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Raleigh A Bowden - One of the best experts on this subject based on the ideXlab platform.
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candidemia in allogeneic blood and marrow transplant recipients evolution of risk factors after the adoption of prophylactic Fluconazole
The Journal of Infectious Diseases, 2000Co-Authors: Raleigh A Bowden, Kieren A Marr, Kristy Seidel, Theodore C WhiteAbstract:: The prophylactic use of Fluconazole is common in blood and marrow transplant (BMT) recipients. To evaluate how Fluconazole has influenced the development of azole resistance and candidemia, weekly mouthwashings were done, and Fluconazole susceptibility was determined for 1475 colonizing and invasive isolates obtained from patients undergoing BMT. Of 585 patients, 256 (44%) were colonized with Candida species during the course of BMT. Of these, 136 patients (53%) had at least 1 mouthwashing sample that yielded Candida species other than C. albicans on culture. Only 4.6% of patients developed candidemia. Overall, C. albicans was the most common colonizing isolate, but it caused only 7% of cases of candidemia. About 5% of colonizing C. albicans strains and 100% (2 of 2) invasive C. albicans strains were Fluconazole-resistant. Colonization, cytomegalovirus disease, and bacteremia are risk factors for the development of candidemia. The use of prophylactic Fluconazole is associated with a low incidence of candidemia and attributable mortality, despite colonization with azole-resistant Candida species in BMT recipients.
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the effect of prophylactic Fluconazole on the clinical spectrum of fungal diseases in bone marrow transplant recipients with special attention to hepatic candidiasis an autopsy study of 355 patients
Medicine, 1998Co-Authors: Jo Anne Van Burik, Raleigh A Bowden, Wendy Leisenring, David Myerson, Robert C Hackman, Howard M Shulman, George E Sale, George B McdonaldAbstract:: We reviewed 355 autopsies performed between 1990 and 1994 at a major marrow transplant center to determine whether Fluconazole prophylaxis prevented visceral fungal infection. Fluconazole prophylaxis was defined by a minimum of 5 prophylactic doses. Fungal infection (any site) was found in 40% of patients transplanted and autopsied at the center. Overall, the proportion of autopsies with any fungal infection was not different for those patients receiving no Fluconazole prophylaxis versus those with prophylactic Fluconazole. With Fluconazole prophylaxis, candidal infections were less frequent, decreasing from 27% to 8%, while Aspergillus infections were more frequent, increasing from 18% to 29%. No increase in deaths related to non-albicans Candida infections was seen. Of the 329 patients with livers examined, hepatic infection caused by Candida species was significantly less common in patients who had received Fluconazole. Fungal liver infection was found in 31 patients (9%), 16% of those who were not treated with Fluconazole and 3% of those who were treated with Fluconazole. Since patients with candidal infections died earlier after marrow transplant than patients with mold infections, we speculate that a longer length of survival may dispose toward acquisition of mold infections. Fluconazole prophylaxis in this cohort of marrow transplant patients undergoing autopsy resulted in a significant reduction in infection caused by Candida species and an increase in mold infections.
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efficacy and safety of Fluconazole prophylaxis for fungal infections after marrow transplantation a prospective randomized double blind study
The Journal of Infectious Diseases, 1995Co-Authors: Monica A Slavin, Barbara A Osborne, Roger Adams, M J Levenstein, H G Schoch, A R Feldman, Joel D Meyers, Raleigh A BowdenAbstract:: A randomized, double-blind, placebo-controlled trial assessed the efficacy and toxicity of 400 mg/day Fluconazole in preventing fungal infections during the first 75 days after marrow transplantation. During prophylaxis, systemic fungal infections occurred in 10 (7%) of 152 Fluconazole-treated patients compared with 26 (18%) of 148 placebo-treated patients (P = .004). There were no Candida albicans infections in Fluconazole recipients compared with 18 in placebo recipients (P < .001) and no significant increase in Candida infections other than C. albicans. Fluconazole also significantly reduced the incidence of superficial fungal infections (P < .001), fungal colonization (P = .037), and empiric amphotericin B use (P = .005). The probability of survival was improved in Fluconazole recipients, in whom 31 deaths occurred up to day 110 after transplantation compared with 52 deaths in placebo recipients (P = .004). No clinically significant toxicity was detected with Fluconazole use. Prophylactic Fluconazole was safe and significantly reduced systemic fungal infections with other benefits, including improved survival at day 110 after marrow transplantation.
Markus Ruhnke - One of the best experts on this subject based on the ideXlab platform.
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voriconazole versus a regimen of amphotericin b followed by Fluconazole for candidaemia in non neutropenic patients a randomised non inferiority trial
The Lancet, 2005Co-Authors: B J Kullberg, Jack D. Sobel, Markus Ruhnke, Peter G Pappas, Claudio Viscoli, John D Cleary, E Rubinstein, L W P Church, J M Brown, Haran T SchlammAbstract:BACKGROUND: Voriconazole has proven efficacy against invasive aspergillosis and oesophageal candidiasis. This multicentre, randomised, non-inferiority study compared voriconazole with a regimen of amphotericin B followed by Fluconazole for the treatment of candidaemia in non-neutropenic patients. METHODS: Non-neutropenic patients with a positive blood culture for a species of candida and clinical evidence of infection were enrolled. Patients were randomly assigned, in a 2:1 ratio, either voriconazole (n=283) or amphotericin B followed by Fluconazole (n=139). The primary efficacy analysis was based on clinical and mycological response 12 weeks after the end of treatment, assessed by an independent data-review committee unaware of treatment assignment. FINDINGS: Of 422 patients randomised, 370 were included in the modified intention-to-treat population. Voriconazole was non-inferior to amphotericin B/Fluconazole in the primary efficacy analysis, with successful outcomes in 41% of patients in both treatment groups (95% CI for difference -10.6% to 10.6%). At the last evaluable assessment, outcome was successful in 162 (65%) patients assigned voriconazole and 87 (71%) assigned amphotericin B/Fluconazole (p=0.25). Voriconazole cleared blood cultures as quickly as amphotericin B/Fluconazole (median time to negative blood culture, 2.0 days). Treatment discontinuations due to all-cause adverse events were more frequent in the voriconazole group, although most discontinuations were due to non-drug-related events and there were significantly fewer serious adverse events and cases of renal toxicity than in the amphotericin B/Fluconazole group. INTERPRETATION: Voriconazole was as effective as the regimen of amphotericin B followed by Fluconazole in the treatment of candidaemia in non-neutropenic patients, and with fewer toxic effects. RELEVANCE TO PRACTICE: There are several options for treatment of candidaemia in non-neutropenic patients, including amphotericin B, Fluconazole, voriconazole, and echinocandins. Voriconazole can be given both as initial intravenous treatment and as an oral stepdown agent.
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multiple molecular mechanisms contribute to a stepwise development of Fluconazole resistance in clinical candida albicans strains
Antimicrobial Agents and Chemotherapy, 1998Co-Authors: Renate Franz, Steven L Kelly, David C Lamb, Diane E Kelly, Markus Ruhnke, Joachim MorschhauserAbstract:Candida albicans is an important opportunistic fungal pathogen of humans and the major cause of oropharyngeal candidiasis (OPC) in AIDS patients (24). The azole antifungal agent Fluconazole is used widely to treat OPC. In recent years, however, there have been numerous reports of treatment failures in patients receiving prolonged Fluconazole therapy, and these treatment failures have been demonstrated to be due to the emergence of Fluconazole-resistant C. albicans strains (5, 26). Different mechanisms may be responsible for drug resistance. Changes in the level of the drug target enzyme, sterol 14α-demethylase, as a consequence of enhanced transcription or amplification of the ERG11 gene (previously termed ERG16), may lead to reduced susceptibility of yeasts to Fluconazole (35, 37) although gene dosage effects are limited (9). Mutations in this gene which lower the affinity of the enzyme for the drug have also been detected (15, 38). Central to the mode of action of azole antifungals against C. albicans is the accumulation of 14α-methylergosta-8,24(28)-dien-3β,6α-diol during treatment, and defects in sterol C5-desaturation prevent the diol from accumulating and also cause resistance in the clinic in isolates from AIDS patients (10–12). Another common resistance mechanism in C. albicans which has been described by several authors is enhanced expression of certain multiple drug resistance proteins, leading to increased Fluconazole efflux out of the cell. In some cases, reduced accumulation of drug in cells appears to account for resistance without changes in sterol 14α-demethylase or sterol C5-desaturase (36). The highly homologous CDR1 and CDR2 genes encode proteins which belong to the superfamily of ATP-binding cassette transporters (25, 31), and the MDR1 gene (previously termed BENr) encodes a protein from the major facilitator superfamily (3). These efflux pumps have been implicated in Fluconazole resistance in C. albicans because some Fluconazole-resistant C. albicans isolates which accumulated less intracellular Fluconazole exhibited increased mRNA levels of the corresponding genes compared to Fluconazole-susceptible isolates (1, 29, 31, 37). When expressed in Fluconazole-hypersusceptible Saccharomyces cerevisiae mutants lacking specific multidrug transporters, CDR1, CDR2, and MDR1 conferred Fluconazole resistance upon transformants (25, 29, 31). In addition, disruption of CDR1 and CDR2 in C. albicans resulted in enhanced susceptibility to the drug (30, 31). In order to determine which of the described mechanisms commonly lead to Fluconazole resistance in clinical C. albicans strains, we undertook a molecular analysis of serial C. albicans isolates from different episodes of OPC in AIDS patients who, after successful treatment of the initial episodes, failed to respond to Fluconazole therapy. This report presents a complete characterization, encompassing all the known Fluconazole resistance mechanisms, for two series of matched isolates which exhibit gradually increasing resistance in vitro and which were obtained from infections resistant to Fluconazole therapy in the patient.
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in vitro activities of voriconazole uk 109 496 against Fluconazole susceptible and resistant candida albicans isolates from oral cavities of patients with human immunodeficiency virus infection
Antimicrobial Agents and Chemotherapy, 1997Co-Authors: Markus Ruhnke, Andrea Maria Schmidtwesthausen, M TrautmannAbstract:The susceptibility of Candida albicans to a new antifungal triazole, voriconazole (UK-109,496), was investigated in 105 isolates obtained from the oral cavities of patients with human immunodeficiency virus (HIV) infection to study this drug's activity against Fluconazole-susceptible and -resistant isolates. MICs were determined by a broth microdilution technique according to document M27-T from the National Committee for Clinical Laboratory Standards and by using a broth microdilution technique and a synthetic high-resolution medium. These antifungal susceptibility testing methods showed high levels of agreement (93% for Fluconazole and 86% for voriconazole). Data from in vitro studies showed that voriconazole has good activity against Fluconazole-susceptible and -resistant C. albicans isolates; the MICs at which 90% of all isolates were inhibited were 0.19 to 0.39 microgram/ml. We found that for isolates for which Fluconazole MICs were high, voriconazole MICs were proportionally higher than those for Fluconazole-susceptible C.albicans (P < 0.001). Pretreatment isolates from six patients with Fluconazole-refractory esophageal candidiasis were included in the study. For these isolates the MICs were < or = 0.39 microgram/ml, and all patients responded to voriconazole. These results suggest that voriconazole is effective even in the treatment of Fluconazole-refractory esophageal candidiasis and should be studied further to determine its clinical relevance in patients with HIV infection.
Kieren A Marr - One of the best experts on this subject based on the ideXlab platform.
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mechanism of increased Fluconazole resistance in candida glabrata during prophylaxis
Antimicrobial Agents and Chemotherapy, 2004Co-Authors: John E Bennett, Koichi Izumikawa, Kieren A MarrAbstract:Candida glabrata can become resistant to Fluconazole, causing persistent colonization and invasive infection during prolonged exposure to the drug. To determine the mechanism of resistance in this setting, weekly oropharyngeal cultures for C. glabrata were obtained over a 2-year period from hematopoietic stem cell transplant recipients who were receiving Fluconazole prophylaxis. In 20 patients from whom at least two isolates of the same karyotype were obtained more than two weeks apart, Fluconazole MICs doubled every 31 days on average. The mechanism of Fluconazole resistance in isolates from the 14 of the 20 patients studied in whom MICs changed at least fourfold was studied. Cellular resistance was accompanied by increased drug efflux as measured by decreased accumulation of Fluconazole and rhodamine 6G and increased abundance of transcripts from two drug transporters, CgCDR1 and PDH1. The rapidity and regularity of the rising resistance indicated that C. glabrata is able to upregulate drug efflux without losing the ability to maintain colonization.
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candidemia in allogeneic blood and marrow transplant recipients evolution of risk factors after the adoption of prophylactic Fluconazole
The Journal of Infectious Diseases, 2000Co-Authors: Raleigh A Bowden, Kieren A Marr, Kristy Seidel, Theodore C WhiteAbstract:: The prophylactic use of Fluconazole is common in blood and marrow transplant (BMT) recipients. To evaluate how Fluconazole has influenced the development of azole resistance and candidemia, weekly mouthwashings were done, and Fluconazole susceptibility was determined for 1475 colonizing and invasive isolates obtained from patients undergoing BMT. Of 585 patients, 256 (44%) were colonized with Candida species during the course of BMT. Of these, 136 patients (53%) had at least 1 mouthwashing sample that yielded Candida species other than C. albicans on culture. Only 4.6% of patients developed candidemia. Overall, C. albicans was the most common colonizing isolate, but it caused only 7% of cases of candidemia. About 5% of colonizing C. albicans strains and 100% (2 of 2) invasive C. albicans strains were Fluconazole-resistant. Colonization, cytomegalovirus disease, and bacteremia are risk factors for the development of candidemia. The use of prophylactic Fluconazole is associated with a low incidence of candidemia and attributable mortality, despite colonization with azole-resistant Candida species in BMT recipients.
Drew J Winston - One of the best experts on this subject based on the ideXlab platform.
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a multicenter randomized trial of Fluconazole versus amphotericin b for empiric antifungal therapy of febrile neutropenic patients with cancer
The American Journal of Medicine, 2000Co-Authors: Drew J Winston, James W Hathorn, Mindy G Schuster, Gary J Schiller, Mary C TerritoAbstract:Abstract purpose: To compare the efficacy and safety of Fluconazole and amphotericin B as empiric antifungal therapy of febrile neutropenic patients with cancer. patients and methods: A total of 317 neutropenic patients ( 3 ) with persistent or recrudescent fever despite 4 or more days of antibacterial therapy were randomly assigned to receive either Fluconazole (400 mg intravenously once daily) or amphotericin B (0.5 mg/kg once daily). Patients were evaluated for the efficacy and safety of each drug by clinical criteria, frequent cultures and radiological procedures, and laboratory values. A response was classified as satisfactory at the end of therapy if the patient was afebrile, had no clinical or microbiological evidence of fungal infection, and did not require study termination due to lack of efficacy, drug toxicity, or death. results: A satisfactory response occurred in 68% of the patients treated with Fluconazole (107 of 158 patients) and in 67% of patients treated with amphotericin B (106 of 159 patients). Progressive or new fungal infections during therapy occurred in 13 (8%) patients treated with Fluconazole (8 with Candida , 5 with Aspergillus ) and in 10 (6%) patients treated with amphotericin B (5 with Candida , 3 with Aspergillus , 2 with other fungi). Adverse events related to study drug (especially fever, chills, renal insufficiency, electrolyte disturbances, and respiratory distress) occurred more often in patients treated with amphotericin B (128 [81%] of 159 patients) than patients treated with Fluconazole (20 [13%] of 158 patients, P = 0.001). Eleven (7%) patients treated with amphotericin B but only 1 (1%) patient treated with Fluconazole were terminated from the study owing to an adverse event ( P = 0.005). Overall mortality (27 [17%] patients treated with Fluconazole versus 34 [21%] patients treated with amphotericin B) and mortality from fungal infection (7 [4%] patients treated with Fluconazole versus 5 [3%] patients treated with amphotericin B) were similar in each study group. conclusions: Intravenous Fluconazole can be an effective and safe alternative to amphotericin B for empiric antifungal therapy in many febrile neutropenic patients. However, because Fluconazole may be ineffective in the treatment of Aspergillus , patients at risk for that infection should be evaluated by chest radiograph, computed tomographic scanning, and cultures before the use of empiric Fluconazole therapy.
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prophylactic Fluconazole in liver transplant recipients a randomized double blind placebo controlled trial
Annals of Internal Medicine, 1999Co-Authors: Drew J Winston, Anita Pakrasi, Ronald W BusuttilAbstract:Background: Among persons who receive solid orgar transplants, liver transplant recipients have the highest incidence of invasive fungal infection; however, no anti-fungal prophylaxis has been proven to be effective. Objective: To evaluate the efficacy and safety of prophylactic Fluconazole in liver transplant recipients. Design: Randomized, double-blind, placebo-controlled trial. Setting: University-affiliated transplantation center. Patients: 212 liver transplant recipients who received Fluconazole (400 mg/d) or placebo until 10 weeks after transplantation. Measurements: Fungal colonization, proven superficial or invasive fungal infection, drug-related side effects, and death. Results: Fungal colonization increased in patients who received placebo (from 60% to 90%) but decreased in patients who received Fluconazole (from 70% to 28%). Proven fungal infection occurred in 45 of 104 placebo recipients (43%) but in only 10 of 108 Fluconazole recipients (9%) (P 0.2), fewer deaths related to invasive fungal infection were seen in the Fluconazole group (2 of 108 patients [2%]) than in the placebo group (13 of 104 patients [13%]) (P = 0.003). Conclusions: Prophylactic Fluconazole after liver transplantation decreases fungal colonization, prevents superficial and invasive fungal infections, and has no appreciable hepatotoxicity. Although Fluconazole prophylaxis is associated with fewer deaths from fungal infection, it does not improve overall survival. Patients receiving prophylactic Fluconazole require close monitoring of serum cyclosporine levels to avoid neurologic toxicity.
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Fluconazole prophylaxis of fungal infections in patients with acute leukemia results of a randomized placebo controlled double blind multicenter trial
Annals of Internal Medicine, 1993Co-Authors: Drew J Winston, Pranatharthi H Chandrasekar, Hillard M Lazarus, Jesse L Goodman, Jeffrey L Silber, Harold W Horowitz, R K Shadduck, C S Rosenfeld, Winston G Ho, Muhammed Z IslamAbstract:OBJECTIVE: To evaluate the efficacy and safety of Fluconazole for prevention of fungal infections. DESIGN: A randomized, placebo-controlled, double-blind, multicenter trial. PATIENTS: Adults (257) undergoing chemotherapy for acute leukemia. INTERVENTION: Patients were randomly assigned to receive either Fluconazole (400 mg orally once daily or 200 mg intravenously every 12 hours) or placebo. The study drug was started at initiation of chemotherapy and continued until recovery of neutrophil count, development of proven or suspected invasive fungal infection, or the occurrence of a drug-related toxicity. MEASUREMENTS: Fungal colonization, proven superficial or invasive fungal infection, empiric antifungal therapy with amphotericin B, drug-related side effects, and mortality. MAIN RESULTS: Fluconazole decreased fungal colonization (83 of 122 [68%] placebo patients compared with 34 of 119 [29%] Fluconazole patients colonized at end of prophylaxis, P < 0.001) and proven fungal infections (27 of 132 [21%] placebo patients compared with 11 of 123 [9%] Fluconazole patients infected, P = 0.02). Superficial fungal infections occurred in 20 of 132 (15%) placebo patients but in only 7 of 123 (6%) Fluconazole patients (P = 0.01), whereas invasive fungal infections developed in 10 of 132 (8%) placebo patients and in 5 of 123 (4%) Fluconazole patients (P = 0.3). Fluconazole was especially effective in eliminating colonization and infection by Candida species other than Candida krusei (66 of 122 [64%] placebo patients colonized at end of prophylaxis compared with 11 of 119 [9%] Fluconazole patients, P < 0.001; 22 of 132 [17%] placebo patients infected compared with 7 of 123 [6%] Fluconazole patients, P = 0.005). Aspergillus infections were infrequent in both Fluconazole (3 cases) and placebo groups (3 cases). The use of amphotericin B, the incidence of drug-related side effects, and overall mortality were similar in both study groups. CONCLUSION: Prophylactic Fluconazole prevents colonization and superficial infections by Candida species other than Candida krusei in patients undergoing chemotherapy for acute leukemia and is well tolerated. Fluconazole could not be clearly shown to be effective for preventing invasive fungal infections, reducing the use of amphotericin B, or decreasing the number of deaths.
S D Brown - One of the best experts on this subject based on the ideXlab platform.
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in vitro studies of two triazole antifungal agents voriconazole uk 109 496 and Fluconazole against candida species
Antimicrobial Agents and Chemotherapy, 1996Co-Authors: A L Barry, S D BrownAbstract:A new triazole derivative (voriconazole or UK-109,496) and Fluconazole were tested against 249 isolates of Candida spp. representing six species. Voriconazole was 10 to 100 times more potent than Fluconazole. Strains with decreased susceptibility to Fluconazole were inhibited by relatively low concentrations of voriconazole.
