Cryptococcus gattii infection: Treatment
- Sharon Chen, PhD, MBBS, FRACP, FRCPA
Sharon Chen, PhD, MBBS, FRACP, FRCPA
- Clinical Associate Professor
- Sydney Medical School, University of Sydney
- Kieren A Marr, MD
Kieren A Marr, MD
- Section Editor — Compromised Host Infections; Fungal Infections
- Professor of Medicine and Oncology
- Johns Hopkins University School of Medicine
- Tania C Sorrell, MD
Tania C Sorrell, MD
- Professor of Clinical Infectious Diseases and Director of the Centre for Infectious Diseases and Microbiology
- Sydney Medical School, University of Sydney
Cryptococcus gattii has emerged as an important fungal pathogen. Infection manifests most often as potentially fatal meningoencephalitis and/or pulmonary disease. The emergence of clusters of cryptococcosis due to C. gattii in British Columbia, Canada, in 1999, with subsequent spread to the United States Pacific Northwest, has challenged our understanding of this disease [1-3]. C. gattii infection had previously been detected infrequently and was thought to be largely restricted to tropical and subtropical regions, including Australia and Papua New Guinea. It is now clear that sporadic cases occur in various regions around the world.
The antifungal treatment and other aspects of management of C. gattii infection will be reviewed here. The microbiology, epidemiology, pathogenesis, clinical manifestations, and diagnosis of C. gattii infection are discussed separately; Cryptococcus neoformans infection is also reviewed elsewhere. (See "Cryptococcus gattii infection: Microbiology, epidemiology, and pathogenesis" and "Cryptococcus gattii infection: Clinical features and diagnosis" and "Microbiology and epidemiology of Cryptococcus neoformans infection" and "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in HIV-infected patients" and "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in HIV-seronegative patients" and "Cryptococcus neoformans infection outside the central nervous system" and "Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in HIV seronegative patients".)
At present, there are no guidelines with interpretative clinical minimum inhibitory concentration (MIC) breakpoints to recognize antifungal susceptibility or resistance in C. gattii. Only C. neoformans has been included in the Clinical Laboratory Standard Institutes (CLSI) guidelines for testing of yeasts . Clinical breakpoints and epidemiologic cut-off values based on MIC distributions of wild-type strains of C. gattii are being studied using both CLSI methodology and the commercial Sensititre YeastOne system (TREK Diagnostics) [5-7].
Despite these limitations, MICs, most commonly determined by broth microdilution, have been reported for C. gattii and may provide help to clinicians in the management of C. gattii infection .
Many studies have documented low antifungal MICs against C. gattii and C. neoformans that have not increased over time [9-11]. However, in some regions, concern has arisen over whether C. gattii may be less susceptible than C. neoformans to some antifungal agents. A group in Brazil reported significantly higher geometric mean MICs for fluconazole, voriconazole, amphotericin B, and flucytosine against C. gattii compared with C. neoformans . In a study from Spain, fluconazole, voriconazole, and posaconazole MICs were significantly higher against C. gattii than against C. neoformans , whilst in Taiwan, C. gattii has been reported to be less susceptible to flucytosine and amphotericin B .
Subscribers log in hereLiterature review current through: Oct 2017. | This topic last updated: Jul 12, 2017.References
- Chaturvedi V, Chaturvedi S. Cryptococcus gattii: a resurgent fungal pathogen. Trends Microbiol 2011; 19:564.
- Harris J, Lockhart S, Chiller T. Cryptococcus gattii: where do we go from here? Med Mycol 2012; 50:113.
- Chen SC, Meyer W, Sorrell TC. Cryptococcus gattii infections. Clin Microbiol Rev 2014; 27:980.
- Reference method for broth dilution antifungal susceptibility testing of yeasts, 3rd Med. CLSI document M27-A3. Clinical and Laboratory Standards Institute, Villanova, PA 2008.
- Espinel-Ingroff A, Chowdhary A, Cuenca-Estrella M, et al. Cryptococcus neoformans-Cryptococcus gattii species complex: an international study of wild-type susceptibility endpoint distributions and epidemiological cutoff values for amphotericin B and flucytosine. Antimicrob Agents Chemother 2012; 56:3107.
- Lockhart SR, Iqbal N, Bolden CB, et al. Epidemiologic cutoff values for triazole drugs in Cryptococcus gattii: correlation of molecular type and in vitro susceptibility. Diagn Microbiol Infect Dis 2012; 73:144.
- Espinel-Ingroff A, Aller AI, Canton E, et al. Cryptococcus neoformans-Cryptococcus 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; 56:5898.
- Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis 2010; 50:291.
- Ellis D, Sorrell T, Chen S. Impact of antifungal resistance in Australia. Microbiol Aust 2007; 28:171.
- Thompson GR 3rd, Wiederhold NP, Fothergill AW, et al. Antifungal susceptibilities among different serotypes of Cryptococcus gattii and Cryptococcus neoformans. Antimicrob Agents Chemother 2009; 53:309.
- Pfaller MA, Messer SA, Boyken L, et al. Global trends in the antifungal susceptibility of Cryptococcus neoformans (1990 to 2004). J Clin Microbiol 2005; 43:2163.
- Trilles L, Fernández-Torres B, Lazéra Mdos S, et al. In vitro antifungal susceptibility of Cryptococcus gattii. J Clin Microbiol 2004; 42:4815.
- Torres-Rodríguez JM, Alvarado-Ramírez E, Murciano F, Sellart M. MICs and minimum fungicidal concentrations of posaconazole, voriconazole and fluconazole for Cryptococcus neoformans and Cryptococcus gattii. J Antimicrob Chemother 2008; 62:205.
- Chen YC, Chang SC, Shih CC, et al. Clinical features and in vitro susceptibilities of two varieties of Cryptococcus neoformans in Taiwan. Diagn Microbiol Infect Dis 2000; 36:175.
- Trilles L, Meyer W, Wanke B, et al. Correlation of antifungal susceptibility and molecular type within the Cryptococcus neoformans/C. gattii species complex. Med Mycol 2012; 50:328.
- Hagen F, Illnait-Zaragozi MT, Bartlett KH, et al. In vitro antifungal susceptibilities and amplified fragment length polymorphism genotyping of a worldwide collection of 350 clinical, veterinary, and environmental Cryptococcus gattii isolates. Antimicrob Agents Chemother 2010; 54:5139.
- Chong HS, Dagg R, Malik R, et al. In vitro susceptibility of the yeast pathogen cryptococcus to fluconazole and other azoles varies with molecular genotype. J Clin Microbiol 2010; 48:4115.
- Iqbal N, DeBess EE, Wohrle R, et al. Correlation of genotype and in vitro susceptibilities of Cryptococcus gattii strains from the Pacific Northwest of the United States. J Clin Microbiol 2010; 48:539.
- Rolston KV. Cryptococcosis due to Cryptococcus gattii. Clin Infect Dis 2013; 57:552.
- Datta K, Rhee P, Byrnes E 3rd, et al. Isavuconazole activity against Aspergillus lentulus, Neosartorya udagawae, and Cryptococcus gattii, emerging fungal pathogens with reduced azole susceptibility. J Clin Microbiol 2013; 51:3090.
- Franco-Paredes C, Womack T, Bohlmeyer T, et al. Management of Cryptococcus gattii meningoencephalitis. Lancet Infect Dis 2015; 15:348.
- Chen S, Sorrell T. University of Sydney, 2015, personal communication.
- Chen SC, Korman TM, Slavin MA, et al. Antifungal therapy and management of complications of cryptococcosis due to Cryptococcus gattii. Clin Infect Dis 2013; 57:543.
- Phillips P, Galanis E, MacDougall L, et al. Longitudinal clinical findings and outcome among patients with Cryptococcus gattii infection in British Columbia. Clin Infect Dis 2015; 60:1368.
- Graybill JR, Sobel J, Saag M, et al. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. The NIAID Mycoses Study Group and AIDS Cooperative Treatment Groups. Clin Infect Dis 2000; 30:47.
- Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infect Dis 2000; 30:710.
- Chen SC, Slavin MA, Heath CH, et al. Clinical manifestations of Cryptococcus gattii infection: determinants of neurological sequelae and death. Clin Infect Dis 2012; 55:789.
- Fisher D, Burrow J, Lo D, Currie B. Cryptococcus neoformans in tropical northern Australia: predominantly variant gattii with good outcomes. Aust N Z J Med 1993; 23:678.
- Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf (Accessed on October 16, 2014).
- Speed B, Dunt D. Clinical and host differences between infections with the two varieties of Cryptococcus neoformans. Clin Infect Dis 1995; 21:28.
- Mitchell DH, Sorrell TC, Allworth AM, et al. Cryptococcal disease of the CNS in immunocompetent hosts: influence of cryptococcal variety on clinical manifestations and outcome. Clin Infect Dis 1995; 20:611.
- Ulett KB, Cockburn JW, Jeffree R, Woods ML. Cerebral cryptococcoma mimicking glioblastoma. BMJ Case Rep 2017; 2017.
- Phillips P, Chapman K, Sharp M, et al. Dexamethasone in Cryptococcus gattii central nervous system infection. Clin Infect Dis 2009; 49:591.
- Lane M, McBride J, Archer J. Steroid responsive late deterioration in Cryptococcus neoformans variety gattii meningitis. Neurology 2004; 63:713.
- Antachopoulos C, Walsh TJ. Immunotherapy of Cryptococcus infections. Clin Microbiol Infect 2012; 18:126.
- Pappas PG, Perfect JR, Cloud GA, et al. Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy. Clin Infect Dis 2001; 33:690.
- Yamaguchi H, Ikemoto H, Watanabe K, et al. Fluconazole monotherapy for cryptococcosis in non-AIDS patients. Eur J Clin Microbiol Infect Dis 1996; 15:787.
- Núñez M, Peacock JE Jr, Chin R Jr. Pulmonary cryptococcosis in the immunocompetent host. Therapy with oral fluconazole: a report of four cases and a review of the literature. Chest 2000; 118:527.
- Yao Z, Liao W, Chen R. Management of cryptococcosis in non-HIV-related patients. Med Mycol 2005; 43:245.
- Lalloo D, Fisher D, Naraqi S, et al. Cryptococcal meningitis (C. neoformans var. gattii) leading to blindness in previously healthy Melanesian adults in Papua New Guinea. Q J Med 1994; 87:343.
- Galanis E, Macdougall L, Kidd S, et al. Epidemiology of Cryptococcus gattii, British Columbia, Canada, 1999-2007. Emerg Infect Dis 2010; 16:251.
- Centers for Disease Control and Prevention (CDC). Emergence of Cryptococcus gattii-- Pacific Northwest, 2004-2010. MMWR Morb Mortal Wkly Rep 2010; 59:865.
- Jenney A, Pandithage K, Fisher DA, Currie BJ. Cryptococcus infection in tropical Australia. J Clin Microbiol 2004; 42:3865.
- ANTIFUNGAL SUSCEPTIBILITIES
- Central nervous system disease
- - Meningoencephalitis
- Induction therapy
- Consolidation and maintenance therapy
- - Cerebral cryptococcomas
- Isolated pulmonary disease
- IRIS-like syndrome
- MONITORING DURING THERAPY
- ADVERSE EFFECTS
- Amphotericin B
- SUMMARY AND RECOMMENDATIONS