infection by Cryptococcus spp. is based on the use of polyenes, azoles and nucleoside analogues (pyrimidines).1 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 C. neoformans, 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 C. gattii, EUCAST has not proposed breakpoints for fluconazole, but it does establish them for amphotericin B (0.5 μg/ml) and posaconazole (1 μg/ml).8 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.9 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.10 Kohno et al. obtained a response rate with isavuconazole as high as 90%.5 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.
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.
FundingNo funding was received.
AuthorshipAll 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.
Conflicts of interestThe authors have no conflicts of interest to declare.
Dr Vicente Merino (Hospital Pharmacy Service, Hospital Universitario Virgen Macarena, Seville).
Dr Maite Ruiz Pérez Pipaón (Infectious Diseases, Microbiology and Parasitology Unit, Hospital Universitario Virgen del Rocío, Seville, Spain).
