title: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institut Pasteur, Mycologie Moléculaire, Centre National de Référence Mycologie et Antifongiques, CNRS URA3012, Paris, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Dromer
authors.forename: Claire
authors.initials: C
authors.lastname: Bernede-Bauduin
authors.forename: Didier
authors.initials: D
authors.lastname: Guillemot
authors.forename: Olivier
authors.initials: O
authors.lastname: Lortholary
mesh_terms: D000328:Adult; D000666:Amphotericin B / Q000627:therapeutic use*; D000935:Antifungal Agents / Q000627:therapeutic use; D003453:Cryptococcosis / Q000150:complications / Q000188:drug therapy*; D003455:Cryptococcus neoformans / Q000187:drug effects / Q000302:isolation & purification; D004359:Drug Therapy, Combination; D005260:Female; D005437:Flucytosine / Q000627:therapeutic use*; D006679:HIV Seropositivity / Q000150:complications; D006801:Humans; D008297:Male; D012955:Societies, Medical; D016896:Treatment Outcome; D014481:United States
chemical_list: D000935:Antifungal Agents; D000666:Amphotericin B; D005437:Flucytosine