***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 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    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 HIV-associated cryptococcal meningitis is associated with an estimated 600 000 deaths worldwide per year . Current st and ard initial therapy consists of amphotericin B ( AmB ) plus flucytosine ( 5-FC ) , but 5-FC remains largely unavailable in Asia and Africa . Alternative , more widely available , and /or more effective antifungal combination treatment regimens are urgently needed . METHODS Eighty HIV-seropositive , antiretroviral naive patients presenting with cryptococcal meningitis were r and omized to 4 treatment arms of 2 weeks duration : group 1 , AmB ( 0.7 - 1 mg/kg ) and 5-FC ( 25 mg/kg 4 times daily ) ; group 2 , AmB ( 0.7 - 1 mg/kg ) and fluconazole ( 800 mg daily ) ; group 3 , AmB ( 0.7 - 1 mg/kg ) and fluconazole ( 600 mg twice daily ) ; and group 4 , AmB ( 0.7 - 1 mg/kg ) and voriconazole ( 300 mg twice daily ) . The primary end point was the rate of clearance of infection from the cerebrospinal fluid ( CSF ) or early fungicidal activity ( EFA ) , as determined by results of serial , quantitative CSF cryptococcal cultures . RESULTS There were no statistically significant differences in the rate of clearance of cryptococcal colony-forming units ( CFU ) in CSF sample s among the 4 treatment groups ; the mean ( ±st and ard deviation ) EFA for treatment groups 1 , 2 , 3 , and 4 were -0.41 ± 0.22 log CFU/mL CSF/day , -0.38 ± 0.18 log CFU/mL CSF/day , -0.41 ± 0.35 log CFU/mL CSF/day , and -0.44 ± 0.20 log CFU/mL CSF/day , respectively . Overall mortality was 12 % ( 9 of 78 patients died ) at 2 weeks and 29 % ( 22 of 75 patients died ) at 10 weeks , with no statistically significant differences among groups . There were few laboratory abnormalities related to the second agents given ; in particular , there were no statistically significant ( ≥ grade 3 ) increases in alanine transaminase level or decreases in neutrophil count . CONCLUSIONS There was no statistically significant difference in EFA between AmB in combination with fluconazole and AmB plus 5-FC for the treatment of HIV-associated cryptococcal meningitis . AmB plus fluconazole ( 800 - 1200 mg/day ) represents an immediately implementable alternative to AmB plus 5-FC . AmB plus voriconazole is an effective alternative combination in patients not receiving interacting medications In a prospect i ve observational study of 54 patients with human immunodeficiency virus-associated cryptococcal meningitis , the early fungicidal activity of amphotericin B ( 1 mg/kg/day ) was significantly greater than that of fluconazole ( 400 mg/day ) . Compared with antiretroviral therapy-naive patients , patients developing cryptococcal meningitis while already receiving antiretroviral therapy had lower baseline fungal burdens and a longer median duration of survival , but there were no differences observed in fungal clearance , cerebrospinal fluid proinflammatory cytokines , or 10-week mortality BACKGROUND The st and ard therapy for human immunodeficiency virus (HIV)-associated cryptococcal meningitis of amphotericin B ( AmB ; 0.7 mg/kg per day ) plus flucytosine frequently takes > 2 weeks to sterilize the cerebral spinal fluid , and acute mortality remains high . A dosage range for AmB of 0.7 - 1 mg/kg per day is noted in current guidelines , but there are no data comparing 0.7 mg/kg per day with 1 mg/kg per day . METHODS Sixty-four HIV-seropositive , antiretroviral therapy-naive patients in Cape Town , South Africa , who experienced their first episode of cryptococcal meningitis during the period May 2005-June 2006 were r and omized to receive either ( 1 ) AmB , 0.7 mg/kg per day , plus flucytosine , 25 mg/kg 4 times per day ( group 1 ; 30 patients ) ; or ( 2 ) AmB , 1 mg/kg per day , plus flucytosine , 25 mg/kg 4 times per day ( group 2 ; 34 patients ) . Regimens were given for 2 weeks , followed by treatment with oral fluconazole . The primary outcome measure was early fungicidal activity , as determined by results of serial , quantitative cerebral spinal fluid cryptococcal cultures . Secondary outcome measures were safety and mortality . The median duration of follow-up was 1 year . RESULTS Early fungicidal activity was significantly greater for group 2 than for group 1 ( mean + /- SD , -0.56 + /- 0.24 vs. -0.45 + /- 0.16 log cfu/mL of cerebral spinal fluid per day ; P = .02 ) . The incidence of renal impairment did not significantly differ between the 2 groups . Anemia was associated with female sex and , less strongly , with membership in group 2 . Renal impairment and anemia reversed after the regimen was switched to fluconazole . Two- and 10-week mortality rates were 6 % and 24 % , respectively , with no difference between groups . CONCLUSIONS AmB , 1 mg/kg per day , plus flucytosine is more rapidly fungicidal than is st and ard-dose AmB plus flucytosine . Because of its size , this study provides limited data on any difference in toxicity between the regimens , but toxicities were manageable and reversible . CLINICAL TRIALS REGISTRATION NUMBER IS RCT N68133435 ( http://www.controlled-trials.com ) The study objective was to obtain preliminary information regarding the safety and efficacy of amphotericin B ( AmB ) lipid complex ( ABLC ) in the treatment of AIDS-associated cryptococcal meningitis . Of 55 patients r and omly assigned to 6 weeks of therapy with ABLC  ( 1.2 - 5.0 mg/[kg.d ] , with ascending doses for three sequential cohorts ) or AmB ( 0.7 - 1.2 mg/[kg.d ] ) , 46 received > or = 12 doses . Transfusion requirements , mean decreases in hemoglobin level , and mean increases in creatinine level were significantly greater with AmB than with ABLC . The total number of adverse events , infusion-related events , and occurrences of hypomagnesemia and hypokalemia associated with each form of therapy were similar . Among 21 recipients of ABLC at a dosage of 5 mg/kg ( daily for 2 weeks and then thrice weekly for 4 weeks ) , symptoms and signs resolved for 18 ( 86 % ) . Of those receiving > or = 12 doses of ABLC , cultures converted to negative for 8 ( 42 % ) , were undeterminable for 3 ( 16 % ) , and remained positive for 8 ( 42 % ) despite resolution of symptoms . Although preliminary , these data suggest ABLC has significant activity in patients with AIDS-associated cryptococcal meningitis . Because this formulation has less hematologic and renal toxicity than does AmB , further evaluation of ABLC is warranted Background : Cryptococcal meningitis in Africa is associated with up to 70 % mortality at 3 months and 500 000 deaths annually . We examined strategies to improve on fluconazole ( FLU ) monotherapy : addition of flucytosine ( 5-FC ) and /or addition of short-course amphotericin B ( AmB ) . Methods : In step 1 , previously reported , patients were r and omized to receive FLU 1200 mg per day with or without 5-FC 100 mg/kg per day for 14 days . In step 2 , 43 patients were similarly r and omized , with addition of AmB 1 mg/kg per day for 7 days to both arms . After 2 weeks , patients received FLU monotherapy and were followed to 10 weeks . The primary endpoint was rate of clearance of infection ( early fungicidal activity , EFA ) . Secondary endpoints related to safety and mortality . Results : Forty patients ( 25 % with Glasgow Coma Scale < 15 ) were analyzed . EFA for the triple combination arm was greater than that for AmB – FLU : −0.50 ± 0.15 log CFU/day vs. −0.38 ± 0.19 log colony forming units per day ( P = 0.03 ) ; and greater than that for step 1 with FLU–5-FC ( −0.28 ± 0.17 ) or FLU alone ( −0.11 ± 0.09 ) . Combined analysis across steps revealed that addition of 5-FC and AmB had significant , independent additive effects on EFA , with trends toward fewer early deaths with addition of 5-FC ( 4/41 vs. 11/39 , P = 0.05 ) and fewer deaths overall with addition of AmB ( 13/39 vs. 20/40 , P = 0.1 ) . Conclusion : Addition of 5-FC and short-course AmB to high-dose FLU significantly enhanced EFA and may be associated with favorable trends in survival . Both these strategies should be tested in a larger phase III study Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more BACKGROUND . It is generally acknowledged that amphotericin B is the most effective treatment for cryptococcal meningitis . However , administration of this drug is accompanied by substantial adverse effects . This double-blind study , performed before the routine availability of highly active antiretroviral therapy , was design ed to compare the efficacy and safety of liposomal amphotericin B to conventional amphotericin deoxycholate in patients with acquired immunodeficiency syndrome ( AIDS ) and acute cryptococcal meningitis . METHODS . Patients were r and omized ( ratio , 1:1:1 ) from multiple sites in the United States and Canada to receive either amphotericin B at 0.7 mg/kg/day ( n = 87 ) , liposomal amphotericin B at 3 mg/kg/day ( n = 86 ) , or liposomal amphotericin B at 6 mg/kg/ 
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A statistically significant trial-level correlation was identified between EFA slope and ACM at 2 weeks , but is likely misleading , as there was no treatment effect on ACM .
CONCLUSIONS Mortality remains high in short time periods in CM clinical trials .