Cryptococcus neoformans
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Cryptococcus neoformans is an encapsulated yeast-like fungus that can live in both plants and animals.This species, also known by its teleomorph name, Filobasidiella neoformans, belongs to the broad class of organisms called "club fungi" or Division Basidiomycota, which is one the five major types of fungi. C. neoformans usually grows as a yeast (unicellular) and replicates by budding. Under certain conditions, both in nature and in the laboratory, C. neoformans can grow as a filamentous fungus as pictured here: picture of the organism[1]. When grown as a yeast, C. neoformans has a prominent capsule composed mostly of polysaccharides. Microscopically, the India ink stain is used for easy visualization of the capsule. The particles of ink pigment do not enter the capsule that surrounds the spherical yeast cell, resulting in a zone of clearance or "halo" around the cells.
The species C. neoformans is composed of three variants (v.): C. neoformans v. gattii, v. grubii, and v. neoformans. C. neoformans v. gattii is found mostly in the tropics, but has also been confirmed on southern Vancouver Island on the southwestern coast of Canada. Cryptococcus gattii has recently been shown to be different enough from other subspecies to be elevated to its own species level. C. neoformans v. grubii and v. neoformans have a worldwide distribution and are often found in soil which has been contaminated by bird excrement. The genome sequence of C. neoformans v. neoformans was published in 2005.[2] Recent studies made on Chernobyl Nuclear Power Plant have shown that colonies of Cryptococcus neoformans developed on the ruins of melted down reactor harvest energy of radiation (primary beta radiation from caesium-137) itself.[3]
Infection with C. neoformans is termed cryptococcosis.
Treatment
Cryptococcosis that does not affect the central nervous system can be treated with fluconazole alone.
Cryptococcal meningitis should be treated for two weeks with intravenous Amphotericin B 0.7–1.0 (mg/kg)/day and oral flucytosine 100 (mg/kg)/day (or intravenous flucytosine 75 (mg/kg)/day if the patient is unable to swallow). This should then be followed by oral fluconazole 200mg daily for ten weeks[4] and then 200 mg daily until the patient's CD4 count is above 100 for three months and his HIV viral load is undetectable.[5][6]
Intravenous Ambisome 4 (mg/kg)/day may be used but is not superior: its main use is in patients who do not tolerate Amphotericin B. The 200 (mg/kg)/day dose for flucytosine is not more effective, is associated with more side-effects and should not be used.
In Africa, oral fluconazole at a rate of 200 mg daily is used. However, this does not result in cure because it merely suppresses the fungus and does not kill it; viable fungus can continue to be grown from CSF of patients who have taken fluconazole for many months. An increased dose of 400 mg daily does not improve outcomes,[7] but preliminary data from Uganda shows that very high doses of 1200 mg or more per day may be effective. The duration of this treatment and the post-treatment maintenance dose is not known.
Antimicrobial Regimen
- Cryptococcus
- 1. Cryptococcus neoformans
- 1.1. Cryptococcus neoformans meningitis in HIV infected patients[8]
- 1.1.1. Induction and consolidation
- Preferred regimen : (Amphotericin B deoxycholate 0.7-1.0 mg/kg IV qd (consider using lipid formulations for patients with renal dysfunction) OR Liposomal AmB 3-4mg/kg IV qd OR Amphotericin B lipid complex (ABLC) 5mg/kg IV qd) PLUS Flucytosine 100mg/kg/day PO or IV qid for at least 2 weeks followed by Fluconazole 400mg (6mg/kg) PO qd for at least 8 weeks.
- Alternative regimen (1): Amphotericin B deoxycholate 0.7-1.0 mg/kg IV qd OR Liposomal AmB 3-4 mg/kg IV qd OR AmB lipid complex 5mg/kg IV qd for 4-6 weeks
- Alternative regimen (2): Amphotericin B deoxycholate 0.7 mg/kg IV qd AND Fluconazole 800mg PO qd for 2 weeks, followed by Fluconazole 800mg PO qd for at least 8 weeks
- Alternative regimen (3): Fluconazole (>800 mg PO qd, 1200mg PO qd is favored) AND Flucytosine 100mg/kg/day PO qid for 6 weeks
- Alternative regimen (4): Fluconazole PO 800-2000mg qd for 10-12 weeks
- 1.1.2. Maintenance and prophylactic therapy
- Preferred regimen for : Initiate HAART 2-10 weeks after commencing initial antifungal therapy AND Fluconazole 200mg PO qd
- Alternative regimen : Itraconazole 200mg PO bid - monitor drug-level OR Amphotericin B deoxycholate (1 mg/kg) per week IV (should be used in azole-intolerant patients).
- Note (1): Consider discontinuing supressive therapy if CD4 count is higher than 100 cells/uL AND undetectable OR very low HIV RNA level for more than 3 months. Consider reinstitution of maintenance therapy if CD4 count <100 cels/uL.
- Note (2): Do not use acetazolamide OR mannitol OR corticosteroids to treat increased intracranial pressure, instead it should be used lombar puncture in the absence of focal neurologic signs or impaired mentation (which, if present, patient must be submitted to CT or MRI scan first).
- 1.2. Cerebral cryptococcomas
- Preferred regimen for induction and consolidation: (Amphotericin B deoxycholate 0.7-1.0 mg/kg IV qd (consider using lipid formulations for patients with renal dysfunction) OR Liposomal AmB 3-4mg/kg IV qd OR Amphotericin B lipid complex (ABLC) 5mg/kg IV qd) PLUS Flucytosine 100mg/kg/day PO or IV qid for at least 2 weeks followed by Fluconazole 400mg (6mg/kg) PO qd for at least 8 weeks
- Note: Consider surgery if lesions are larger than 3cm, accessible lesions with mass effect or lesions that are enlarging and not explained by IRIS.
- 1.3. Cryptococcus neoformans meningitis in HIV negative patients
- Preferred regimen: Amphotericin B deoxycholate 0.7-1.0 mg/kg IV qd PLUS Flucytosine 100mg/kg/day PO or IV qid for at least 4 weeks (which may be extended to 6 weeks if there is any neurological complication) followed by Fluconazole 400mg PO qd for 8 weeks. If there's toxicity to AmBd, consider changing to LFAmB in the second 2 weeks.
- Note (1): After induction and consolidation therapy, start Fluconazole 200mg (3mg/kg) PO qd for 6-12 months.
- Note (2): If Flucytosine is not given, consider lengthening the induction therapy for at least 2 weeks.
- 1.4. Cryptococcus neoformans pulmonary disease - immunosupressed
- Mild-moderate symptoms, without severe immunosupression and absence of diffuse pulmonary infiltrates:
- Preferred regimen: Fluconazole 400mg PO qd for 6-12 months
- Severe pneumonia or disseminated disease or CNS infection:
- Preferred regimen: treat like CNS cryptococcosis.
- Note (1): In HIV- infected patients, treatment should be stopped after 1 year if CD4 count is >100 and a cryptococcal antigen titer is <1:512 and not increasing.
- Note (2): Consider corticosteroid if ARDS is present in a context which it might be attributed to IRIS.
- 1.5 Cryptococcus neoformans pulmonary disease - non-immunosupressed
- Mild-moderate symptoms, without severe immunosupression and absence of diffuse pulmonary infiltrates:
- Preferred regimen: Fluconazole 400mg PO qd for 6-12 months
- Alternative regimen: if Fluconazole is unavailable or contraindicated, Itraconazole 200mg PO bid, Voriconazole 200 mg PO bid, and Posaconazole 400mg PO bid
- If there's severe pneumonia, disseminated disease or CNS infection:
- Preferred regimen: treat like CNS cryptococcosis for 6-12 months.
- 1.6 Cryptococcus neoformans non-lung, non-CNS infection
- Cryptococcemia or disseminated cryptococcic disease (involvement of at least 2 noncontiguous sites or cryptococcal antigen titer >1:512):
- Preferred regimen: treat like CNS infection.
- If infection occurs at a single site and no immunosupressive risk factors
- Preferred regimen: Fluconazole 400mg PO qd for 6-12 months
- 1.7. Cryptococcosis in Children
- Preferred regimen for induction and consolidation: Amphotericin B deoxycholate 1.0 mg/kg qd IV PLUS Flucytosine 100mg/kg PO or IV qid for 2 weeks followed by Fluconazole 10-12mg/kg PO qd for 8 weeks
- Alternative regimen: patients with renal dysfunction: change Amphotericin B deoxycholate by Liposomal AmB 5mg/kg IV qd or Amphotericin B lipid complex (ABLC) 5mg/kg IV qd
- Preferred regimen for maintenance: Fluconazole 6mg/kg PO qd. Discontinuation of maintenance therapy is poorly studied and should be individualized.
- Cryptococcal pneumonia:
- Preferred regimen Fluconazole 6-12mg/kg PO qd for 6-12 months
- 1.8. Cryptococcosis in Pregnant Women
- Preferred regimen for induction and consolidation: Amphotericin B deoxycholate 0.7-1.0 mg/kg IV qd (consider using lipid formulations for patients with renal dysfunction - Liposomal AmB 3-4mg/kg IV qd OR Amphotericin B lipid complex (ABLC) 5mg/kg IV qd. Consider using Flucytosine in relationship to benefit risk basis, since it is a Category C drug for pregnancy. Start Fluconazole after delivery. Avoid use during first trimester and consider use in the last 2 trimesters with the need for continuous antifungal therapy during pregnancy.
- Note: If pulmonary cryptococcosis: perform close follow-up and administer fluconazole after delivery.
- 2. Cryptococcus gatti
- Disseminated cryptococcosis or CNS disease:
- Preferred regimen: treatment is the same as C. neoformans.
- Pulmonary disease: single and small cryptococcoma:
- Preferred regimen: Fluconazole 400mg per day PO for 6-18months
- Pulmonary disease: Very large or multiple cryptococcomas:
- Preferred regimen: administer Flucytosine AND AmB deocycholate for 4-6 weeks, followed by fluconazole for 6-18 months.
- Note: Surgery should be considered if there is compression of vital structures OR failure to reduce the size of the cryptococcoma after 4 weeks of therapy
References
- ↑ Photomicrograph hosted by the Tree of Life project and specifically contributed by the Duke University Mycology Research Unit; the picture is part of the Hymenomycetes article. Retrieved 2005-03-15
- ↑ Loftus BJ; et al. "The genome of the basidiomycetous yeast and human pathogen Cryptococcus neoformans". Science. 307 (5713): 1321&ndash, 24. PMID 15653466.
- ↑ Dadachova E; et al. "Ionizing Radiation Changes the Electronic Properties of Melanin and Enhances the Growth of Melanized Fungi". PLoS One. 2(5). doi:10.1371/journal.pone.0000457. PMID 17520016.
- ↑ Saag MS, Graybill RJ, Larsen RA; et al. (2000). "Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America". Clin Infect Dis. 30 (4): 710&ndash, 8. PMID 10770733.
- ↑ Martínez E, García-Viejo MA, Marcos MA; et al. (2000). "Discontinuation of secondary prophylaxis for cryptococcal meningitis in HIV-infected patients responding to highly active antiretroviral therapy". AIDS. 14 (16): 2615&ndash, 26. PMID 11101078.
- ↑ Vibhagool A, Sungkanuparph S, Mootsikapun P; et al. (2003). "Discontinuation of secondary prophylaxis for Cryptococcal meningitis in Human Immunodeficiency Virus-infected patients treated with highly active antiretroviral therapy: a prospective, multicenter, randomized study". Clin Infect Dis. 36: 1329&ndash, 31. doi:10.1086/374849. PMID 12746781.
- ↑ CF Schaars, Meintjes GA, Morroni C; et al. (2006). "Outcome of AIDS-associated cryptococcal meningitis initially treated with 200 mg/day or 400 mg/day of fluconazole". BMC Infect Dis. 6: 118. doi:10.1186/1471-2334-6-118.
- ↑ Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ; et al. (2010). "Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america". Clin Infect Dis. 50 (3): 291–322. doi:10.1086/649858. PMID 20047480.