Table 1. Geographic Distribution and Clinical Characteristics of the Two Varieties of C. neoformans.
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C. neoformans var. neoformans |
C. neoformans var.gattii |
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Serotypes |
A and D |
B and C |
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Ecology |
Worldwide Most often found in bird droppings |
Tropical and subtropical climates Most often associated with eucalyptus trees |
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Host preference |
More prevalent in immunocompromised hosts |
Confined to immunocompetent hosts |
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Clinical manifestation |
Acute, sub-acute, chronic onset Diffuse, disseminated process. Any organ can be infected; central nervous system most common |
Most commonly chronic onset Localized infections (cryptococcoma). Generally central nervous system and lungs only |
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Pathology |
Multiorgan disease generally detected, with high fungal burdens |
Large localized nodular infections. Granulomatous reaction in tissues. |
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Prognosis |
Mortality ~ 10-15% |
Lower mortality, but requires longer course of antifungal therapy and surgical resection . Frequent neurological sequelae. |
Table 2. Currently Available Antifungal Agents Against Cryptococcus Neoformans, and Their Characteristics.
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Antifungal Agents |
Mode of Administration |
Range |
MICs(µg/ml) |
Benefits |
Limitations |
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MIC50 |
MIC90 |
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Polyenes: |
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Amphotericin B |
IV,IT, IP |
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Liposomal formulations of amphotericin B |
IV |
0.25-1 |
0.5 |
1 |
Standard therapy |
Poor diffusion into body compartment high toxicity profile |
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Anti-metabolites: |
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Flucytosine (5-FC) |
PO |
1 - >64 |
4 |
8 |
Excellent penetration into body compartments, including CSF |
Development of resistance High toxicity profile |
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Azoles: |
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Ketoconazole |
PO |
0.12-1 |
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Erratic absorption Poor CSF penetration Significant drug-drug interaction
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Miconazole |
IV |
Not available |
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Short half-life Serious toxicity profile Scarce clinical data
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Fluconazole |
PO, IV, IP |
0.125->64 |
4 |
16 |
Excellent penetration into body compartments, including CSF
|
Emergence of resistance |
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Itraconazole |
PO |
<0.03-0.5 |
0.125 |
0.25 |
High lipophilicity -> adequate penetration into certain body compartments |
Poor penetration into CSF |
Table 3. Recommended treatment for cryptococcosis. [Download PDF]
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Clinical syndromes |
Antifungal drugs |
Duration |
Comments |
| Non-immunosuppressed patients | |||
MeningitisStandard therapy
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AmB 0.7 - 1 mg/kg/day and 5-FC 25 mg/kg q6h
OR |
> 4 weeks |
5-FC can be discontinued when CSF culture becomes negative. If 5-FC is used for > 2 weeks, 5-FC levels should be measured. Peak level (obtained 2 hours after the dose): 70-80 ug/ml, and trough level: 30-40 ug/ml. |
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AmBisome* 4 - 5 mg/kg/day and 5-FC 25 mg/kg q6h |
> 6 weeks |
Lipid formulation of AmB* is less nephrotoxic, but experience is limited. |
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Alternative therapy |
AmB 0.7 - 1 mg/kg/day and 5-FC 25 mg/kg q6h followed by fluconazole 400 mg/day
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> 2 weeks
> 2 months |
AmB and 5-FC until CSF culture becomes negative. Alternative therapy is recommended for less severely ill patients. |
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Pulmonary |
Asymptomatic patients: Treatment can be withhold.
Symptomatic patients: Fluconazole 200-400 mg/day or itraconazole 200-400 mg/day |
6-12 months |
A lumbar puncture should be performed to rule out meningeal involvement. especially in symptomatic patients. For severe symptoms, recommend treating as for cryptococcal meningitis with AmB with or without 5-FC. Therapy can be changed to fluconazole when infection is stable. |
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Non-pulmonary, extra-neural |
Fluconazole 200-400 mg/day or itraconazole 200-400 mg/day |
6-12 months |
A lumbar puncture should be performed to rule out meningeal involvement. For severe infection, recommend treating as for cryptococcal meningitis. |
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Clinical syndromes |
Antifungal drugs |
Duration |
Comments |
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AIDS patients - |
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Meningitis Standard therapy |
Acute therapy: AmB 0.7 - 1 mg/kg/day and 5-FC 25 mg/kg q6h
followed by fluconazole 400 mg/day
Chronic suppressive therapy: Fluconazole 200 mg/ day or AmB 1 mg/kg/week
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> 2 weeks
> 10 weeks
lifelong |
Induction therapy with AmB and 5-FC until clinically stable and CSF culture becomes negative. AmB can be replaced by lipid formulation* (ABLC or AmBisome at 4-5 mg/kg/day) to lessen nephrotoxicity. Chronic suppressive therapy can be safely discontinued when CD4 > 100/mm3 and undetectable HIV viral load for > 3 months on HAART. |
|
Alternative therapy |
Acute therapy: Fluconazole 800 mg/day and 5-FC 25 mg/kg q6h
Chronic suppressive therapy: As above. |
> 6 weeks |
This regimen can be considered in less severely ill patients. 5-FC can be discontinued when CSF culture becomes negative.
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Pulmonary or other extra-neural infection. |
Fluconazole 200-400 mg/day or itraconazole 200-400 mg/day
followed by lifelong chronic suppressive therapy with fluconazole 200 mg/day |
6-12 months |
A lumbar puncture should be performed to rule out cryptococcal meningitis. All patients should be treated. For severe symptoms, recommend treating as for cryptococcal meningitis with AmB with or without 5-FC. Therapy can be changed to fluconazole when infection is stable. Chronic suppressive therapy can be safely discontinued when CD4> 100//mm3 and undetectable HIV viral load for > 3 months on HAART. |
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Clinical syndromes |
Antifungal drugs |
Duration |
Comments |
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Non-AIDS, immunocompromised hosts |
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Meningitis |
Acute therapy: AmB 0.7 - 1 mg/kg/day and 5-FC 25 mg/kg q6h
OR |
> 6 weeks |
5-FC can be discontinued when CSF culture becomes negative or patient is clinically improved, whatever is longer. If 5-FC is used for > 2 weeks, 5-FC levels should be measured. Peak level (obtained 2 hours after the dose): 70-80 ug/ml, and trough level: 30-40 ug/ml.
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AmBisome* 4 - 5 mg/kg/day and 5-FC 25 mg/kg q6h
Chronic suppressive therapy: Fluconazole 400-800 mg/day then fluconazole 200 mg/day
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> 6 weeks
8-10 weeks > 12 months |
Lipid formulation of AmB* is less nephrotoxic, but experience is limited. Lipid formulation of AmB might be a preferred treatment for transplant recipients. For patients receiving chronic corticosteroid therapy, reduce steroid dosage to an equivalence of 10 mg/day of prednisone is recommended. |
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Pulmonary or other extra-neural infection. |
Fluconazole 200-400 mg/day or itraconazole 200-400 mg/day
|
> 6-12 months |
A lumbar puncture should be performed to rule out cryptococcal meningitis. All patients should be treated. Treatment should be continued until the infection is fully resolved. For severe symptoms, recommend treating as for cryptococcal meningitis with AmB with or without 5-FC. Therapy can be changed to fluconazole when infection is stable. |
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Note: ABLC might be comparable to AmBisome in efficacy but is more nephrotoxic.
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