Treatment Of Cryptococcal Meningitis

Cryptococcal meningitis is caused by Cryptococcus neoformans. It is less acute in onset than bacterial meningitis and may occur as part of the Immune Reconstitution Syndrome (IRIS). Diagnosis is confirmed by India Ink Stain and cryptococcal antigen tests (CrAg) in the cerebrospinal fluid after LP. Treatment of cryptococcal disease must be with amphotericin B based regimens. Ideally amphotericin B must be combined with flucytosine. However, combination therapy with amphotericin B and fluconazole is recommended as flucytosine is not available. In the absence of amphotericin B, high dose fluconazole can be used as an alternative therapy. Amphotericin B and fluconazole therapy is characterised by a 2-week induction phase, followed by 8 weeks consolidation phase and a maintenance therapy which is continued until adequate immune reconstitution is achieved.

Diagnosis of cryptococcal meningitis is based on either LP positive CSF CrAg /India Ink stain or positive serum CrAg plus headache or relevant symptoms

Pay attention to raised CSF pressure management and monitoring of renal function as per the Consolidated ART Guidelines.

	Medicine	Adult dose	Frequency	Duration
	amphotericin B iv (infusion) Give KCl 1.2g PO BO, and MMT 500mg PO BD to prevent hypokalaemia and hypomagnaesemia	0.7mg/kg	once a day	2 weeks
plus	fluconazole po	1200mg	once a day	2 weeks
then	fluconazole po	800mg	once a day	8 weeks
then	fluconazole po	200mg	once a day for at least one year.	until CD4 count >200 cells/mm3 for 6 months and VL less than 1000 copies per ml for 6 months

If flucytosine is available:

	Medicine	Adult Dose	Frequency	Duration
	amphotericin B iv (infusion) Give KCl 1.2g PO BD, and MMT 500mg PO BD to prevent hypokalaemia and hypomagnaesemia	1mg/kg	once a day	for 1 week
plus	flucytosine po	100mg/kg	divided into four doses	for 1 week
then	fluconazole po [paeds; adolescence]	1200mg 12mg/kg/day; max 800mg/day	once a day	for 1 week
then	fluconazole po	800mg	once a day	for 8 weeks
then	fluconazole po	200mg	once a day for at least 1 year	until CD4 count >200 cells/mm3 for 6 months and VL less than 1000 copies per ml for 6 months

If Amphotericin B IV is not available:

	Medicine	Adult Dose	Frequency	Duration
	fluconazole po	1200mg	once a day	for 2 weeks
then	fluconazole po	800mg	once a day	for 8 weeks
then	fluconazole po	200mg	once a day for at least 1 year	until CD4 count >200 cells/mm3 for 6 months and VL less than 1000 copies per ml for 6 months

For neonate, infant or child initial test dose of Amphotericin B 100 micrograms/kg (maximum 1 mg) included as part of first dose, then 250 micrograms/kg daily, gradually increased up to 1 mg/kg daily (maximum of 1.5mg/kg daily). Prolonged treatment is usually necessary.

If treatment is interrupted for longer than 7 days, recommence at 250 micrograms/kg daily and increase gradually.

Then:

Neonate under 2 weeks:

Medicine	Dose	Frequency
fluconazole po	6-12mg/kg	every 72 hours

Neonate 2 - 4 weeks:

Medicine	Dose	Frequency
fluconazole po	6-12mg/kg	every 48 hours

Infant or Child:

Medicine	Dose	Frequency
fluconazole po	6-12mg/kg (maximum 800mg)	daily

Treatment should continue according to response and should be for at least 8 weeks for cryptococcal meningitis.

Management of Amphotericin B associated toxicities

Liposomal amphotericin B has less renal toxicities. Amphotericin B deoxycholate is associated with renal tubular toxicities and can lead to electrolyte abnormalities such as hypokalemia and hypomagnesemia. It can also result in anaemia and administration related febrile reactions.

Amphotericin B is often provided as a powder and should be mixed with 5% dextrose water. It should NEVER be mixed with normal saline or half normal saline as this will result in precipitation of the amphotericin B. To minimise renal toxicities, amphotericin B must be administered slowly over 4 hours. Initial therapeutic doses should be given as amphotericin B 0.7-1mg/kg/day.
For adults, pre-hydration with 1000mL (1L) of normal saline with 20mEq of potassium chloride over 2 hours is recommended based on the volume status of the patient. Patients must receive oral potassium supplementation such as 1200mg twice a day. The potassium supplementation minimizes the extent of hypokalemia that can develop. Where available supplementation with magnesium trisilicate 500mg orally is also recommended.
Renal function must be monitored at baseline. U&Es should be measured twice weekly and abnormal results repeated daily until they normalize. Amphotericin B should be discontinued if renal toxicity is noted but can be restarted at a reduced dosage if the U&Es are improving.

If the potassium is less that 3.3mmol/L increase oral KCL to 600-1200mg three times daily and monitor U&Es daily. If potassium levels do not increase despite oral potassium replacement this may be due to low magnesium levels therefore consider measuring magnesium levels and replenishing magnesium if necessary. If the creatinine increases (which is already too late and should be avoided), a dose of amphotericin B can be omitted, and pre-hydration increased to 1L of normal saline every 8 hours and creatinine rechecked. If creatinine normalises, pre-hydrate with 1L normal saline with 20-mEq KCl and restart at amphotericin B (0.7mg/kg/day) given over 4 hours and thereafter consider giving amphotericin B on alternate days. Monitor renal function two to three times weekly.

If repeat creatinine remains elevated or continues to increase, discontinue amphotericin B and initiate high dose fluconazole 1200mg orally once daily.