Table 1. Geographic Distribution and Clinical Characteristics of the Two Varieties of C. neoformans.

 

C. neoformans var. neoformans

C. neoformans var.gattii

Serotypes

A and D

B and C

Ecology

Worldwide

Most often found in bird droppings

Tropical and subtropical climates

Most often associated with eucalyptus trees

Host preference

More prevalent in  immunocompromised hosts

Confined to immunocompetent hosts

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

Pathology

Multiorgan disease generally detected, with high fungal burdens

Large localized nodular infections.

Granulomatous reaction in tissues.

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.

Antifungal Agents

Mode of

Administration

 

Range

 MICs(g/ml) 

 

Benefits

 

Limitations

MIC50    

  MIC90

 Polyenes:

 

 

 

 

 

 

  Amphotericin B

IV,IT, IP

 

 

 

 

 

  Liposomal formulations

  of amphotericin B

 

IV

 

0.25-1

 

0.5

 

1

 

Standard therapy

 

Poor diffusion into body compartment

high toxicity profile

Anti-metabolites:

 

 

 

 

 

 

  Flucytosine

(5-FC)

PO

1 - >64

4

8

Excellent penetration into body compartments, including CSF

Development of resistance

High toxicity profile

Azoles:

 

 

 

 

 

 

  Ketoconazole

PO

0.12-1

 

 

 

Erratic absorption

Poor CSF penetration

Significant drug-drug interaction

 

  Miconazole

IV

Not available

 

 

 

Short half-life

Serious toxicity profile

Scarce clinical data

 

  Fluconazole

PO, IV, IP

0.125->64

4

16

Excellent penetration into body compartments, including CSF

 

Emergence of resistance

  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]

Clinical syndromes

Antifungal drugs

Duration

Comments

Non-immunosuppressed  patients      

Meningitis

     Standard therapy

 

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.

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.

     Alternative therapy

AmB 0.7 - 1 mg/kg/day

and 5-FC 25 mg/kg q6h

followed by

fluconazole 400 mg/day

 

> 2 weeks

 

 

> 2 months

AmB and 5-FC until CSF culture becomes negative.

Alternative therapy is recommended for less severely ill patients.

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.

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.


 

Clinical syndromes

Antifungal drugs

Duration

Comments

AIDS patients -

 

 

 

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

 

 

> 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.

 

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.


 

Clinical syndromes

Antifungal drugs

Duration

Comments

Non-AIDS, immunocompromised hosts

 

 

 

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.

 

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

 

> 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.  

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.

Note: ABLC might be comparable to AmBisome in efficacy but is more nephrotoxic.