Major role for amphotericin B-flucytosine combination in severe cryptococcosis

Abstract

Background: The Infectious Diseases Society of America published in 2000 practical guidelines for the management of cryptococcosis. However, treatment strategies have not been fully validated in the various clinical settings due to exclusion criteria during therapeutic trials. We assessed here the optimal therapeutic strategies for severe cryptococcosis using the observational prospective CryptoA/D study after analyzing routine clinical care of cryptococcosis in university or tertiary care hospitals.

Methodology/principal findings: Patients were enrolled if at least one culture grew positive with Cryptococcus neoformans. Control of sterilization was warranted 2 weeks (Wk2) and 3 months (Mo3) after antifungal therapy onset. 208 HIV-positive or -negative adult patients were analyzed. Treatment failure (death or mycological failure) at Wk2 and Mo3 was the main outcome measured. Combination of amphotericin B+flucytosine (AMB+5FC) was the best regimen for induction therapy in patients with meningoencephalitis and in all patients with high fungal burden and abnormal neurology. In those patients, treatment failure at Wk2 was 26% in the AMB+5FC group vs. 56% with any other treatments (p<0.001). In patients treated with AMB+5FC, factors independently associated with Wk2 mycological failure were high serum antigen titer (OR [95%CI] = 4.43[1.21-16.23], p = 0.025) and abnormal brain imaging (OR = 3.89[1.23-12.31], p = 0.021) at baseline. Haematological malignancy (OR = 4.02[1.32-12.25], p = 0.015), abnormal neurology at baseline (OR = 2.71[1.10-6.69], p = 0.030) and prescription of 5FC for less than 14 days (OR = 3.30[1.12-9.70], p = 0.030) were independently associated with treatment failure at Mo3.

Conclusion/significance: Our results support the conclusion that induction therapy with AMB+5FC for at least 14 days should be prescribed rather than any other induction treatments in all patients with high fungal burden at baseline regardless of their HIV serostatus and of the presence of proven meningoencephalitis.

Figure 1. Flow chart showing the actual number of patients with cryptococcosis included in the description of clinical presentation, determinant of induction treatment choices and analysis of week 2 (Wk2) outcome.

HIV-positive and -negative patients with cryptococcal meningoencephalitis (CSF pos) or with no proven central nervous system involvement (CSF neg) were enrolled in the prospective multicenter CryptoA/D observational study. The Wk2 workup requested control of sterilisation of the body sites infected with C. neoformans at baseline. Treatments prescribed for more than 5 days included amphotericin B (AMB), flucytosine (5FC) and/or fluconazole (FCZ). Overall, of the 208 patients eligible for analysis at baseline, at the time of the Wk2 workup, 184 were alive with mycological outcome assessed, 14 were alive without mycological evaluation and 10 had died.

Figure 2. Flow chart showing the actual number of patients with cryptococcosis included in the description and analysis of the consolidation phase and outcome 3 months (Mo3) after onset of antifungal therapy.

Of the 208 patients enrolled initially, 10 died during the induction phase and 9 were lost to follow-up leaving 189 patients for the description of disease and outcome. At the Mo3 workup, 168 patients were assessable including 148 patients alive with mycological assessment and 20 who had died. The remaining 21 patients alive were not included in the final analysis since they had no mycological evaluation at the Mo3 workup.