Standard Azole Research Articles

Functional Expression of Recombinant Candida auris Proteins in Saccharomyces cerevisiae Enables Azole Susceptibility Evaluation and Drug Discovery

Candida auris infections are difficult to treat due to acquired drug resistance against one or multiple antifungal drug classes. The most prominent resistance mechanisms in C. auris are overexpression and point mutations in Erg11, and the overexpression of efflux pump genes CDR1 and MDR1. We report the establishment of a novel platform for molecular analysis and drug screening based on acquired azole-resistance mechanisms found in C. auris. Constitutive functional overexpression of wild-type C. auris Erg11, Erg11 with amino acid substitutions Y132F or K143R and the recombinant efflux pumps Cdr1 and Mdr1 has been achieved in Saccharomyces cerevisiae. Phenotypes were evaluated for standard azoles and the tetrazole VT-1161. Overexpression of CauErg11 Y132F, CauErg11 K143R, and CauMdr1 conferred resistance exclusively to the short-tailed azoles Fluconazole and Voriconazole. Strains overexpressing the Cdr1 protein were pan-azole resistant. While CauErg11 Y132F increased VT-1161 resistance, K143R had no impact. Type II binding spectra showed tight azole binding to the affinity-purified recombinant CauErg11 protein. The Nile Red assay confirmed the efflux functions of CauMdr1 and CauCdr1, which were specifically inhibited by MCC1189 and Beauvericin, respectively. CauCdr1 exhibited ATPase activity that was inhibited by Oligomycin. The S. cerevisiae overexpression platform enables evaluation of the interaction of existing and novel azole drugs with their primary target CauErg11 and their susceptibility to drug efflux.

Antifungal Activity of Linear and Disulfide-Cyclized Ultrashort Cationic Lipopeptides Alone and in Combination with Fluconazole against Vulvovaginal Candida spp.

Vulvovaginal candidiasis (VVC) occurs in over 75% of women at least once during their lifetime and is an infection that significantly affects their health. Candida strains resistant to standard azole antifungal therapy and relapses of VVC are more and more common. Hypothetically, biofilm is one of the main reasons of relapses and failure of the therapy. Ultrashort cationic lipopeptides (USCLs) exhibit high antimicrobial activities. Our previous study on USCLs revealed that disulfide cyclization can result in selective antifungal compounds. Therefore, four USCL were selected and their antifungal activity were studied on 62 clinical strains isolated from VVC. The results confirmed previous premises that cyclic analogs have increased selectivity between fungal cells and keratinocytes and improved anticandidal activity compared to their linear analogs against both planktonic and biofilm cultures. On the other hand, linear lipopeptides in combination with fluconazole showed a synergistic effect. It was found that the minimum inhibitory concentrations of the tested compounds in combination with fluconazole were at least four times lower than when used separately. Our results indicate that combination therapy of VVC with USCLs and fluconazole at low non-toxic concentrations can be beneficial owing to the synergistic effect. However, further in vivo studies are needed to confirm this hypothesis.

Aripiprazole repurposed as an inhibitor of biofilm formation and sterol biosynthesis in multidrug-resistant Candida albicans

Drug repurposing is an anticipative chemotherapeutic strategy that accentuates the inadequacy of antifungal drugs. The study identifies an antipsychotic drug, aripiprazole, as a biofilm and hyphal inhibitor of Candida albicans. Microtitre plate biofilm inhibition, metabolic activity and hyphal inhibitory assays were used to assess the potency of aripiprazole; and filipin staining, reactive oxygen species staining, cAMP rescue, propidium iodide staining, computational studies and qRT-PCR assays were used to elucidate its mode of action. The study revealed aripiprazole functioned in a manner similar to standard azoles, particularly the imidazole, ketoconazole, by inhibiting pseudohyphal formation during the early stages of hyphal development. The action of aripiprazole on C. albicans was dose-dependent and it exhibited varied mechanisms of action at low and high dosages. At low dosage, aripiprazole outperformed ketoconazole in terms of inhibiting biofilm formation, hyphal filamentations, and yeast flocculation, whereas at higher dosage it mimicked ketoconazole. This study illustrates the anti-candidal potential and mechanistic activities of aripiprazole, and indicates the future use of this drug as an anti-biofilm agent.

1413. A Phase IIa Efficacy, Safety, Tolerability and Pharmacokinetic (PK) Study of Encochleated Amphotericin B in Patients with Mucocutaneous (Esophogeal, Oropharyngeal, Vulvovaginal) Candidiasis Who are Refractory or Intolerant to Standard Non-Intravenous Therapies

BackgroundCurrent oral therapeutic options for chronic mucocutaneous candidiasis (CMC) are often associated with resistance and toxicity. Amphotericin B (AMB) has broad fungicidal activity and markedly resists emergence of resistance but requires parenteral administration and monitoring for significant nephrotoxicity, which worsens with chronic treatment. Encochleated amphotericin B (CAMB) is a novel oral formulation of AMB. In animal models, CAMB demonstrates antifungal activity with similar efficacy as intraperitoneal AMB deoxycholate, but without the associated toxicity. This on-going patient volunteer study assesses the efficacy, safety, tolerability and PK of CAMB in patients with CMC who are refractory or intolerant to standard oral azole antifungals.MethodsFour patients have completed the clinical protocol treatment period: 3 patients with STAT3 deficient Hyper IgE syndrome and CMC, and one patient with chronic esophageal candidiasis. Eligible patients were dose escalated (Figure 1), with option of enrolling in an extension phase. Serial plasma PK samples were collected over 24 hours over the study period, with data available from two patients (Figure 2). ResultsCAMB was well tolerated by all four patients, and all are currently on the extension phase (Figure 3). There was significant improvement in clinical severity symptom scores of esophageal and oropharyngeal symptoms; CAMB01 achieved reduction in clinical symptoms by 57% (800 mg/day), CAMB02 by 85% (400 mg/day), CAMB03 50% (800 mg/day) and CAMB04 50% (800 mg/day). CAMB02 maintained higher plasma PK exposure throughout the study compared with CAMB01, a possible explanation for clinical response at a lower 400 mg/day dose. Reported adverse events were grade 1, mostly nausea and dizziness. There were no signs of liver, kidney or hematologic toxicity in any of the patients, with CAMB01 and CAMB02 receiving study drug for ~1 year.ConclusionCAMB was well tolerated in patient volunteers with long-standing symptomatic azole-resistant CMC. All four patients have met the primary endpoint of achieving 3 50% clinical response. CAMB is a promising oral therapy for patients with history of CMC, with potential use in treatment and prophylaxis of invasive fungal infections.Disclosures M. Lionakis, Matinas BioPharma Inc: Research Support, Research support. R. Lu, Matinas BioPharma Inc: Employee and Shareholder, Salary. R. Mannino, Matinas BioPharma Inc: Employee and Shareholder, Salary.

Characterization, antifungal and cytotoxic evaluation of green synthesized zinc oxide nanoparticles using Ziziphus nummularia leaf extract

Zinc oxide nanoparticles (ZnO NPs) were synthesized using Ziziphus nummularia leaf extract. The characterization was done by various spectral analysis and antifungal (anti-candidal) activity against multidrug resistant clinical isolates and their cytotoxic potential was evaluated. The ZnO NPs were 17.33 nm in size and were spherical/irregular in shape. The antifungal activity of ZnO NPs was better than four standard azole antibiotics and they also showed potent cytotoxic effect against HeLa cancer cell line. The results strongly suggest the applicability of green synthesized ZnO NPs as antifungal agent and also its use in cancer diagnosis and treatment.

Local Probiotic Therapy for Vaginal Candida albicans Infections.

The high rate of vaginal Candida albicans recurrence is attributed to azole resistance rates as high as 15%. The aim of this study was to determine the clinical and microbiological efficacy of standard azole therapy for treatment of vaginal C. albicans infection alone and in combination with local probiotic as well as the effects on vaginal microbiota. This study included 436 women with vaginal candidiasis randomly assigned to two treatment groups. The first group, with 207 patients (12 dropouts), was administered 150 mg fluconazole and a single vaginal globule of fenticonazole (600 mg) on the same day. The second group of 209 patients (8 dropouts) followed the same treatment schedule; however, ten applications of a vaginal probiotic containing Lactobacillus acidophilus, L. rhamnosus, Streptococcus thermophilus, and L. delbrueckii subsp. bulgaricus were also administered beginning the fifth day after azole treatment. Microbiological analysis of the therapy efficacy in the first treatment group showed C. albicans resistance in over 30% of patients. Clinical complaints persisted after treatment administration in 79.7% (n = 165) of women in this group. Clinical complaints in the second group decreased to 31.1% (n = 65) and microbiological efficacy also improved among investigated parameters, from 93.7% (n = 193) to 95.2% (n = 198). The local application of probiotics after administration of combined azoles for treatment of vaginal C. albicans infections increases therapy efficacy and could prevent relapse.

Posaconazole vs fluconazole/itraconazole in the prophylaxis of invasive fungal infections in immunocompromised patients: A cost-effectiveness analysis in Greece

Background:Invasive fungal infections (IFIs) present a major issue in clinical practice, due to their high morbidity and mortality rates. In a pivotal multi-centre, randomized clinical trial, posaconazole prophylaxis prevented IFIs more effectively than did either fluconazole or itraconazole, and improved overall survival.Objective:The aim of this study was to perform an economic evaluation of the aforementioned therapeutic strategies for IFI prophylaxis in neutropenic patients, in the Greek healthcare setting.Method:A decision analytic model was developed, which described the course of neutropenic patients under posaconazole or standard azole (fluconazole or itraconazole) treatment. Effectiveness data for each treatment regimen were derived from published results of a pivotal, multi-centre, randomized clinical trial. Cost and healthcare resources utilization data depict Greek clinical practice and are derived from official Greek sources, from a third party payer perspective.Results:Prophylaxis with posaconazole resulted in fewer IFIs (0.05 vs 0.11 per patient) compared to treatment with fluconazole or itraconazole, during the first 100 days from initiation of prophylaxis treatment. The cost per avoided IFI with posaconazole was €6455, while the incremental cost per life year gained (LYG) was estimated at €24,196. Extensive sensitivity analyses corroborated the base-case results. Possible limitations of the study are the exclusion of indirect and outpatient costs from the analysis and the inherent uncertainty with regards to the transferability of the clinical efficacy results of the clinical trial to the Greek healthcare setting.Conclusions:The utilization of posaconazole for prophylaxis of IFIs neutropenic patients is a therapeutic strategy that provides superior clinical efficacy, while being cost-effective compared to alternative therapies.

Adapting a global cost-effectiveness model to local country requirements: posaconazole case study

Background:Many countries have various requirements for local economic analyses to assess the value of a new health technology and/or to secure reimbursement. This study presents a case study of an economic model developed to assess the cost-effectiveness of posaconazole vs standard azole therapy (fluconazole/itraconazole) to prevent invasive fungal infections (IFIs), which was adapted by at least 11 countries.Methods:Modeling techniques were used to assess the cost-effectiveness of posaconazole vs fluconazole/itraconazole as IFI prophylaxis in patients with acute myelogenous leukemia or myelodysplastic syndromes and chemotherapy-induced neutropenia. For the core model, the probabilities of experiencing an IFI, IFI-related death, and death from other causes were estimated from clinical trial data. Long-term mortality, drug costs, and IFI treatment costs were obtained from secondary sources. Locally changed parameters were probabilities of long-term death and survival, currency, drug costs, health utility, IFI treatment costs, and discount rate.Results:Locally adapted cost-effective modeling studies indicate that prophylaxis with posaconazole, compared with fluconazole/itraconazole, prolongs survival, and, in most countries, is cost-saving. In all countries, the model predicted that prophylaxis with posaconazole would be associated with an increase in life-years, with increases ranging from 0.016–0.1 life-year saved. In all countries, use of the model led to posaconazole being approved by the appropriate reimbursement authority.Limitations:The study did not have power to detect differences between posaconazole and fluconazole or itraconazole separately. The risk of death after 100 days was assumed to be equal for those who did and did not develop an IFI, and equal probabilities of IFI-related and other death during the trial period were used for both groups.Conclusions:A core economic model was successfully adapted locally by several countries. The model showed that posaconazole was cost-saving or cost-effective vs fluconazole/itraconazole and led to positive reimbursement listings.

PIN44 Cost-Effectiveness of Posaconazole Compared to Fluconazole/Itraconazole for the Prevention of Invasive Fungal Infections in Neutropenic Patients

Invasive Fungal Infections (IFIs) present a major issue in clinical practice, due to their high morbidity and mortality rates. In a pivotal multicentre, randomized clinical trial posaconazole prophylaxis prevented IFIs more effectively than did either fluconazole or itraconazole, and improved overall survival. The aim of this study was to perform an economic evaluation of the afore-mentioned therapeutic strategies for IFI prophylaxis in neutropenic patients, in the Greek health care setting. A decision analytic model was developed, which described the course of neutropenic patients under posaconazole or standard azole (fluconazole or itraconazole) treatment. The effectiveness data for each treatment regimen were derived from published results of a pivotal, multicentre, randomized clinical trial. The cost and health care resources utilization data used, depict Greek clinical practice and are derived from official Greek sources. In order to obtain some of the model imputs, expert opinion from Greek Hematologists specializing in treating IFIs, was also used. Prophylaxis with Posaconazole resulted in fewer IFIs (0,05 vs. 0,11 per patient) compared to treatment with fluconazole or itraconazole, during the first 100 days from initiation of prophylaxis treatment. The cost per avoided IFI with Posaconazole was 6,455€, while the cost for every incremental life year gained (LYG) was estimated at 24,196€. Extensive sensitivity analyses (one-way and probabilistic) corroborated the base-case results. The utilization of Posaconazole for prophylaxis of IFIs in hematology patients with neutropenia is a therapeutic strategy that provides superior clinical efficacy, while being cost-effective compared to alternative therapies.

Cost-effectiveness of posaconazole versusfluconazole or itraconazole in the prevention of invasive fungal infections among high-risk neutropenic patients in Spain

BackgroundWe evaluated the cost-effectiveness of posaconazole compared with standard azole therapy (SAT; fluconazole or itraconazole) for the prevention of invasive fungal infections (IFI) and the reduction of overall mortality in high-risk neutropenic patients with acute myelogenous leukaemia (AML) or myelodysplastic syndromes (MDS). The perspective was that of the Spanish National Health Service (NHS).MethodsA decision-analytic model, based on a randomised phase III trial, was used to predict IFI avoided, life-years saved (LYS), total costs, and incremental cost-effectiveness ratio (ICER; incremental cost per LYS) over patients' lifetime horizon. Data for the analyses included life expectancy, procedures, and costs associated with IFI and the drugs (in euros at November 2009 values) which were obtained from the published literature and opinions of an expert committee. A probabilistic sensitivity analysis (PAS) was performed.ResultsPosaconazole was associated with fewer IFI (0.05 versus 0.11), increased LYS (2.52 versus 2.43), and significantly lower costs excluding costs of the underlying condition (€6,121 versus €7,928) per patient relative to SAT. There is an 85% probability that posaconazole is a cost-saving strategy compared to SAT and a 97% probability that the ICER for posaconazole relative to SAT is below the cost per LYS threshold of €30,000 currently accepted in Spain.ConclusionsPosaconazole is a cost-saving prophylactic strategy (lower costs and greater efficacy) compared with fluconazole or itraconazole in high-risk neutropenic patients.

Economic Evaluation of Posaconazole Versus Standard Azole Therapy as Prophylaxis against Invasive Fungal Infections in Patients with Prolonged Neutropenia in Canada

Posaconazole prophylaxis in high-risk neutropenic patients prevents invasive fungal infection (IFI). An economic model was used to assess the cost effectiveness of posaconazole from a Canadian health care system perspective. A decision-analytic model was developed based on data from a randomized trial comparing posaconazole with standard azole (fluconazole or itraconazole) therapy. The model was extrapolated to a lifetime horizon using one-month Markov cycles; lifetime survival was specific to the underlying disease. Drug and treatment costs associated with IFI were estimated using published literature. The model was used to estimate total costs, IFIs avoided, life-years gained and the incremental cost-effectiveness ratio of posaconazole versus standard azole therapy, in 2007 Canadian dollars. Based on the clinical trial data, posaconazole was associated with fewer cases of IFI (0.05 versus 0.11; P=0.003), increased life-years (2.52 years versus 2.43 years) and slightly lower costs ($6,601 versus $7,045) per patient relative to standard azole therapy over a lifetime horizon. Higher acquisition costs for posaconazole were offset by IFI-associated inpatient costs for those prophylaxed with standard azoles. Probabilistic sensitivity analysis indicated a 59% probability that posaconazole was cost-saving versus standard azole therapy and a 96% probability that the incremental cost-effectiveness ratio for posaconazole was at or below the $50,000 per life-year saved threshold. In Canada, posaconazole appears to be cost-saving relative to standard azole therapy in IFI prevention among high-risk neutropenic patients.

Costo Efectividad de Posaconazol versus Fluconazol/Itraconazol en el Tratamiento Profiláctico de las Infecciones Fúngicas Invasivas en México

Cost effectiveness of posaconazole versus fluconazole/itraconazole therapy in the prophylaxis against invasive fungal Infections among high-risk neutropenic patients in Mexico. ObjectiveTo estimate the cost effectiveness and long-term combined effects of Posaconazole versus fluconazole/itraconazole (standard azole) therapy in the prophylaxis against invasive fungal Infections among high-risk neutropenic patients in Mexico. MethodsA previously validated Markov model was used to compare the projected lifetime costs and effects of two theoretical groups of patients, one receiving Posaconazole and the other receiving standard azole. The model estimates total costs, numbers of IFIs, and QALY per patient in each prophylaxis group. To extrapolate trial results to a lifetime horizon, the model was extended with one-month Markov cycles in which mortality risk is specific to the underlying disease. Data on the probabilities of IFI were obtained from Study Protocol PO1899. Drug costs were taken from average wholesale drug reports for 2009. Cost and health effects were discounted at 5% according to the Mexican guideline. The analysis was conducted from the Mexican healthcare perspective using 2008 unit cost prices. ResultsOur model projects an accumulated cost to the Mexican healthcare system per patient receiving the Posaconazol regimen of $US 5,634 compared to $US 7,463 for the standard azole regimen. The accumulated discounted effect is 3.13 LY or 2.25 QALYs per patient receiving Posaconazol, compared to 2.96 LY or 2.13 QALYs per patient receiving standard azole. Posaconazol remained the dominant strategy across each scenario. Probabilistic sensitivity analysis tested numerous assumptions about the model cost and efficacy parameters and found that the results were robust to most changes. ConclusionPosaconazole provides modest incremental benefits compared with standard azole therapy in the prophylaxis against IFIs among high-risk neutropenic patients. Routine Posaconazole use appears a cost saving when the likelihood of IFIs or the cost of treatment medications is high.

Posaconazole

Posaconazole (Noxafil®) is an oral, second-generation, extended-spectrum triazole whose approved indications include prophylaxis of invasive fungal disease (IFD) in immunocompromised patients. In pivotal head-to-head trials, posaconazole was significantly more effective in preventing IFD than standard azole therapy (i.e. oral fluconazole or itraconazole) in chemotherapy-induced neutropenic patients with acute myelogenous leukaemia (AML) or myelodysplastic syndromes (MDS) and was noninferior to treatment with fluconazole in patients with graft-versus-host disease (GVHD) who were receiving intensive immunosuppressive therapy following haematopoietic stem cell transplantation. In both indications, prophylactic posaconazole was associated with significantly lower rates of IFD-related mortality. The overall tolerability profile of posaconazole was generally similar to that of the other prophylactic treatments. The large body of modelled cost-effectiveness analyses from a healthcare payer perspective on the use of prophylactic posaconazole suggest that it is a dominant or cost-effective option relative to prophylaxis with standard azole therapy in neutropenic patients with AML/MDS, and fluconazole in patients with GVHD. Based on clinical trial data in these patient groups, antifungal prophylaxis with posaconazole was predicted to be a dominant or cost-effective option relative to prophylaxis with standard oral azoles, with regard to the incremental cost per QALY gained, life-year (LY) gained and/or other outcomes in cost-effectiveness analyses in numerous countries. In those analyses in which posaconazole did not dominate the comparator, posaconazole was considered cost effective, as the incremental cost per QALY or LY gained with posaconazole was lower than assumed willingness-to-pay thresholds. Sensitivity analyses consistently demonstrated that these results were robust to plausible changes in key model assumptions. In conclusion, prophylactic treatment with posaconazole is clinically effective in preventing IFD in neutropenic patients with AML/MDS and patients with GVHD. Available pharmacoeconomic data from several countries, despite some inherent limitations, support the use of posaconazole as a dominant or cost-effective prophylactic antifungal treatment relative to prophylaxis with standard oral azoles in these patient populations at high risk of developing IFD.

Cost-Effectiveness of Posaconazole Compared with Standard Azole Therapy for Prevention of Invasive Fungal Infections in Patients at High Risk in Switzerland

Objective: To evaluate the cost-effectiveness of posaconazole versus standard azoles in the prevention of invasive fungal infection (IFI) in high-risk patients, using a pharmacoeconomic model that was adapted to a Swiss setting. Methods: Decision tree models based on the results of two registration trials and subsequent Markov models over patient lifetimes were developed for patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) with neutropenia and for hematopoietic stem cell transplant recipients with graft-versus-host disease (GVHD). Results: By reducing IFIs in AML/MDS patients with posaconazole prophylaxis, the contained IFI-related treatment costs more than compensated for the incremental cost of posaconazole, resulting in savings of CHF 1,118 per patient. Lifetime posaconazole prophylaxis resulted in a benefit of 0.16 life years saved per patient compared with fluconazole/itraconazole. In patients with GVHD, posaconazole prophylaxis prevented 0.04 IFIs, resulting in incremental costs of CHF 7,040 per patient. Lifetime posaconazole prophylaxis resulted in a benefit of 0.15 life years saved per patient, with an incremental cost-effectiveness rate of CHF 48,324 per life year saved. Conclusions: Given the conditions of the Swiss setting, posaconazole can be considered a cost-effective early treatment strategy that increases survival in patients at risk for IFI and may have a substantial benefit for the economic burden of IFI.

Comparable Efficacy and Safety with Voriconazole or Posaconazole as Primary Antifungal Prophylaxis in Acute Myeloid Leukemia (AML) Patients Receiving Induction Chemotherapy.

Abstract 2059Poster Board II-36 Background:Patients with prolonged neutropenia are at significant risk for invasive fungal infections (IFI's). The incidence of proven or probable IFI's range from 5-24% in patients treated with AML. Furthermore, the mortality rate in this high-risk population has been reported to be as high as 86% for invasive pulmonary aspergillosis. Given the high mortality rate associated with IFI's and our inability to reliably diagnose active cases, prophylactic therapy has emerged as the preferred approach in this high risk patient population. Recently, Cornely et al. conducted a large, prospective randomized trial evaluating prophylactic posaconazole vs. fluconazole or itraconazole in AML/MDS patients receiving induction chemotherapy. Posaconazole (P) was found to be superior to the standard azoles with respect to the incidence of proven or probable IFI's and demonstrated an overall survival benefit. Given these findings, our institution adopted P as primary antifungal (AF) prophylaxis in this setting. Previously our standard prophylactic approach was voriconazole (V) which has a similar spectrum of activity and is available in an oral and IV formulation in contrast to P which is only available orally. There does not appear to be any comparative published literature to date between these two extended-spectrum azoles in the prophylactic setting. We report herein on the efficacy and safety of voriconazole and posaconazole as primary AF prophylaxis between January 2005 and June 2008. Methods:Patients > 18 yo receiving AML/MDS induction chemotherapy without documentation of IFI were included in this retrospective analysis. The voriconazole group received 400mg PO BID × 1 day, then 200mg PO BID. The posaconazole group received 200 mg PO TID with meals. Therapy was initiated on the first day of chemotherapy or 24 hrs post anthracycline and continued until neutrophil recovery, initiation of empiric AF therapy, occurrence of proven/probable IFI, or adverse event (AE) requiring discontinuation of therapy. Proven/probable IFI was defined in accordance with the EORTC/MSG criteria. Results:195 patients were evaluable (N=129 V; N=66 P). Baseline characteristics were similar between the two groups with respect to age, sex, diagnosis, cytogenetics, disease status, days of neutropenia, and utilization of growth factors. Median time on prophylaxis was 16 (range: 4-44) and 14 (range: 3-69) days, respectively for P and V. Nine pts (7%; 95% CI (3-13%)) developed proven/probable IFI (6 non-albicans candida, 2 fusarium, 1 zygo) in the V group versus four (6%; 95% CI (2-15%)) IFIs ( 2 trichosporon, 1 fusarium, 1 scedosporium) in the P group. Median time of prophylactic therapy to diagnosis of IFI was 29 days for P vs 25 days for V, respectively. Eight pts (6%) discontinued V therapy because of AE's (4 hallucinations, 1 rash, 2 LFT elevation, 1 torsades) vs five pts (7.5%) for P (3 LFT elevation, 1 vomiting, 1 rash). Conclusion:In the present analysis, we report the comparable efficacy and safety of voriconazole and posaconazole as primary AF prophylaxis in high risk AML/MDS patients receiving induction chemotherapy. There were no differences in the incidence of proven/probable IFI's, time to IFI, time to empiric AF therapy, or AE's requiring discontinuation of therapy. Disclosures:Wetzstein:Pfizer Pharmaceuticals: Honoraria; Schering-Plough Pharmaceuticals: Honoraria. Off Label Use: Voriconazole as primary antifungal prophylaxis therapy in AML patients receiving induction chemotherapy.

Economic evaluation of posaconazole vs. standard azole prophylaxis in high risk neutropenic patients in the Netherlands

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients experience prolonged neutropenia after treatment with intensive chemotherapy, leading to a high risk of invasive fungal infections (IFI). The present study evaluates the cost effectiveness of posaconazole vs. standard azoles for the prevention of IFIs in neutropenic patients in the Netherlands. A decision-tree model was developed using data from a randomized trial that compared posaconazole and standard azole (fluconazole or itraconazole) prophylaxis in neutropenic patients receiving remission-induction chemotherapy for AML/MDS (Cornely et al., N Engl J Med 2007;356:348-359). Following initiation of prophylaxis, clinical events are modeled with chance nodes reflecting probabilities of IFIs, IFI-related death, and death from other causes. Patients surviving the prophylaxis are assumed to have a life expectancy according to the underlying condition. This allows translation of the trial outcomes to a lifetime horizon. Data on life expectancy, quality of life, medical resource consumption and costs were obtained from the literature. Model outcomes include cost per life year (LY) gained and cost per quality adjusted life year (QALY) gained. The total cost (treatment of breakthrough IFI + prophylaxis) for posaconazole amounted to 4412 euros (95% uncertainty interval 3403 euros - 5666 euros), which is -183 euros (-1985 euros to 1564 euros) less than costs with standard azoles. Posaconazole prophylaxis resulted in 0.08 (0.02-0.15) QALYs gained in comparison with prophylaxis with standard azoles. Results from a probabilistic sensitivity analysis indicate that there is a 90% probability that the cost per QALY gained with posaconazole is below 20,000 euros. Additional scenario analyzes with different assumptions confirmed these findings. Given the underlying data and assumptions, the economic evaluation demonstrated that posaconazole prophylaxis is expected to be cost-effective compared with fluconazole/itraconazole in neutropenic AML/MDS patients after intensive chemotherapy.

Pharmacokinetics of Oral Posaconazole in Neutropenic Patients Receiving Chemotherapy for Acute Myelogenous Leukemia or Myelodysplastic Syndrome

To analyze the pharmacokinetics of posaconazole administered as prophylaxis for invasive fungal infection (IFI) in neutropenic patients receiving chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Pharmacokinetic subanalysis of a phase III, prospective, randomized, multicenter, evaluator-blinded trial comparing posaconazole with standard azoles (fluconazole and itraconazole). One hundred ninety-four patients with AML or MDS who received posaconazole oral suspension 200 mg 3 times/day with meals or a nutritional supplement for a minimum of 7 days to achieve steady state and for a maximum of 12 weeks. For the first 20 patients, blood samples were collected before the first dose on day 8 and at 2, 4, 6, and 24 hours after that first dose; for all other patients, blood samples were collected at 1 and 3 hours after the first dose on day 8 and during the first episode of evaluation for a possible IFI. The effects of the following covariates on average (Cav) and maximum (Cmax) posaconazole plasma concentrations at steady state were explored: age, sex, and race-ethnicity; proven or probable IFI; baseline body weight and body surface area; and baseline (on or before day 7) increases in liver enzyme levels, mucositis, neutropenia, diarrhea, vomiting, or use of an H2-receptor antagonist or proton pump inhibitor. Diarrhea, proton pump inhibitor use, gamma-glutamyl transferase level of 2 or more times the upper limit of normal, and race-ethnicity reduced Cav. Although statistically significant, these results were not considered clinically significant and did not necessitate posaconazole dosage adjustments. Mean Cav and Cmax values did not appear different in the six patients with IFIs (three with proven IFIs, three with probable IFIs) compared with the entire sample of 194 patients; however, a definitive conclusion cannot be made due to the small sample size of patients with IFI. No factor found to affect posaconazole concentrations predominated in patients with IFIs. Oral posaconazole 200 mg 3 times/day provided plasma concentrations adequate for preventing IFIs. No dosage adjustments are recommended based on any covariate tested.

Bending properties of wood treated with a new organic wood preservative system

This study investigated the effect of treatment of southern pine with a new generation, all organic wood preserving system on the mechanical properties in bending. Static bending tests showed no deleterious effects of treatment on property values when compared with untreated controls. Values for samples treated to 0.774kg/m3 total active ingredients (ai) were lower when compared to a lower retention (0.184kg/m3) or to a standard copper azole system, but were not different than water-treated controls.

Economic Evaluation of Posaconazole Versus Standard Azole Prophylaxis in High Risk Neutropenic Patients in The Netherlands.

Background: Acute leukemia and high risk myelodysplastic syndrome patients experience prolonged neutropenia after treatment with intensive chemotherapy, leading to a high risk of acquiring potentially fatal invasive fungal infections (IFI). Pharmacoeconomic analysis is considered a valuable tool to justify the significant costs involved in managing these fungal infections. The present study evaluates the cost-effectiveness of posaconazole versus standard azoles for the prevention of IFIs in neutropenic patients in the Netherlands.Methods: A decision-tree model was developed that starts with the choice of antifungal prophylaxis: posaconazole or standard azole treatment (fluconazole or itraconazole). The decision tree was estimated using data from a recently published prospective, randomized, double blind, multi-center trial that compared both treatments in neutropenic patients receiving remission-induction chemotherapy for AML/MDS (Cornely et al., 2007). Following initiation of prophylaxis, clinical events are modeled with chance nodes reflecting probabilities of IFIs, IFI related death, and death from other causes. It is assumed that patients surviving the prophylactic period will have a life expectancy that reflects that of the underlying condition. This allows translation of the trial outcomes to a lifetime horizon. Data on life expectancy, quality of life, medical resource consumption and costs were obtained from the literature. Model outcomes include incremental cost per IFI avoided, incremental cost per life years saved and incremental cost per QALYs gained.Results: The total cost (treatment of breakthrough IFI + prophylaxis) for posaconazole amounted to €4,566 (95% uncertainty interval €3,574 –€5,769), which is €63 (−€1,552 - €1,903) less than costs with standard azoles. Posaconazole prophylaxis resulted in 0.1 (0.03 – 0.15) QALYs gained in comparison to prophylaxis with standard azoles. Results from a probabilistic sensitivity analysis indicate that there is a 87% probability that the cost per QALY gained with posaconazole is below €20,000, a commonly accepted threshold for cost-effectiveness. Additional scenario analyses with different assumptions confirmed these findings.Conclusion: Given the underlying data and assumptions, our economic evaluation demonstrated that posaconazole prophylaxis is cost and QALY saving compared to fluconazole / itraconazole in neutropenic AML/MDS patients after intensive chemotherapy.

Cost-Effectiveness of Antifungal Strategies in High-Risk Neutropenic Patients.

Objective. Empirical antifungal therapy (Emp AF) is a standard of care for high-risk neutropenic patients with persistent or recurrent fever under broad-spectrum antibiotics. We conducted a cost-effectiveness analysis of four competitive strategies to reduce the burden of invasive fungal infection (IFI): the Emp AF, a preemptive antifungal strategy (PE AF) where AF is restricted to patients with clinical symptoms and/or mycological criteria of IFI, a prophylaxis with standard azole therapy (Fluconazole proph), and a prophylaxis with posaconazole (Posaconazole proph).Methods. A decision analytic model was developed to estimate costs and outcomes of the four strategies among patients with acute myeloid leukaemia at high risk of developing an IFI due to chemotherapy-induced neutropenia. The probabilities of receiving AF therapy, and experiencing IFI, either aspergillus or candidemia, were stratified according to induction and consolidation/autologous transplant phase of therapy.1,2 In the two prophylaxis strategies, patients could receive AF therapy, although at a lower rate than in the Emp AF. Length of stay and hospitalization costs depended on:1.IFI or no IFI;2.transfer into intensive care unit or not;3.dying or not (French national hospitalization database including 9,182 stays in 2005).AF drug costs were estimated as the product of the recorded drug consumption,1,2 and 2005 published mean average wholesale price from AP-HP central pharmacy, with exception of ambisome, voriconazole, caspofungine, and posaconazole where administrated national prices were taken. Second-order probabilistic Monte Carlo sensitivity was conducted to assess the effects of parameter uncertainty on the study findings.Results. In the induction phase of therapy, Emp AF (93.3% survival; 95.4% no IFI; €34,505 hospitalization costs) dominated (i.e., higher effectiveness, and lower hospitalization costs) PE AF and Fluconazole Proph strategies. Posaconazole Proph provided higher efficiency (93.5% survival; 97.3% no IFI) at higher hospitalization costs (€34,793) as compared to Emp AF. Results were sensitive to the relative risk of aspergillus invasive infection of posaconazole vs fluconazole (RR=0.11)2, and AF drug costs. In the consolidation/autologous transplant phases where the incidence of IFI is lower,1 all strategies provided similar effectiveness on survival and IFI prevention. Hospitalization costs and overall AF drug costs increased substantially from PE AF strategy (€24,761; €632) to Fluconazole Proph (€26,592; €1,457), Emp AF (€26,856; €1,419), and Posaconazole Proph (€28,094; €3,074).Conclusions. One AF strategy does not fit all high-risk neutropenic situations. In the induction phase of therapy, Emp AF and Posaconazole Proph provide the best outcomes with higher effectiveness and lower hospitalisation costs than PE AF and Fluconazole AF. In the consolidation/autologous phases of therapy, PE AF minimizes costs for similar outcomes in all AF strategies.