, Volume 182, Issue 9–10, pp 855–861 | Cite as

Fluconazole Non-susceptible Cryptococcus neoformans, Relapsing/Refractory Cryptococcosis and Long-term Use of Liposomal Amphotericin B in an AIDS Patient

  • Rodrigo de Carvalho Santana
  • Letícia Aparecida Schiave
  • Alda Soares dos Santos Quaglio
  • Cristiane Masetto de Gaitani
  • Roberto Martinez


The treatment of cryptococcosis is hampered by inefficacy or intolerance to the recommended antifungal agents. A patient diagnosed with AIDS had multiple relapses of cryptococcal infection, which became refractory to antifungal agents during the course of therapy. During the follow-up, the patient developed renal toxicity due to amphotericin B use and non-susceptibility of isolated Cryptococcus neoformans to fluconazole was detected. Thereafter, antifungal treatment was performed exclusively with liposomal amphotericin B, reaching a cumulative dose of 19,180 mg over 46 months. The final relapse of cryptococcosis occurred during the maintenance phase with liposomal formulation in a once-weekly dose. Measurement of the minimum serum concentrations of amphotericin B, determined sequentially before and after this relapse, suggested the importance of monitoring drug levels when the liposomal formulation is used for a long period.


Cryptococcus Antifungal susceptibility Fluconazole Liposomal amphotericin B Cryptococcal meningitis 



Letícia Aparecida Schiave received a scholarship from the São Paulo Research Foundation (FAPESP) related to the research project on the determination of amphotericin B levels (Grant # 2012/51030-4). Erika Nascimento performed the antifungal susceptibility tests. The Foundation of Support to Teaching, Research and Assistance of the University Hospital of the Ribeirão Preto Medical School, University of São Paulo (FAEPA) supported the disclosure of this study.

Compliance with Ethical Standards

Conflict of interest

The authors declare no conflicts of interest.


  1. 1.
    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(3):291–322.CrossRefPubMedGoogle Scholar
  2. 2.
    Jarvis JN, BicanicT Loyse A, Namarika D, Jackson A, Nussbaum JC, et al. Determinants of mortality in a combined cohort of 501 patients with HIV-associated cryptococcal meningitis: implications for improving outcomes. Clin Infect Dis. 2014;58(5):736–45.CrossRefPubMedGoogle Scholar
  3. 3.
    Mora DJ, da Cunha Colombo ER, Ferreira-Paim K, Andrade-Silva LE, Nascentes GA, Silva-Vergara ML. Clinical, epidemiological and outcomes features of patients with cryptococcosis in Uberaba, Minas Gerais, Brazil. Mycopathologia. 2012;173:321–7.CrossRefPubMedGoogle Scholar
  4. 4.
    Nascimento E, Vitali LH, Tonani L, Kress MR, Takayanagui OM, Martinez R. Refractory and/or relapsing cryptococcosis associated with AIDS: clinical features, genotype and virulence factors of Cryptococcus spp. isolates. Am J Trop Med Hyg. 2016;94(5):975–81.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Espié E, Pinoges L, Balkan S, ChanchLaya N, Molfino L, Narom P, Pujades-Rodrígues M. Cryptococcal meningitis in HIV-infected patients: a longitudinal study in Cambodia. Trop Med Int Health. 2010;15(11):1375–81.CrossRefPubMedGoogle Scholar
  6. 6.
    Pan W, Khayhan K, Hagen F, Wahyuninqsih R, Chakrabarti A, Chawhary A, et al. Resistance of Asian Cryptococcus neoformans serotype A is confined to few microsatellite genotypes. PLoS ONE. 2012;7(3):e32868.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Chen YC, Chang TY, Liu JW, Chen FJ, Chien CC, Lee CH, et al. Increasing trend of fluconazole non susceptible Cryptococcus neoformans in patients with invasive cryptococcosis: a 12-year longitudinal study. BMC Infect Dis. 2015;15:277.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Italia JL, Singh D, Ravi MNV, Kumar R. High-performance liquid chromatographic analysis of amphotericin B in rat plasma using α-naphthol as an internal standard. Anal Chim Acta. 2009;634(1):110–4.CrossRefPubMedGoogle Scholar
  9. 9.
    Dromer F, Mathoulin-Péllissier S, Launay O, Lortholary O, French Cryptococcosis Study Group, 2007. Determinants of disease presentation and outcome during cryptococcosis: the Crypto A/D study. PloS Med. 2007;4(2):e21.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Espinel-Ingroff A, Aller AI, Canton E, Castañón-Olivares LR, Chondhary A, Cordoba S, et al. Cryptococcus neoformansCryptococcus gattii species complex: an international study of wild-type susceptibility endpoint distributions and epidemiological cutoff values for fluconazole, itraconazole, posaconazole and voriconazole. Antimicrob Agents Chemother. 2012;56(11):5898–906.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Sionov E, Chang YC, Kwon-Chung KJ. Azole heteroresistance in Cryptococcus neoformans: emergence of resistant clones with chromosomal disomy in the mouse brain during fluconazole treatment. Antimicrob Agents Chemother. 2013;57(10):5127–30.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Cheong JW, McCormack J. Fluconazole resistance in cryptococcal disease: emerging or intrinsic? Med Mycol. 2013;51(3):261–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Aller AI, Martin-Mazuelos E, Lorenzo F, Gomez-Mateos J, Steele Moore L, Holloway WJ, et al. Correlation of fluconazole MICs with clinical outcome in cryptococcal infection. Antimicrob Agents Chemother. 2000;44:1544–8.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Bicanic T, Harrison T, Niepieklo A, Dyakopu W, Meintjes G. Symptomatic relapse of HIV-associated cryptococcal meningitis after initial fluconazole monotherapy: the role of fluconazole resistance and immune reconstitution. Clin Infect Dis. 2006;43(8):1069–73.CrossRefPubMedGoogle Scholar
  15. 15.
    Agudelo CA, Muñoz C, Ramirez A, Tobón AM, de BedouBact C, Cano LE, et al. Response to therapy in patientswith cryptococcosis and AIDS: association with in vitro susceptibility to fluconazole. Rev Iberoam Micol. 2015;32(4):214–28.CrossRefPubMedGoogle Scholar
  16. 16.
    Loyse A, Thangaraj H, Easterbrook P, Ford N, Roy M, Chiller T, Govender N, et al. Cryptococcal meningitis: improving access to essential antifungal medicines in resource-poor countries. Lancet Infect Dis. 2013;13(7):629–37.CrossRefPubMedGoogle Scholar
  17. 17.
    Strenger V, Meinitzer A, Donnerer J, Hofer N, Dornbusch HJ, Wanz U, et al. Amphotericin B transfer to CSF following intravenous administration of liposomal amphotericin B. J Antimicrob Chemother. 2014;69(4):2522–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Cesaro S, Zigmol M, Burlina AB, Tridello G, Visintin G, Messina C. Assessment of nephrotoxicity of high-cumulative dose of liposomal amphotericin B in a pediatric patient who underwent allogeneic bone marrow transplantation. Pediatr Transplant. 2006;10(2):255–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Michot JM, Gubavu C, Fourn E, Maigne G, Teicher E, Angoulvant A, et al. Very prolonged liposomal amphotericin B use leading to a lysosomal storage disease. Int J Antimicrob Agents. 2014;43(6):566–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Bekersky I, Fielding RM, Dressler DE, Lee JW, Buell DN, Walsh TJ. Pharmacokinetics, excretion, and mass balance of liposomal amphotericin B, (AmBisome) and amphotericin B deoxycholate in humans. Antimicrob Agents Chemother. 2012;46(3):828–33.CrossRefGoogle Scholar
  21. 21.
    Walsh TJ, Yeldandi V, McEvoy M, Gonzalez C, ChaNock S, Freifield A, et al. Safety, tolerance and pharmacokinetics of a small unilamellar liposomal formulation of amphotericin B (AmBisome) in neutropenic patients. Antimicrob Agents Chemother. 1998;42(9):2391–8.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2017

Authors and Affiliations

  • Rodrigo de Carvalho Santana
    • 1
  • Letícia Aparecida Schiave
    • 1
  • Alda Soares dos Santos Quaglio
    • 1
  • Cristiane Masetto de Gaitani
    • 2
  • Roberto Martinez
    • 1
  1. 1.Departament of Internal Medicine, Ribeirão Preto Medical SchoolSão Paulo UniversityRibeirão PretoBrazil
  2. 2.School of Pharmaceutical Sciences of Ribeirão PretoSão Paulo UniversitySão PauloBrazil

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