***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    Input: BACKGROUND Treatment with low-dose amphotericin B ( 0.4 mg per kilogram of body weight per day ) or oral azole therapy in patients with the acquired immunodeficiency syndrome ( AIDS ) and cryptococcal meningitis has been associated with high mortality and low rates of cerebrospinal fluid sterilization . METHODS In a double-blind multicenter trial we r and omly assigned patients with a first episode of AIDS-associated cryptococcal meningitis to treatment with higher-dose amphotericin B ( 0.7 mg per kilogram per day ) with or without flucytosine ( 100 mg per kilogram per day ) for two weeks ( step one ) , followed by eight weeks of treatment with itraconazole ( 400 mg per day ) or fluconazole ( 400 mg per day ) ( step two ) . Treatment was considered successful if cerebrospinal fluid cultures were negative at 2 and 10 weeks or if the patient was clinical ly stable at 2 weeks and asymptomatic at 10 weeks . RESULTS At two weeks , the cerebrospinal fluid cultures were negative in 60 percent of the 202 patients receiving amphotericin B plus flucytosine  and in 51 percent of the 179 receiving amphotericin B alone ( P=0.06 ) . Elevated intracranial pressure was associated with death in 13 of 14 patients during step one . The clinical outcome did not differ significantly between the two groups . Seventy-two percent of the 151 fluconazole recipients and 60 percent of the 155 itraconazole recipients had negative cultures at 10 weeks ( 95 percent confidence interval for the difference in percentages , -100 to 21 ) . The proportion of patients who had clinical responses was similar with fluconazole ( 68 percent ) and itraconazole ( 70 percent ) . Overall mortality was 5.5 percent in the first two weeks and 3.9 percent in the next eight weeks , with no significant difference between the groups . In a multivariate analysis , the addition of flucytosine during the initial two weeks and treatment with fluconazole for the next eight weeks were independently associated with cerebrospinal fluid sterilization . CONCLUSIONS For the initial treatment of AIDS-associated cryptococcal meningitis , the use of higher-dose amphotericin B plus flucytosine is associated with an increased rate of cerebrospinal fluid sterilization and decreased mortality at two weeks , as compared with regimens used in previous studies . Although consolidation therapy with fluconazole is associated with a higher rate of cerebrospinal fluid sterilization , itraconazole may be a suitable alternative for patients unable to take fluconazole Background Cryptococcus is the most common cause of adult meningitis in Africa . We evaluated the activity of adjunctive sertraline , previously demonstrated to have in vitro and in vivo activity against Cryptococcus . Methods We enrolled 172 HIV-infected Ug and ans with cryptococcal meningitis from August 2013 through August 2014 into an open-label dose-finding study to assess safety and microbiologic efficacy . Sertraline 100–400mg/day was added to st and ard therapy of amphotericin + fluconazole 800mg/day . We evaluated early fungicidal activity via Cryptococcus cerebrospinal fluid ( CSF ) clearance rate , sertraline pharmacokinetics , and in vitro susceptibility . Findings Participants receiving any sertraline dose averaged a CSF clearance rate of −0·37 ( 95%CI : −0·41 , −0·33 ) colony forming units (CFU)/mL/day . Incidence of paradoxical immune reconstitution inflammatory syndrome ( IRIS ) was 5 % ( 2/43 ) and relapse was 0 % through 12-weeks . Sertraline  reached steady state concentrations in plasma by day 7 , with median steady-state concentrations of 201 ng/mL ( IQR , 90–300 ; n=49 ) with 200mg/day and 399 ng/mL ( IQR , 279–560 ; n=30 ) with 400mg/day . Plasma concentrations reached 83 % of steady state levels by day 3 . The median projected steady state brain tissue concentration at 200mg/day was 3·7 ( IQR , 2·0–5·7 ) mcg/mL and 6·8 ( IQR , 4·6–9·7 ) mcg/mL at 400mg/day . Minimum inhibitory concentrations were ≤2 mcg/mL for 27 % ( 35/128 ) , ≤4 mcg/mL for 84 % ( 108/128 ) , ≤6 mcg/mL for 91 % ( 117/128 ) , and ≤8 mcg/mL for 100 % of 128 Cryptococcus isolates . Interpretation Sertraline  had faster cryptococcal CSF clearance , decreased IRIS , and decreased relapse compared with historical experiences . Sertraline reaches therapeutic levels in a clinical setting . This inexpensive and off-patent oral medication is a promising adjunctive antifungal therapy . Funding National Institutes of Health , Gr and Challenges Canada BACKGROUND Cryptococcal meningitis accounts for more than 100,000 human immunodeficiency virus (HIV)–related deaths per year . We tested two treatment strategies that could be more sustainable in Africa than the st and ard of 2 weeks of amphotericin B plus flucytosine and more effective than the widely used fluconazole monotherapy . METHODS We r and omly assigned HIV‐infected adults with cryptococcal meningitis to receive an oral regimen ( fluconazole [ 1200 mg per day ] plus flucytosine [ 100 mg per kilogram of body weight per day ] for 2 weeks ) , 1 week of amphotericin B ( 1 mg per kilogram per day ) , or 2 weeks of amphotericin B ( 1 mg per kilogram per day ) . Each patient assigned to receive amphotericin B was also r and omly assigned to receive fluconazole or flucytosine as a partner drug . After induction treatment , all the patients received fluconazole consolidation therapy and were followed to 10 weeks . RESULTS A total of 721 patients underwent r and omization . Mortality in the oral‐regimen , 1‐week amphotericin B , and 2‐week amphotericin B groups was 18.2 % ( 41 of 225 ) , 21.9 % ( 49 of 224 ) , and 21.4 % ( 49 of 229 ) , respectively , at 2 weeks and was 35.1 % ( 79 of 225 ) , 36.2 % ( 81 of 224 ) , and 39.7 % ( 91 of 229 ) , respectively , at 10 weeks . The upper limit of the one‐sided 97.5 % confidence interval for the difference in 2‐week mortality was 4.2 percentage points for the oral‐regimen group versus the 2‐week amphotericin B groups and 8.1 percentage points for the 1‐week amphotericin B groups versus the 2‐week amphotericin B groups , both of which were below the predefined 10‐percentage‐point noninferiority margin . As a partner drug with amphotericin B , flucytosine was superior to fluconazole ( 71 deaths [ 31.1 % ] vs. 101 deaths [ 45.0 % ] ; hazard ratio for death at 10 weeks , 0.62 ; 95 % confidence interval [ CI ] , 0.45 to 0.84 ; P=0.002 ) . One week of amphotericin B plus flucytosine was associated with the lowest 10‐week mortality ( 24.2 % ; 95 % CI , 16.2 to 32.1 ) . Side effects , such as severe anemia , were more frequent with 2 weeks than with 1 week of amphotericin B or with the oral regimen . CONCLUSIONS One week of amphotericin B plus flucytosine and 2 weeks of fluconazole plus flucytosine were effective as induction therapy for cryptococcal meningitis in re source ‐limited setting s. ( ACTA Current Controlled Trials number , IS RCT N45035509 . Objective : HIV-infected patients with treated cryptococcal meningitis are at risk for further neurological deterioration after commencing combination antiretroviral therapy ( cART ) , mostly because of cryptococcosis-associated immune reconstitution inflammatory syndrome ( C-IRIS ) . Identifying predictors of C-IRIS could enable risk stratification . Design : Prospect i ve , longitudinal cohort study for 24 weeks . Setting : Durban , South Africa . Participants : One hundred and thirty HIV-infected patients with first cryptococcal meningitis episode Intervention : Antifungal therapy ( amphotericin 1 mg/kg median 14 days , followed by consolidation and maintenance fluconazole ) and cART ( commenced median of 18 days from cryptococcal meningitis diagnosis ) . Main outcome measure : Clinical , blood , and cerebrospinal fluid ( CSF ) markers associated with C-IRIS before and during cART and clinical significance of CSF cryptococcal culture negativity pre-cART commencement . Results : Of 106 patients commencing cART , 27 ( 25.5 % ) developed C-IRIS , 16 ( 15.1 % ) neurological deterioration-not C-IRIS , and 63 ( 59.4 % ) no neurological deterioration . On multivariable analysis , C-IRIS was associated with persistent CSF cryptococcal growth [ hazard ratio ( HR ) 0.27 , P = 0.026 ] and lower CSF protein ( HR 0.53 , P = 0.059 ) prior to cART and lower CD4 + T-cell increases ( HR 0.99 , P = 0.026 ) but not change in HIV viral load during cART . Using survival analysis , patients with a negative cryptococcal culture pre-cART commencement ( n = 51 ; 48.1 % ) experienced fewer episodes of neurological deterioration , C-IRIS , and cryptococcal relapse/persistence than patients with culture positivity ( n = 55 ; 51.9 % , HR 0.33 , 0.33 , and 0.12 and P = 0.0003 , 0.0042 , and 0.0004 , respectively ) . Conclusion : Persistent CSF cryptococcal growth at cART initiation and poor CD4 + T-cell increases on cART are strong predictors of C-IRIS . Approaches aim ed at achieving CSF culture negativity prior to cART should be evaluated as a strategy to reduce rates of C-IRIS David Boulware and colleagues investigate clinical features in a prospect i ve cohort with AIDS and recent cryptococcal meningitis after initiation of antiretroviral therapy  to identify biomarkers for prediction and diagnosis of CM-IRIS ( cryptococcal meninigitis-related immune reconstitution inflammatory syndrome ) Background . Amphotericin-based combination antifungal therapy reduces mortality from human immunodeficiency virus (HIV)-associated cryptococcal meningitis . However , 40%–50 % of individuals have positive cerebrospinal fluid ( CSF ) fungal cultures at completion of 2 weeks of amphotericin induction therapy . Residual CSF culture positivity has historically been associated with poor clinical outcomes . We investigated whether persistent CSF fungemia was associated with detrimental clinical outcomes in a contemporary African cohort . Methods . Human immunodeficiency virus-infected individuals with cryptococcal meningitis in Ug and a and South Africa received amphotericin ( 0.7–1.0 mg/kg per day ) plus fluconazole ( 800 mg/day ) for 2 weeks , followed by “ enhanced consolidation ” therapy with fluconazole 800 mg/day for at least 3 weeks or until cultures were sterile , and then 400 mg/day for 8 weeks . Participants were r and omized to receive antiretroviral therapy ( ART ) either 1–2 or 5 weeks after diagnosis and observed for 6 months . Survivors were classified as having sterile or nonsterile CSF based on 2-week CSF cultures . Mortality , immune reconstitution inflammatory syndrome ( IRIS ) , and culture-positive relapse were compared in those with sterile or nonsterile CSF using Cox regression . Results . Of 132 participants surviving 2 weeks , 57 % had sterile CSF at 2 weeks , 23 died within 5 weeks , and 40 died within 6 months . Culture positivity was not significantly associated with mortality ( adjusted 6-month hazard ratio , 1.2 ; 95 % confidence interval , 0.6–2.3 ; P = .28 ) . Incidence of IRIS or relapse was also not significantly related to culture positivity . Conclusions . Among patients , all treated with enhanced consolidation antifungal therapy and ART , residual cryptococcal culture positivity was 
    Output:
    
Currently recommended fluconazole doses may be inadequate for cryptococcosis .