Combination Flucytosine and High-Dose Fluconazole Compared with Fluconazole Monotherapy for the Treatment of Cryptococcal Meningitis: A Randomized Trial in Malawi
Background. Cryptococcal meningitis is a major cause of human immunodeficiency virus (HIV)–associated morbidity and mortality in Africa. Improved oral treatment regimens are needed because amphotericin B is neither available nor feasible in many centers. Fluconazole at a dosage of 1200 mg per day is...
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| Published in | Clinical infectious diseases Vol. 50; no. 3; pp. 338 - 344 |
|---|---|
| Main Authors | , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Oxford
The University of Chicago Press
01.02.2010
University of Chicago Press Oxford University Press |
| Subjects | |
| Online Access | Get full text |
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| Abstract | Background. Cryptococcal meningitis is a major cause of human immunodeficiency virus (HIV)–associated morbidity and mortality in Africa. Improved oral treatment regimens are needed because amphotericin B is neither available nor feasible in many centers. Fluconazole at a dosage of 1200 mg per day is more fungicidal than at a dosage of 800 mg per day, but mortality rates remain unacceptably high. Therefore, we examined the effect of adding oral flucytosine to fluconazole. Methods. From 13 February through 2 December 2008, HIV-seropositive, antiretroviral-naive patients experiencing their first episode of cryptococcal meningitis were randomized to receive (1) 14 days of fluconazole (1200 mg per day) alone or (2) in combination with flucytosine (100 mg/kg per day) followed by fluconazole (800 mg per day), with both groups undergoing 10 weeks of follow-up. The primary end point was early fungicidal activity, derived from quantitative cerebrospinal fluid cultures on days 1, 3, 7, and 14. Secondary end points were safety and 2- and 10-week mortality. Results. Forty-one patients were analyzed. Baseline mental status, cryptococcal burden, opening pressure, CD4+ cell count, and HIV load were similar between groups. Combination therapy was more fungicidal than fluconazole alone (mean early fungicidal activity ± standard deviation, −0.28±0.17 log colony-forming units [CFU]/mL per day vs −0.11±0.09 log CFU/mL per day; P<.001). The combination arm had fewer deaths by 2 weeks (10% vs 37%) and 10 weeks (43% vs 58%). More patients had grade III or IV neutropenia with combination therapy (5 vs 1, within the first 2 weeks; P=.20), but there was no increase in infection-related adverse events. Conclusions. The results suggest that optimal oral treatment for cryptococcal meningitis is high-dose fluconazole with flucytosine. Efforts are needed to increase availability of flucytosine in Africa. Clinical trials registration. isrctn.org Identifier: ISRCTN02725351. |
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| AbstractList | Cryptococcal meningitis is a major cause of human immunodeficiency virus (HIV)-associated morbidity and mortality in Africa. Improved oral treatment regimens are needed because amphotericin B is neither available nor feasible in many centers. Fluconazole at a dosage of 1200 mg per day is more fungicidal than at a dosage of 800 mg per day, but mortality rates remain unacceptably high. Therefore, we examined the effect of adding oral flucytosine to fluconazole.
From 13 February through 2 December 2008, HIV-seropositive, antiretroviral-naive patients experiencing their first episode of cryptococcal meningitis were randomized to receive (1) 14 days of fluconazole (1200 mg per day) alone or (2) in combination with flucytosine (100 mg/kg per day) followed by fluconazole (800 mg per day), with both groups undergoing 10 weeks of follow-up. The primary end point was early fungicidal activity, derived from quantitative cerebrospinal fluid cultures on days 1, 3, 7, and 14. Secondary end points were safety and 2- and 10-week mortality.
Forty-one patients were analyzed. Baseline mental status, cryptococcal burden, opening pressure, CD4(+) cell count, and HIV load were similar between groups. Combination therapy was more fungicidal than fluconazole alone (mean early fungicidal activity +/- standard deviation -0.28 +/- 0.17 log colony-forming units [CFU]/mL per day vs -0.11 +/- 0.09 log CFU/mL per day; P < .001). The combination arm had fewer deaths by 2 weeks (10% vs 37%) and 10 weeks (43% vs 58%). More patients had grade III or IV neutropenia with combination therapy (5 vs 1, within the first 2 weeks; P = .20), but there was no increase in infection-related adverse events.
The results suggest that optimal oral treatment for cryptococcal meningitis is high-dose fluconazole with flucytosine. Efforts are needed to increase availability of flucytosine in Africa. Clinical trials registration. isrctn.org Identifier: ISRCTN02725351. Background. Cryptococcal meningitis is a major cause of human immunodeficiency virus (HIV)–associated morbidity and mortality in Africa. Improved oral treatment regimens are needed because amphotericin B is neither available nor feasible in many centers. Fluconazole at a dosage of 1200 mg per day is more fungicidal than at a dosage of 800 mg per day, but mortality rates remain unacceptably high. Therefore, we examined the effect of adding oral flucytosine to fluconazole. Methods. From 13 February through 2 December 2008, HIV-seropositive, antiretroviral-naive patients experiencing their first episode of cryptococcal meningitis were randomized to receive (1) 14 days of fluconazole (1200 mg per day) alone or (2) in combination with flucytosine (100 mg/kg per day) followed by fluconazole (800 mg per day), with both groups undergoing 10 weeks of follow-up. The primary end point was early fungicidal activity, derived from quantitative cerebrospinal fluid cultures on days 1, 3, 7, and 14. Secondary end points were safety and 2- and 10-week mortality. Results. Forty-one patients were analyzed. Baseline mental status, cryptococcal burden, opening pressure, CD4 + cell count, and HIV load were similar between groups. Combination therapy was more fungicidal than fluconazole alone (mean early fungicidal activity ± standard deviation, −0.28 ± 0.17 log colony-forming units [CFU]/mL per day vs −0.11 ± 0.09 log CFU/mL per day; P<.001). The combination arm had fewer deaths by 2 weeks (10% vs 37%) and 10 weeks (43% vs 58%). More patients had grade III or IV neutropenia with combination therapy (5 vs 1, within the first 2 weeks; P = .20), but there was no increase in infection-related adverse events. Conclusions. The results suggest that optimal oral treatment for cryptococcal meningitis is high-dose fluconazole with flucytosine. Efforts are needed to increase availability of flucytosine in Africa. Clinical trials registration. isrctn.org Identifier: ISRCTN02725351. Background . Cryptococcal meningitis is a major cause of human immunodeficiency virus (HIV)–associated morbidity and mortality in Africa. Improved oral treatment regimens are needed because amphotericin B is neither available nor feasible in many centers. Fluconazole at a dosage of 1200 mg per day is more fungicidal than at a dosage of 800 mg per day, but mortality rates remain unacceptably high. Therefore, we examined the effect of adding oral flucytosine to fluconazole. Methods . From 13 February through 2 December 2008, HIV-seropositive, antiretroviral-naive patients experiencing their first episode of cryptococcal meningitis were randomized to receive (1) 14 days of fluconazole (1200 mg per day) alone or (2) in combination with flucytosine (100 mg/kg per day) followed by fluconazole (800 mg per day), with both groups undergoing 10 weeks of follow-up. The primary end point was early fungicidal activity, derived from quantitative cerebrospinal fluid cultures on days 1, 3, 7, and 14. Secondary end points were safety and 2- and 10-week mortality. Results . Forty-one patients were analyzed. Baseline mental status, cryptococcal burden, opening pressure, CD4+ cell count, and HIV load were similar between groups. Combination therapy was more fungicidal than fluconazole alone (mean early fungicidal activity ± standard deviation, −0.28±0.17 log colony-forming units [CFU]/mL per day vs −0.11±0.09 log CFU/mL per day; P<.001). The combination arm had fewer deaths by 2 weeks (10% vs 37%) and 10 weeks (43% vs 58%). More patients had grade III or IV neutropenia with combination therapy (5 vs 1, within the first 2 weeks; P=.20), but there was no increase in infection-related adverse events. Conclusions . The results suggest that optimal oral treatment for cryptococcal meningitis is high-dose fluconazole with flucytosine. Efforts are needed to increase availability of flucytosine in Africa. Clinical trials registration . isrctn.org Identifier: ISRCTN02725351. Background. Cryptococcal meningitis is a major cause of human immunodeficiency virus (HIV)-associated morbidity and mortality in Africa. Improved oral treatment regimens are needed because amphotericin B is neither available nor feasible in many centers. Fluconazole at a dosage of 1200 mg per day is more funglcldal than at a dosage of 800 mg per day, but mortality rates remain unacceptably high. Therefore, we examined the effect of adding oral flucytosine to fluconazole. Methods. From 13 February through 2 December 2008, HIV-seropositive, antiretroviralnalve patients experiencing their first episode of cryptococcal meningitis were randomized to receive (1) 14 days of fluconazole (1200 mg per day) alone or (2) In combination with flucytosine (100 mg/kg per day) followed by fluconazole (800 mg per day), with both groups undergoing 10 weeks of follow-up. The primary end point was early fungicidal activity, derived from quantitative cerebrospinal fluid cultures on days 1, 3, 7, and 14. Secondary end points were safety and 2- and 10-week mortality. Results. Forty-one patients were analyzed. Baseline mental status, cryptococcal burden, opening pressure, CD4 super(+) cell count, and HIV load were similar between groups. Combination therapy was more fungicidal than fluconazole alone (mean early fungicidal activity plus or minus standard deviation, -0.28 plus or minus 0.17 log colony-forming units [CFU]/mL per day vs -0.11 plus or minus 0.09 log CFU/mL per day; P < .001). The combination arm had fewer deaths by 2 weeks (10% vs 37%) and 10 weeks (43% vs 58%). More patients had grade III or IV neutropenia with combination therapy (5 vs 1, within the first 2 weeks; P = .20), but there was no increase in infection-related adverse events. Conclusions. The results suggest that optimal oral treatment for cryptococcal meningitis is high-dose fluconazole with flucytosine. Efforts are needed to increase availability of flucytosine in Africa. Cryptococcal meningitis is a major cause of human immunodeficiency virus (HIV)-associated morbidity and mortality in Africa. Improved oral treatment regimens are needed because amphotericin B is neither available nor feasible in many centers. Fluconazole at a dosage of 1200 mg per day is more fungicidal than at a dosage of 800 mg per day, but mortality rates remain unacceptably high. Therefore, we examined the effect of adding oral flucytosine to fluconazole. From 13 February through 2 December 2008, HIV-seropositive, antiretroviral-naive patients experiencing their first episode of cryptococcal meningitis were randomized to receive (1) 14 days of fluconazole (1200 mg per day) alone or (2) in combination with flucytosine (100 mg/kg per day) followed by fluconazole (800 mg per day), with both groups undergoing 10 weeks of follow-up. The primary end point was early fungicidal activity, derived from quantitative cerebrospinal fluid cultures on days 1, 3, 7, and 14. Secondary end points were safety and 2- and 10-week mortality. Forty-one patients were analyzed. Baseline mental status, cryptococcal burden, opening pressure, CD4... cell count, and HIV load were similar between groups. Combination therapy was more fungicidal than fluconazole alone (mean early fungicidal activity ± standard deviation, -0.28 ± 0.17 log colony-forming units [CFU]/mL per day vs -11 ± 0.09 log CFU/mL per day; P < .001). The combination arm had fewer deaths by 2 weeks (10% vs 37%) and 10 weeks (43% vs 58%). More patients had grade III or IV neutropenia with combination therapy (5 vs 1, within the first 2 weeks; P = .20), but there was no increase in infection-related adverse events. The results suggest that optimal oral treatment for cryptococcal meningitis is high-dose fluconazole with flucytosine. Efforts are needed to increase availability of flucytosine in Africa. (ProQuest: ... denotes formulae/symbols omitted.) Background. Cryptococcal meningitis is a major cause of human immunodeficiency virus (HIV)–associated morbidity and mortality in Africa. Improved oral treatment regimens are needed because amphotericin B is neither available nor feasible in many centers. Fluconazole at a dosage of 1200 mg per day is more fungicidal than at a dosage of 800 mg per day, but mortality rates remain unacceptably high. Therefore, we examined the effect of adding oral flucytosine to fluconazole. Methods. From 13 February through 2 December 2008, HIV-seropositive, antiretroviral-naive patients experiencing their first episode of cryptococcal meningitis were randomized to receive (1) 14 days of fluconazole (1200 mg per day) alone or (2) in combination with flucytosine (100 mg/kg per day) followed by fluconazole (800 mg per day), with both groups undergoing 10 weeks of follow-up. The primary end point was early fungicidal activity, derived from quantitative cerebrospinal fluid cultures on days 1, 3, 7, and 14. Secondary end points were safety and 2- and 10-week mortality. Results. Forty-one patients were analyzed. Baseline mental status, cryptococcal burden, opening pressure, CD4+ cell count, and HIV load were similar between groups. Combination therapy was more fungicidal than fluconazole alone (mean early fungicidal activity ± standard deviation, −0.28±0.17 log colony-forming units [CFU]/mL per day vs −0.11±0.09 log CFU/mL per day; P<.001). The combination arm had fewer deaths by 2 weeks (10% vs 37%) and 10 weeks (43% vs 58%). More patients had grade III or IV neutropenia with combination therapy (5 vs 1, within the first 2 weeks; P=.20), but there was no increase in infection-related adverse events. Conclusions. The results suggest that optimal oral treatment for cryptococcal meningitis is high-dose fluconazole with flucytosine. Efforts are needed to increase availability of flucytosine in Africa. Clinical trials registration. isrctn.org Identifier: ISRCTN02725351. |
| Author | Kenala, Jullita Phulusa, Jacob Kamwendo, Deborah Nussbaum, Jesse C. Jaffar, Shabbar Jackson, Arthur Namarika, Dan Kanyemba, Creto Hosseinipour, Mina C. Jarvis, Joseph N. Harrison, Thomas S. van der Horst, Charles M. |
| Author_xml | – sequence: 1 givenname: Jesse C. surname: Nussbaum fullname: Nussbaum, Jesse C. email: jesse.nussbaum@ucsf.edu organization: University of North Carolina (UNC) Project, Malawi – sequence: 2 givenname: Arthur surname: Jackson fullname: Jackson, Arthur organization: University of North Carolina (UNC) Project, Malawi – sequence: 3 givenname: Dan surname: Namarika fullname: Namarika, Dan organization: University of North Carolina (UNC) Project, Malawi – sequence: 4 givenname: Jacob surname: Phulusa fullname: Phulusa, Jacob organization: University of North Carolina (UNC) Project, Malawi – sequence: 5 givenname: Jullita surname: Kenala fullname: Kenala, Jullita organization: University of North Carolina (UNC) Project, Malawi – sequence: 6 givenname: Creto surname: Kanyemba fullname: Kanyemba, Creto organization: University of North Carolina (UNC) Project, Malawi – sequence: 7 givenname: Joseph N. surname: Jarvis fullname: Jarvis, Joseph N. organization: Desmond Tutu HIV Centre, Cape Town, South Africa – sequence: 8 givenname: Shabbar surname: Jaffar fullname: Jaffar, Shabbar organization: Department of Epidemiology and Population, London School of Hygiene and Tropical Medicine, London, England – sequence: 9 givenname: Mina C. surname: Hosseinipour fullname: Hosseinipour, Mina C. organization: University of North Carolina (UNC) Project, Malawi – sequence: 10 givenname: Deborah surname: Kamwendo fullname: Kamwendo, Deborah organization: University of North Carolina (UNC) Project, Malawi – sequence: 11 givenname: Charles M. surname: van der Horst fullname: van der Horst, Charles M. organization: Division of Infectious Diseases, University of North Carolina, Chapel Hill – sequence: 12 givenname: Thomas S. surname: Harrison fullname: Harrison, Thomas S. organization: Department of Cellular and Molecular Medicine, Division of Infectious Diseases, St. George's University of London, London, England |
| BackLink | http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22367988$$DView record in Pascal Francis https://www.ncbi.nlm.nih.gov/pubmed/20038244$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | 2009 Infectious Diseases Society of America 2010 by the Infectious Diseases Society of America 2010 2015 INIST-CNRS Copyright University of Chicago, acting through its Press Feb 1, 2010 |
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| Keywords | Nervous system diseases Mycosis Fluconazole Azole derivatives Fluoropyrimidine derivatives Cryptococcosis Infection Antifungal agent Treatment Central nervous system disease Triazole derivatives Flucytosine Pyrimidine derivatives Meningitis High dose Comparative study |
| Language | English |
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| PublicationTitle | Clinical infectious diseases |
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| Snippet | Background. Cryptococcal meningitis is a major cause of human immunodeficiency virus (HIV)–associated morbidity and mortality in Africa. Improved oral... Background . Cryptococcal meningitis is a major cause of human immunodeficiency virus (HIV)–associated morbidity and mortality in Africa. Improved oral... Cryptococcal meningitis is a major cause of human immunodeficiency virus (HIV)-associated morbidity and mortality in Africa. Improved oral treatment regimens... Background. Cryptococcal meningitis is a major cause of human immunodeficiency virus (HIV)-associated morbidity and mortality in Africa. Improved oral... |
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| SubjectTerms | Administration, Oral Adult Aged AIDS AIDS-Related Opportunistic Infections - drug therapy AIDS-Related Opportunistic Infections - microbiology AIDS-Related Opportunistic Infections - mortality Antibiotics. Antiinfectious agents. Antiparasitic agents Antifungal agents Antifungal Agents - administration & dosage Antifungal Agents - adverse effects Antifungal Agents - therapeutic use ARTICLES AND COMMENTARIES Biological and medical sciences Cells Cerebrospinal fluid Cerebrospinal Fluid - microbiology Comparative analysis Cryptococcal meningitis Cryptococcus Cryptococcus - isolation & purification Dosage Drug Therapy, Combination Effects Female Fluconazole - administration & dosage Fluconazole - adverse effects Fluconazole - therapeutic use Flucytosine - administration & dosage Flucytosine - adverse effects Flucytosine - therapeutic use HIV HIV Infections - complications Human immunodeficiency virus Human mycoses Humans Infections Infectious diseases Malawi Male Medical sciences Medical treatment Meningitis Meningitis, Cryptococcal - drug therapy Meningitis, Cryptococcal - microbiology Meningitis, Cryptococcal - mortality Middle Aged Miscellaneous mycoses Mortality Mycoses Neutropenia Pharmacology. Drug treatments Treatment Outcome Viral meningitis Young Adult |
| Title | Combination Flucytosine and High-Dose Fluconazole Compared with Fluconazole Monotherapy for the Treatment of Cryptococcal Meningitis: A Randomized Trial in Malawi |
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