1. Cryptococcosis: Treatment outcome
Síle Molloy, PhD
Centre for Global Health, Institute of Infection and Immunity
St. George’s, University of London

2. Intended Learning Outcomes
To be aware of the 10 week and 1 year survival on antifungal therapy
To be aware of the predictors of poor prognosis in cryptococcal meningitis
To appreciate the role of maintenance fluconazole therapy in preventing relapses

3. Deaths from Cryptococcal meningitis by region
Global: ,100 (119, ,300)
Sub-Saharan Africa: ,900 (75%)
Asia and Pacific: 39, (22%)
Latin America: , (1.3%)
North Africa & Middle East: 1, (1.1%)
Europe: , (1.0%)
Caribbean: (0.4%)
North America: (0.4%)
Rajasingham et al., Lancet Infect Dis, 2017; 17 (8):

4. 10-weeks and 1 year mortality on antifungal therapy
Treatment outcome
10-weeks and 1 year mortality on antifungal therapy
BEST: Clinical trial setting
35-40% 10 weeks mortality
2 weeks Amphotericin B-based therapy
USUAL REALITY:
Malawi: Fluconazole: 10 wk mortality >50%
One year 22% survival on fluconazole
Jarvis et al., Clin Infect Dis. 2014;58(5):736-45
Zambia: 2 wk AmB routine use
39% in hospital mortality
Rothe et al . The solid line shows estimated proportion of survivors and the dotted lines show 95% confidence intervals. Amongst the 47 patients who did not survive on fluconazole to 52 weeks, two had positive CSF cultures at 10 weeks and were switched to fluconazole. The remaining 45 died
Siddiqi et al. Clin Infect Dis. 2014;58(12):
Rothe et al. PLoS ONE. 2013; 8(6): e67311.

5. Predictors of poor prognosis (10-week mortality)
Altered mental status (GCS <15)
High fungal burden
Older age (>50 years)
Low body weight
Anaemia (haemoglobin <7.5 g/dL)
High peripheral white cell count
Serial measurement of cryptococcal antigen titers to gauge treatment response does not have any proven benefit
Jarvis et al., Clin Infect Dis, 2014, 58 (5)

6. Relapse following optimal treatment for acute cryptococcal meningitis
30-40% of patients before introduction of consolidation and maintenance strategies
Consolidation schedule
Fluconazole 800mg from end of induction therapy till start ART, followed by Fluconazole mg
Maintenance schedule
Reduce to Fluconazole 200mg from 10 weeks
Bozzette et al N Engl J Med 1991;324;580-4

7. Relapse following optimal treatment for acute cryptococcal meningitis
To diagnose relapse a patient MUST have :-
New clinical signs and symptoms consistent with cryptococcosis after an initial clinical improvement AND
Positive cultures after initial CSF sterilisation
Surrogate markers like India ink, CrAg titres, and biochemical markers are insufficient to diagnose relapse.
Maziarz & Perfect. Infect Dis Clin N Am. 2016; 30:

8. Persistent Cryptococcal meningitis
Persistent cryptococcal disease is defined as persistently positive CSF cultures after 1 month of antifungal therapy
Like relapse, surrogate markers like India ink, CrAg titres, and biochemical markers are insufficient to diagnose persistent disease
Maziarz & Perfect. Infect Dis Clin N Am. 2016; 30:

9. Management of relapsed and persistent disease
Both persistent and relapsed infections must be distinguished from c-IRIS and raised intracranial pressure
Relapse and persistence is rare except where Fluconazole monotherapy is used for induction therapy
Management
Re-initiation of induction therapy (Amphotericin B)
Until CSF sterilisation
Antifungal susceptibility testing (where available)
Checks for changes in minimum inhibitory concentration (MIC) from the original isolate
Perfect et al. Clin Infect Dis. 2010;50(3):

10. Summary
Most CM deaths are in sub-Saharan Africa where 10-week mortality in routine setting is >50%
Fungal burden and altered mental status are important prognostic indicators
Long-term maintenance antifungal therapy reduces the rate of relapse from >50% to less than 5%
Culture is required to diagnose relapse or persistent disease
Re-initiation of induction therapy at a higher dose and longer duration is recommended
Antifungal susceptibility testing on all relapse isolates

11. END