1. Cryptococcosis: Antifungal therapy management
Prof. Thomas S. Harrison
Centre for Global Health, Institute of Infection and Immunity
St. George’s, University of London; St George's University Hospitals NHS Foundation Trust

2. Intended learning outcomes
To be aware of the different phases of antifungal management of cryptococcal meningitis (CM)
To be aware of the different antifungal regimens used in the different phases
AND
New data re importance flucytosine (5-FC), duration Amphotericin B (in HIV-CM)
To be aware of the timing of initiation/modification of ART after HIV-related cryptococcal meningitis
To be aware of the antifungal management of pulmonary and other forms of cryptococcosis

3. Management
Patients with suspected symptomatic CNS or systemic cryptococcosis
Admission to hospital for thorough evaluation
Optimal antifungal therapy for:-
Cryptococcal Meningo-encephalitis
Severe Pulmonary / Disseminated non-pulmonary non-CNS cryptococcosis
IF CM confirmed - Measurement and Management of intracranial pressure
IF HIV-seropositive – appropriate Timing of Initiation / Re-introduction or modification of Antiretroviral Therapy (ART)

4. Acute HIV-associated cryptococcal meningitis
Phased antifungal therapy
Induction phase
Consolidation phase
Maintenance
2 weeks
Amphotericin-based combination therapy
8 weeks
Based on... Van der Horst et al. NEJM 1997; 337:15–21
Supported by… Brouwer et al. Lancet 2004; 363:1764–67
Survival advantage with combination shown by… Day et al. NEJM 2013; 368:1291
Long term therapy (at least 1 year)
Until immune reconstitution
Van der Horst et al. NEJM 1997; 337:15–21
Brouwer et al. Lancet 2004; 363:1764–67
Day et al. NEJM 2013; 368:1291

5. Acute HIV-related cryptococcal meningitis
Management of intracranial hypertension
Extra 1L Normal Saline/day
Electrolyte replacement and monitoring Monitor Hb, neutrophils, creatinine
Phlebitis: flush lines well, replace early
Investigate & treat for other HIV-related complications: TB, bacterial infections
Monitor for and manage CM-IRIS
Rx Adjuncts
Induction phase
Consolidation phase
Maintenance
Antifungal treatment
WHO Rapid advice guideline, WHO November, 2011
NB with AmB plus Flucytosine
Phlebitis – flush lines well, replace promptly
Saline and Fluid loading – reduces nephrotoxicity
Pre-emptive K+ and Mg+ replacement
Monitoring: Renal function / electrolytes,
Anaemia – transfuse if needed
Adjust flucytosine dose if renal impairment
If managed appropriately, 6% discontinuation within 2 wks
But anaemia in particular & renal impair associated with reduced survival Bicanic T et al. Antimicrob Agents Chem. 2015; 59:7224

6. Acute HIV-related cryptococcal meningitis
Phase
Antifungal agent(dose)
Duration
Primary Induction therapy
AmBd (0.7-1mg/kg/d)
+ 5-Flucytosine (5-FC) (100mg/kg/d)
2 weeks
Initial combination therapy with amphotericin B (AmB) and flucytosine is associated with reduced mortality among patients with HIV-associated cryptococcal meningitis compared with AmB alone
Large effect
40% reduction in mortality at 10 wks
Amb plus flucon appeared intermediate
Day et al N Engl J Med. 2013;368: 1291–1302.

7. Acute HIV-related cryptococcal meningitis
NEW data ACTA trial (IAS Paris, 2017)
Flucytosine is superior to fluconazole as partner drug with AmB
Hazard Ratio (95% CI)
AmB+FLU vs
AmB vs 5FC
p-value
(log-rank test)
10 week mortality
1.62
(1.19 to 2.20)
0.002
Very confident this will drive generic 5FC in next 1-2 years
Molloy et al IAS Paris 2017

8. Acute HIV-related cryptococcal meningitis
NEW data ACTA trial (IAS Paris, 2017)
AmB+5FC for one week: at least as good, better tolerated than 2 weeks.
2-weeks Fluconazole 1200mg/d+5FC – also highly effective
So 1 week amb 5fc best arm and oral flucon 5fc second best alternative
Can reduce mortality to 25-35% at 10 weeks compared with 50-60% with flucon mono, and 40-45% with 2 wks AmB combination
Until 5fc there 2 weeks ampho plus fluconazole
Molloy et al IAS Paris 2017

9. Acute Cryptococcal meningitis – resource rich settings
Liposomal Amphotericin B vs Conventional AmB
Liposomal amphotericin B (at 3-4 mg/kg/d)
Not more effective, but
Less side effects than conventional AmB deoxycholate
Hamill et al. Clin Infect Dis. 2010; 51:225-32

10. Non-HIV-related cryptococcal meningitis
Phase
Antifungal agent (dose)
Duration
Transplant-related:
L-AMB 3-4mg/kg/d
Plus 5-FC 100mg/day
L-AMB 6mg/kg/d (if no 5FC)
2-4 weeks
4-6 weeks
Non-HIV, non-transplant, including apparently immunocompetent:
AmBd 0.7-1mg/kg/d or L-AMB 3-4mg/kg/d
Duration
Induction therapy
Long induction – usually start of switch to L-AmB – if you can
Adapted from Perfect et al Clin Infect Dis ;50(3):

11. Acute cryptococcal meningitis
Phase
Antifungal agent (dose)
Duration
Consolidation
Fluconazole 400mg-800mg/d
8 weeks
Was concern re flucon and nevirapine
Not substantiated as cilnical issue and now nev not used, and given safety of flucon many use 800 to 10 weeks

12. Acute cryptococcal meningitis
Phase
Antifungal agent(dose)
Duration
Maintenance
Fluconazole 200mg/d
[Itraconazole 200mg BD or
AmBd 1mg/kg IV weekly are inferior alternatives, rarely if ever needed]
1 year or longer*
Flucon resistance v rare with rapidly active induction (not flucon mono)
*After 1 year of suppression therapy, if CD4 counts reconstitutes to >100 and viral load is undetectable for >3 months, consider discontinuation of therapy : Re-institute if CD4<100.
Adapted from Perfect et al Clin Infect Dis. 2010;50(3):

13. Timing of antiretroviral therapy
Early ART initiation is associated with:-
Increased mortality
Increased risk of IRIS
Defer ART for 4-6 weeks after starting antifungal therapy.
In unmasking CM-IRIS (first presentation CM early after ART start) – continue ART
In those presenting with CM with non- adherence /failing ART, defer re-start of ART, with/without switch to second line ART, until 4 weeks
Boulware et al. N Engl J Med. 2014; 370:

14. Pulmonary cryptococcosis, other sites
Mild pulmonary disease:
And Other sites: – if CNS disease ruled out§, no fungemia, single site of infection, no immunosuppressive risk factors
Fluconazole for 6-12 months*,
Severe disease any site, or Concomitant CNS disease:
Treat as for CNS disease
*IF solitary pulmonary nodule completely resected, no evidence extrapulmonary disease and immunocompetent patient,
Then some experts suggest can hold or stop antifungal therapy and observe
§ important to do LP especially if immunosuppressed in any way
Adapted from Perfect et al Clin Infect Dis. 2010;50(3):

15. Summary Antifungal Recommendations
Amphotericin B-based induction kills C. neoformans faster and improves both short and long term outcome from cryptococcal meningitis compared with fluconazole monotherapy
Flucytosine as partner drug improves survival
Fluid and saline load during AmB therapy. Monitor infusion sites, and for anaemia and renal function and potassium loss during AmB-based therapy. Pre-emptively replace potassium, magnesium
Defer initiation or re-starting or switch of antiretroviral therapy for 4-6 weeks after cryptococcal meningitis
Fluconazole is highly effective as maintenance to prevent disease relapse

16. END