Major Role for Amphotericin B–Flucytosine Combination in Severe Cryptococcosis

Abstract

BackgroundThe 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 FindingsPatients 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/SignificanceOur 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.

In Vitro Antifungal Susceptibilities and Amplified Fragment Length Polymorphism Genotyping of a Worldwide Collection of 350 Clinical, Veterinary, and Environmental Cryptococcus gattii Isolates

“…Severe cases of cryptococcosis in immunocompetent and -compromised patients are treated according to the guidelines of the Infectious Diseases Society of America, according to which treatment consists of an induction therapy for 2 weeks with a combination of amphotericin B and flucytosine, followed by a 10-week consolidation therapy with fluconazole (11,24).…”

Combination anti-fungal therapy in cryptococcal meningitis

“…The lower death rate among patients receiving flu cy to sine, as compared with the rate among those receiving ampho ter i cin B monotherapy, may have been due to lower rates of disability in these patients, which protected them from further complications, or lower rates of disease relapse, an association that has been previously identified. 24,25 In conclusion, the results of this study suggest that initial combination therapy with am photer i cin B and flu cy to sine for 2 weeks in our setting was associated with reduced mortality among patients with HIV-associated cryptococcal meningitis, as compared with 4 weeks of am pho ter i cin B monotherapy. Combination therapy with flu con azole for 2 weeks was not found to offer a benefit.…”

Cryptococcosis Neuro-Brain in 42 Patients at the University Hospital of Brazzaville

“…The standard attack treatment of neuromeningeal cryptococcosis is intravenous amphotericin B associated with 5-fluorocytosine for at least 15 days. The effectiveness of this combination is proven despite the rarity of these molecules in our regions (Schwarz et al, 2007;Dromer et al, 2008).…”