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Eric Dannaoui - One of the best experts on this subject based on the ideXlab platform.
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In vitro antifungal combination of Flucytosine with amphotericin B, voriconazole, or micafungin against Candida auris shows no antagonism.
Antimicrobial agents and chemotherapy, 2019Co-Authors: A.l. Bidaud, Françoise Botterel, Anuradha Chowdhary, Eric DannaouiAbstract:Candida auris is an emerging, multidrug resistant pathogen, responsible for invasive hospital-acquired infections. Flucytosine is an effective anti-Candida drug, but which cannot be used as a monotherapy because of the risk of development of resistant mutants during treatment. It is therefore noteworthy to test possible combinations with Flucytosine that may have a synergistic interaction. In this study, we determined the in vitro interaction between Flucytosine and amphotericin B, micafungin, or voriconazole. These combinations have been tested against 15 C. auris isolates. The MIC range (Gmean) of Flucytosine, amphotericin B, micafungin and voriconazole were 0.125 to 1 μg/mL (0.42 μg/ml), 0.25 to 1 μg/ml (0.66 μg/ml), 0.125 to 0.5 μg/ml (0.3 μg/ml) and 0.03 to 4 μg/ml (1.05 μg/ml), respectively. When tested in combination, indifferent interactions were mostly observed with fractional inhibitory concentration index values from 0.5 to 1, 0.31 to 1.01 and 0.5 to 1.06 for the combination of Flucytosine with amphotericin B, micafungin and voriconazole, respectively. A synergy was observed for the strain CBS 10913 from Japan. No antagonism was observed for any combination. Combination of Flucytosine with amphotericin B or micafungin may be relevant for the treatment of C. auris infections.
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Combination of Amphotericin B with Flucytosine Is Active In Vitro against Flucytosine-Resistant Isolates of Cryptococcus neoformans
Antimicrobial agents and chemotherapy, 2006Co-Authors: Patrick Schwarz, Françoise Dromer, Olivier Lortholary, Guilhem Janbon, Eric DannaouiAbstract:The combination of Flucytosine and amphotericin B was tested against 10 Flucytosine-resistant isolates of Cryptococcus neoformans by checkerboard, killing curves, and Etest. Although differences were observed depending on the technique used, antagonism was never observed. The synergistic interaction was related to the mechanism of Flucytosine resistance of the isolates.
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Efficacy of Amphotericin B in Combination with Flucytosine against Flucytosine-Susceptible or Flucytosine-Resistant Isolates of Cryptococcus neoformans during Disseminated Murine Cryptococcosis
Antimicrobial agents and chemotherapy, 2006Co-Authors: Patrick Schwarz, Françoise Dromer, Olivier Lortholary, Eric DannaouiAbstract:Whether or not Flucytosine should be administered to patients infected with Cryptococcus neoformans isolates found to be resistant to Flucytosine in vitro remains a controversial issue. Thus, the efficacy of amphotericin B and Flucytosine in combination was investigated by mortality and fungal burden studies in a murine model of disseminated cryptococcosis using two clinical isolates of Cryptococcus neoformans, one susceptible and one resistant (i.e., 64 μg/ml) to Flucytosine. Amphotericin B was given intraperitoneally at 0.25 or 0.5 mg/kg/day, while Flucytosine was given at 100 or 250 mg/kg/day orally. Treatment was started 24 h or day 6 after inoculation and continued for 5 days in fungal burden and mortality studies, respectively. The combination of amphotericin B at 0.5 mg/kg/day and Flucytosine at 250 mg/kg/day was significantly more effective than monotherapies for reducing fungal burden in brain, spleen, and lungs after infection by the Flucytosine-susceptible isolate and in brain and spleen for the Flucytosine-resistant isolate. For the Flucytosine-resistant isolate, the combination of amphotericin B at 0.5 mg/kg/day with Flucytosine at 100 mg/kg/day was significantly better than monotherapies for reducing the fungal burden in the brain. Survival obtained after the combination of amphotericin B at 0.5 mg/kg/day and Flucytosine at 250 mg/kg/day increased compared to that obtained with monotherapies for both isolates, but the difference was statistically significant only for the Flucytosine-susceptible isolate. Antagonism was never observed. This study demonstrates the beneficial effect of the addition of Flucytosine to amphotericin B against experimental disseminated cryptococcal infection even when the C. neoformans isolate is resistant to Flucytosine.
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In Vitro Interaction of Flucytosine with Conventional and New Antifungals against Cryptococcus neoformans Clinical Isolates
Antimicrobial agents and chemotherapy, 2003Co-Authors: Patrick Schwarz, Françoise Dromer, Olivier Lortholary, Eric DannaouiAbstract:Combinations of Flucytosine with conventional and new antifungals were evaluated in vitro against 30 clinical isolates of Cryptococcus neoformans. Synergy determined by checkerboard analysis was observed with combinations of fluconazole, itraconazole, voriconazole, amphotericin B, and caspofungin with Flucytosine against 77, 60, 80, 77, and 67% of the isolates, respectively. Antagonism was never observed. Killing curves showed indifferent interactions between triazoles and Flucytosine and synergy between amphotericin B and Flucytosine.
Françoise Dromer - One of the best experts on this subject based on the ideXlab platform.
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Flucytosine and cryptococcosis: time to urgently address the worldwide accessibility of a 50-year-old antifungal
The Journal of antimicrobial chemotherapy, 2013Co-Authors: Angela Loyse, Olivier Lortholary, Françoise Dromer, Jeremy N. Day, Thomas S. HarrisonAbstract:Current, widely accepted guidelines for the management of HIV-associated cryptococcal meningoencephalitis (CM) recommend amphotericin B combined with Flucytosine (5-FC) for ≥2 weeks as the initial induction treatment of choice. However, access to Flucytosine in Africa and Asia, where disease burden is greatest, is inadequate at present. While research into identifying effective and well-tolerated antifungal combinations that do not contain Flucytosine continues, an ever-increasing body of evidence from in vitro, in vivo and clinical studies points to the benefits of Flucytosine in the treatment of CM in both intravenous combinations with amphotericin B and oral combinations with high-dose fluconazole. This article provides an up-to-date review of this evidence, and the current issues and challenges regarding increasing access to this key component of combination antifungal therapy for cryptococcosis.
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Clonal Population of Flucytosine- Resistant Candida tropicalis from Blood Cultures, Paris, France
Emerging infectious diseases, 2008Co-Authors: Marie Desnos-ollivier, Stéphane Bretagne, Claire Bernède, Vincent Robert, Dorothée Raoux, Elisabeth Chachaty, Elisabeth Forget, Claire Lacroix, Françoise DromerAbstract:Candida tropicalis is a diploid ascomycetes yeast responsible for 4%-24% of candidemia. Resistance to Flucytosine is rarely described for this species but was observed for 45 (35%) of 130 C. tropicalis isolates recovered from blood cultures in the Paris area in a 4-year survey. The aims of this study were to test the hypothesis that the Flucytosine-resistant isolates could represent a subgroup and to determine the relationship between epidemiologic and genomic data. Epidemiologic data and gene sequences were analyzed, and molecular typing was performed. Our results suggest that a clone of Flucytosine-resistant isolates, associated with malignancies and a lower mortality than that for other C. tropicalis isolates, is widespread in the Paris area. We propose the analysis of 2 polymorphic microsatellite markers coupled with URA3 sequencing to track the clone.
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Combination of Amphotericin B with Flucytosine Is Active In Vitro against Flucytosine-Resistant Isolates of Cryptococcus neoformans
Antimicrobial agents and chemotherapy, 2006Co-Authors: Patrick Schwarz, Françoise Dromer, Olivier Lortholary, Guilhem Janbon, Eric DannaouiAbstract:The combination of Flucytosine and amphotericin B was tested against 10 Flucytosine-resistant isolates of Cryptococcus neoformans by checkerboard, killing curves, and Etest. Although differences were observed depending on the technique used, antagonism was never observed. The synergistic interaction was related to the mechanism of Flucytosine resistance of the isolates.
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Efficacy of Amphotericin B in Combination with Flucytosine against Flucytosine-Susceptible or Flucytosine-Resistant Isolates of Cryptococcus neoformans during Disseminated Murine Cryptococcosis
Antimicrobial agents and chemotherapy, 2006Co-Authors: Patrick Schwarz, Françoise Dromer, Olivier Lortholary, Eric DannaouiAbstract:Whether or not Flucytosine should be administered to patients infected with Cryptococcus neoformans isolates found to be resistant to Flucytosine in vitro remains a controversial issue. Thus, the efficacy of amphotericin B and Flucytosine in combination was investigated by mortality and fungal burden studies in a murine model of disseminated cryptococcosis using two clinical isolates of Cryptococcus neoformans, one susceptible and one resistant (i.e., 64 μg/ml) to Flucytosine. Amphotericin B was given intraperitoneally at 0.25 or 0.5 mg/kg/day, while Flucytosine was given at 100 or 250 mg/kg/day orally. Treatment was started 24 h or day 6 after inoculation and continued for 5 days in fungal burden and mortality studies, respectively. The combination of amphotericin B at 0.5 mg/kg/day and Flucytosine at 250 mg/kg/day was significantly more effective than monotherapies for reducing fungal burden in brain, spleen, and lungs after infection by the Flucytosine-susceptible isolate and in brain and spleen for the Flucytosine-resistant isolate. For the Flucytosine-resistant isolate, the combination of amphotericin B at 0.5 mg/kg/day with Flucytosine at 100 mg/kg/day was significantly better than monotherapies for reducing the fungal burden in the brain. Survival obtained after the combination of amphotericin B at 0.5 mg/kg/day and Flucytosine at 250 mg/kg/day increased compared to that obtained with monotherapies for both isolates, but the difference was statistically significant only for the Flucytosine-susceptible isolate. Antagonism was never observed. This study demonstrates the beneficial effect of the addition of Flucytosine to amphotericin B against experimental disseminated cryptococcal infection even when the C. neoformans isolate is resistant to Flucytosine.
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In Vitro Interaction of Flucytosine with Conventional and New Antifungals against Cryptococcus neoformans Clinical Isolates
Antimicrobial agents and chemotherapy, 2003Co-Authors: Patrick Schwarz, Françoise Dromer, Olivier Lortholary, Eric DannaouiAbstract:Combinations of Flucytosine with conventional and new antifungals were evaluated in vitro against 30 clinical isolates of Cryptococcus neoformans. Synergy determined by checkerboard analysis was observed with combinations of fluconazole, itraconazole, voriconazole, amphotericin B, and caspofungin with Flucytosine against 77, 60, 80, 77, and 67% of the isolates, respectively. Antagonism was never observed. Killing curves showed indifferent interactions between triazoles and Flucytosine and synergy between amphotericin B and Flucytosine.
Olivier Lortholary - One of the best experts on this subject based on the ideXlab platform.
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Acquired Flucytosine Resistance during Combination Therapy with Caspofungin and Flucytosine for Candida glabrata Cystitis
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Caroline Charlier, Olivier Lortholary, Carine El Sissy, Sophie Bachelier-bassi, Anne Scemla, Gilles Quesne, Emilie Sitterlé, Christophe Legendre, Marie-elisabeth BougnouxAbstract:Treatment of Candida glabrata cystitis remains a therapeutic challenge, and an antifungal combination using Flucytosine is one option. We describe two patients with refractory C. glabrata cystitis who failed Flucytosine combined with caspofungin with early-acquired high-level resistance to Flucytosine due to nonsense mutations in the FUR1 gene. Rapidly acquired Flucytosine resistance with microbiological failure should discourage combination of caspofungin and Flucytosine during urinary candidiasis.
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Flucytosine and cryptococcosis: time to urgently address the worldwide accessibility of a 50-year-old antifungal
The Journal of antimicrobial chemotherapy, 2013Co-Authors: Angela Loyse, Olivier Lortholary, Françoise Dromer, Jeremy N. Day, Thomas S. HarrisonAbstract:Current, widely accepted guidelines for the management of HIV-associated cryptococcal meningoencephalitis (CM) recommend amphotericin B combined with Flucytosine (5-FC) for ≥2 weeks as the initial induction treatment of choice. However, access to Flucytosine in Africa and Asia, where disease burden is greatest, is inadequate at present. While research into identifying effective and well-tolerated antifungal combinations that do not contain Flucytosine continues, an ever-increasing body of evidence from in vitro, in vivo and clinical studies points to the benefits of Flucytosine in the treatment of CM in both intravenous combinations with amphotericin B and oral combinations with high-dose fluconazole. This article provides an up-to-date review of this evidence, and the current issues and challenges regarding increasing access to this key component of combination antifungal therapy for cryptococcosis.
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Combination of Amphotericin B with Flucytosine Is Active In Vitro against Flucytosine-Resistant Isolates of Cryptococcus neoformans
Antimicrobial agents and chemotherapy, 2006Co-Authors: Patrick Schwarz, Françoise Dromer, Olivier Lortholary, Guilhem Janbon, Eric DannaouiAbstract:The combination of Flucytosine and amphotericin B was tested against 10 Flucytosine-resistant isolates of Cryptococcus neoformans by checkerboard, killing curves, and Etest. Although differences were observed depending on the technique used, antagonism was never observed. The synergistic interaction was related to the mechanism of Flucytosine resistance of the isolates.
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Efficacy of Amphotericin B in Combination with Flucytosine against Flucytosine-Susceptible or Flucytosine-Resistant Isolates of Cryptococcus neoformans during Disseminated Murine Cryptococcosis
Antimicrobial agents and chemotherapy, 2006Co-Authors: Patrick Schwarz, Françoise Dromer, Olivier Lortholary, Eric DannaouiAbstract:Whether or not Flucytosine should be administered to patients infected with Cryptococcus neoformans isolates found to be resistant to Flucytosine in vitro remains a controversial issue. Thus, the efficacy of amphotericin B and Flucytosine in combination was investigated by mortality and fungal burden studies in a murine model of disseminated cryptococcosis using two clinical isolates of Cryptococcus neoformans, one susceptible and one resistant (i.e., 64 μg/ml) to Flucytosine. Amphotericin B was given intraperitoneally at 0.25 or 0.5 mg/kg/day, while Flucytosine was given at 100 or 250 mg/kg/day orally. Treatment was started 24 h or day 6 after inoculation and continued for 5 days in fungal burden and mortality studies, respectively. The combination of amphotericin B at 0.5 mg/kg/day and Flucytosine at 250 mg/kg/day was significantly more effective than monotherapies for reducing fungal burden in brain, spleen, and lungs after infection by the Flucytosine-susceptible isolate and in brain and spleen for the Flucytosine-resistant isolate. For the Flucytosine-resistant isolate, the combination of amphotericin B at 0.5 mg/kg/day with Flucytosine at 100 mg/kg/day was significantly better than monotherapies for reducing the fungal burden in the brain. Survival obtained after the combination of amphotericin B at 0.5 mg/kg/day and Flucytosine at 250 mg/kg/day increased compared to that obtained with monotherapies for both isolates, but the difference was statistically significant only for the Flucytosine-susceptible isolate. Antagonism was never observed. This study demonstrates the beneficial effect of the addition of Flucytosine to amphotericin B against experimental disseminated cryptococcal infection even when the C. neoformans isolate is resistant to Flucytosine.
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In Vitro Interaction of Flucytosine with Conventional and New Antifungals against Cryptococcus neoformans Clinical Isolates
Antimicrobial agents and chemotherapy, 2003Co-Authors: Patrick Schwarz, Françoise Dromer, Olivier Lortholary, Eric DannaouiAbstract:Combinations of Flucytosine with conventional and new antifungals were evaluated in vitro against 30 clinical isolates of Cryptococcus neoformans. Synergy determined by checkerboard analysis was observed with combinations of fluconazole, itraconazole, voriconazole, amphotericin B, and caspofungin with Flucytosine against 77, 60, 80, 77, and 67% of the isolates, respectively. Antagonism was never observed. Killing curves showed indifferent interactions between triazoles and Flucytosine and synergy between amphotericin B and Flucytosine.
David W. Denning - One of the best experts on this subject based on the ideXlab platform.
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Flucytosine therapeutic monitoring: 15 years experience from the UK
The Journal of antimicrobial chemotherapy, 2007Co-Authors: Alessandro C. Pasqualotto, Susan J. Howard, Caroline B. Moore, David W. DenningAbstract:BACKGROUND: There is uniform consensus that Flucytosine blood concentrations should be measured to avoid toxicity and ensure adequate efficacy. OBJECTIVES AND METHODS: The purpose of this study was to evaluate all Flucytosine levels performed in a regional centre in the UK from October 1991 to May 2006. Concentrations were measured by bioassay. RESULTS: We reviewed 1071 Flucytosine levels in 233 patients, including 33 neonates. Overall, only 20.5% of levels were in the expected therapeutic range. Low levels were observed in 40.5%, of which 5.1% were undetectable levels ( 100 mg/L). High Flucytosine levels occurred more frequently amongst neonates, which could be related to an immature renal system resulting in drug accumulation. CONCLUSIONS: Our findings reveal that the vast majority of patients were out of range for Flucytosine levels. These data emphasize the importance of monitoring Flucytosine levels.
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high prevalence of antifungal resistance in candida spp from patients with aids
Journal of Antimicrobial Chemotherapy, 1994Co-Authors: Caroline B. Moore, H M Wardle, L A Ganguli, M Keaney, David W. DenningAbstract:: Three hundred and forty-eight isolates of Candida spp. from patients treated at a regional infectious diseases unit for AIDS, immunocompromised patients admitted to the Hope Hospital and isolates referred from around the North West of England were tested for their in-vitro susceptibility to amphotericin B, fluconazole and Flucytosine using standardized methods. Candida albicans comprised 73% of isolates, Candida glabrata 10% and Candida parapsilosis 7%. Ninety-six percent of isolates were susceptible to amphotericin B and resistance to > or = 12.5 mg/L fluconazole was found in 61 (17.5%) of the 348 isolates tested. Among isolates from patients with AIDS the incidence of fluconazole resistance was 33% whereas in other patients the incidence was only 11%. Flucytosine resistance was seen in only 12 (3.4%) isolates, 11 of which were C. albicans and in 6.5% of isolates from patients with AIDS. Resistance to fluconazole and Flucytosine is now sufficiently prevalent among Candida spp. isolated from patients with AIDS to warrant routine susceptibility testing of yeast isolates.
Thomas S. Harrison - One of the best experts on this subject based on the ideXlab platform.
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Flucytosine and cryptococcosis: time to urgently address the worldwide accessibility of a 50-year-old antifungal
The Journal of antimicrobial chemotherapy, 2013Co-Authors: Angela Loyse, Olivier Lortholary, Françoise Dromer, Jeremy N. Day, Thomas S. HarrisonAbstract:Current, widely accepted guidelines for the management of HIV-associated cryptococcal meningoencephalitis (CM) recommend amphotericin B combined with Flucytosine (5-FC) for ≥2 weeks as the initial induction treatment of choice. However, access to Flucytosine in Africa and Asia, where disease burden is greatest, is inadequate at present. While research into identifying effective and well-tolerated antifungal combinations that do not contain Flucytosine continues, an ever-increasing body of evidence from in vitro, in vivo and clinical studies points to the benefits of Flucytosine in the treatment of CM in both intravenous combinations with amphotericin B and oral combinations with high-dose fluconazole. This article provides an up-to-date review of this evidence, and the current issues and challenges regarding increasing access to this key component of combination antifungal therapy for cryptococcosis.
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Pharmacodynamics of Liposomal Amphotericin B and Flucytosine for Cryptococcal Meningoencephalitis: Safe and Effective Regimens for Immunocompromised Patients
The Journal of infectious diseases, 2013Co-Authors: Lucy O'connor, Susan J. Howard, Joanne Livermore, Andrew Sharp, Joanne Goodwin, Lea Gregson, Timothy Felton, Julie Schwartz, Michael Neely, Thomas S. HarrisonAbstract:Background. Cryptococcal meningoencephalitis is a lethal infection with relatively few therapeutic options. The optimal dosage of liposomal amphotericin B (LAmB) alone or in combination with Flucytosine is not known. Methods. A murine model of cryptococcal meningoencephalitis was used. The fungal density in the brain was determined using quantitative cultures. Pharmacokinetic–pharmacodynamic relationships were determined for LAmB and Flucytosine administered alone. The effect of the combination was described using the Greco model and a mathematical model. The results were bridged to humans. Results. Inoculation resulted in hematogenous dissemination and logarithmic growth within the central nervous system. There was histological evidence of multifocal infection throughout the brain. Both LAmB and Flucytosine produced a dose-dependent reduction in fungal burden. The effect of the combination of agents in the brain was additive. Bridging studies suggested that a human dosage of LAmB 3 mg/kg/d resulted in a submaximal antifungal effect. Regimens of LAmB 6 mg/kg/d alone, LAmB 3 mg/kg/d plus fl ucytosine 50 mg/kg/d, and LAmB 3m g/kg/d plus Flucytosine 100 mg/kg/d all resulted in near-maximal antifungal activity. Conclusions. Potential regimens for further study in clinical trials include LAmB 6 mg/kg/d alone, LAmB 3 mg/kg/d plus Flucytosine 50 mg/kg/d, and LAmB 3 mg/kg/d plus Flucytosine 100 mg/kg/d.
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Oral versus Intravenous Flucytosine in Patients with Human Immunodeficiency Virus-Associated Cryptococcal Meningitis
Antimicrobial agents and chemotherapy, 2006Co-Authors: Annemarie E Brouwer, Adul Rajanuwong, Wirongrong Chierakul, Hendrikus J. M. Van Kan, Elizabeth M. Johnson, Prapit Teparrukkul, V. Wuthiekanun, Nicholas P. J. Day, Thomas S. HarrisonAbstract:In a randomized controlled trial of amphotericin B-based therapy for human immunodeficiency virus (HIV)-associated cryptococcal meningitis in Thailand, we also compared the mycological efficacy, toxicity, and pharmacokinetics of oral versus intravenous Flucytosine at 100 mg/kg of body weight/day for the initial 2 weeks. Half of 32 patients assigned to the two arms containing Flucytosine were randomized to oral and half to intravenous Flucytosine. Early fungicidal activity was determined from serial quantitative cultures of cerebrospinal fluid (CSF), and toxicity was assessed by clinical and laboratory monitoring. Flucytosine and fluorouracil concentrations in plasma and CSF were measured by high-performance liquid chromatography. No significant bone marrow or hepatotoxicity was seen, there was no detectable difference in bone marrow toxicity between patients on intravenous and those on oral formulation, and no patients discontinued treatment. In patients receiving intravenous Flucytosine, the median 24-h area under the concentration-time curve was significantly higher than in the oral group. Despite this difference, there was no difference in early fungicidal activity between patients on intravenous compared with patients on oral Flucytosine. The results suggest that either formulation can be used safely at this dosage in a developing country setting, without drug concentration monitoring. The bioavailability of the oral formulation may be reduced in late-stage HIV-infected patients in Thailand. Concentrations of Flucytosine with intravenous formulation at 100 mg/kg/day may be in excess of those required for maximal fungicidal activity.
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combination antifungal therapies for hiv associated cryptococcal meningitis a randomised trial
The Lancet, 2004Co-Authors: Annemarie E Brouwer, Adul Rajanuwong, G E Griffin, Wirongrong Chierakul, Robert A Larsen, Thomas S. HarrisonAbstract:Summary Background It frequently takes more than 2 weeks for drug treatments for cryptococcal meningitis to sterilise cerebrospinal fluid (CSF). In-vitro and animal studies lend support to the use of combinations of amphotericin B, Flucytosine, and fluconazole for treatment of cryptococcosis. We compared the fungicidal activity of combinations of these drugs for initial treatment of patients with cryptococcal meningitis. Methods 64 patients with a first episode of HIV-associated cryptococcal meningitis were randomised to initial treatment with: amphotericin B (0·7 mg/kg daily); amphotericin B plus Flucytosine (100 mg/kg daily); amphotericin B plus fluconazole (400 mg daily); or triple therapy with amphotericin B, Flucytosine, and fluconazole. Our primary endpoint was fungicidal activity, measured by the rate of reduction in CSF cryptococcal colony-forming units (CFU) from serial quantitative CSF cultures on days 3, 7, and 14 of treatment. Findings Baseline CSF CFU counts were an important prognostic factor. Clearance of cryptococci from the CSF was exponential and was significantly faster with amphotericin B plus Flucytosine than with amphotericin B alone (p=0·0006), amphotericin B plus fluconazole ( p=0·02), or triple therapy (p=0·02).