Head-to-Head Comparison of Inhibitory and Fungicidal Activities of Fluconazole,Itraconazole, Voriconazole,Posaconazole, and Isavuconazole against Clinical Isolates of Trichosporon asahii

Treatment of disseminated Trichosporon infections still remains difficult. Amphotericin B frequently displays inadequate fungicidal activity and echinocandins have no meaningful antifungal effect against this genus. Triazoles are currently the drugs of choice for the treatment of Trichosporon infections. This study evaluates the inhibitory and fungicidal activities of five triazoles against 90 clinical isolates of Trichosporon asahii. MICs (μg/ml) were determined according to Clinical and Laboratory Standards Institute microdilution method M27-A3 at 24 and 48 h using two endpoints, MIC-2 and MIC-0 (the lowest concentrations that inhibited ∼50 and 100% of growth, respectively). Minimum fungicidal concentrations (MFCs; μg/ml) were determined by seeding 100 μl of all clear MIC wells (using an inoculum of 10⁴ CFU/ml) onto Sabouraud dextrose agar. Time-kill curves were assayed against four clinical T. asahii isolates and the T. asahii ATCC 201110 strain. The MIC-2 (∼50% reduction in turbidity compared to the growth control well)/MIC-0 (complete inhibition of growth)/MFC values that inhibited 90% of isolates at 48 h were, respectively, 8/32/64 μg/ml for fluconazole, 1/2/8 μg/ml for itraconazole, 0.12/0.5/2 μg/ml for voriconazole, 0.5/2/4 μg/ml for posaconazole, and 0.25/1/4 μg/ml for isavuconazole. The MIC-0 endpoints yielded more consistent MIC results, which remained mostly unchanged when extending the incubation to 48 h (98 to 100% agreement with 24-h values) and are easier to interpret. Based on the time-kill experiments, none of the drugs reached the fungicidal endpoint (99.9% killing), killing activity being shown but at concentrations not reached in serum. Statistical analysis revealed that killing rates are dose and antifungal dependent. The lowest concentration at which killing activity begins was for voriconazole, and the highest was for fluconazole. These results suggest that azoles display fungistatic activity and lack fungicidal effect against T. asahii. By rank order, the most active triazole is voriconazole, followed by itraconazole ∼ posaconazole ∼ isavuconazole > fluconazole.     

Posaconazole Prophylaxis in Experimental Azole-Resistant Invasive Pulmonary Aspergillosis

We investigated the efficacy of posaconazole prophylaxis in preventing invasive aspergillosis due to azole-resistant Aspergillus fumigatus isolates. Using a neutropenic murine model of pulmonary infection, posaconazole prophylaxis was evaluated using three isogenic clinical isolates, with posaconazole MICs of 0.063 mg/liter (wild type), 0.5 mg/liter (F219I mutation), and 16 mg/liter. A fourth isolate harboring TR₃₄/L98H (MIC of 0.5 mg/liter) was also tested. Posaconazole prophylaxis was effective in A. fumigatus with posaconazole MICs of ≤0.5 mg/liter, where 100% survival was reached. However, breakthrough infection was observed in mice infected with the isolate for which the posaconazole MIC was >16 mg/liter.     

Cryptococcus neoformans-Cryptococcus gattii Species Complex: an International Study of Wild-Type Susceptibility Endpoint Distributions and Epidemiological Cutoff Values for Fluconazole,Itraconazole, Posaconazole,and Voriconazole

Epidemiological cutoff values (ECVs) for the Cryptococcus neoformans-Cryptococcus gattii species complex versus fluconazole, itraconazole, posaconazole, and voriconazole are not available. We established ECVs for these species and agents based on wild-type (WT) MIC distributions. A total of 2,985 to 5,733 CLSI MICs for C. neoformans (including isolates of molecular type VNI [MICs for 759 to 1,137 isolates] and VNII, VNIII, and VNIV [MICs for 24 to 57 isolates]) and 705 to 975 MICs for C. gattii (including 42 to 260 for VGI, VGII, VGIII, and VGIV isolates) were gathered in 15 to 24 laboratories (Europe, United States, Argentina, Australia, Brazil, Canada, Cuba, India, Mexico, and South Africa) and were aggregated for analysis. Additionally, 220 to 359 MICs measured using CLSI yeast nitrogen base (YNB) medium instead of CLSI RPMI medium for C. neoformans were evaluated. CLSI RPMI medium ECVs for distributions originating from at least three laboratories, which included ≥95% of the modeled WT population, were as follows: fluconazole, 8 μg/ml (VNI, C. gattii nontyped, VGI, VGIIa, and VGIII), 16 μg/ml (C. neoformans nontyped, VNIII, and VGIV), and 32 μg/ml (VGII); itraconazole, 0.25 μg/ml (VNI), 0.5 μg/ml (C. neoformans and C. gattii nontyped and VGI to VGIII), and 1 μg/ml (VGIV); posaconazole, 0.25 μg/ml (C. neoformans nontyped and VNI) and 0.5 μg/ml (C. gattii nontyped and VGI); and voriconazole, 0.12 μg/ml (VNIV), 0.25 μg/ml (C. neoformans and C. gattii nontyped, VNI, VNIII, VGII, and VGIIa,), and 0.5 μg/ml (VGI). The number of laboratories contributing data for other molecular types was too low to ascertain that the differences were due to factors other than assay variation. In the absence of clinical breakpoints, our ECVs may aid in the detection of isolates with acquired resistance mechanisms and should be listed in the revised CLSI M27-A3 and CLSI M27-S3 documents.     

Multiplex Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Method for Simultaneous Quantification in Human Plasma of Fluconazole,Itraconazole, Hydroxyitraconazole,Posaconazole, Voriconazole,Voriconazole-N-Oxide,Anidulafungin, and Caspofungin

Therapeutic drug monitoring (TDM) may contribute to optimizing the efficacy and safety of antifungal therapy because of the large variability in drug pharmacokinetics. Rapid, sensitive, and selective laboratory methods are needed for efficient TDM. Quantification of several antifungals in a single analytical run may best fulfill these requirements. We therefore developed a multiplex ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method requiring 100 μl of plasma for simultaneous quantification within 7 min of fluconazole, itraconazole, hydroxyitraconazole, posaconazole, voriconazole, voriconazole-N-oxide, caspofungin, and anidulafungin. Protein precipitation with acetonitrile was used in a single extraction procedure for eight analytes. After reverse-phase chromatographic separation, antifungals were quantified by electrospray ionization-triple-quadrupole mass spectrometry by selected reaction monitoring detection using the positive mode. Deuterated isotopic compounds of azole antifungals were used as internal standards. The method was validated based on FDA recommendations, including assessment of extraction yields, matrix effect variability (<9.2%), and analytical recovery (80.1 to 107%). The method is sensitive (lower limits of azole quantification, 0.01 to 0.1 μg/ml; those of echinocandin quantification, 0.06 to 0.1 μg/ml), accurate (intra- and interassay biases of −9.9 to +5% and −4.0 to +8.8%, respectively), and precise (intra- and interassay coefficients of variation of 1.2 to 11.1% and 1.2 to 8.9%, respectively) over clinical concentration ranges (upper limits of quantification, 5 to 50 μg/ml). Thus, we developed a simple, rapid, and robust multiplex UPLC-MS/MS assay for simultaneous quantification of plasma concentrations of six antifungals and two metabolites. This offers, by optimized and cost-effective lab resource utilization, an efficient tool for daily routine TDM aimed at maximizing the real-time efficacy and safety of different recommended single-drug antifungal regimens and combination salvage therapies, as well as a tool for clinical research.Differences in oral drug bioavailability, altered volumes of distribution, drug-drug interactions, impaired hepatic and/or renal drug clearance, and the genetic background of hepatic metabolism contribute to the large intra- and interindividual variability of pharmacokinetics of antifungal agents in patients with life-threatening fungal infections. A given drug dosing regimen can yield very different plasma concentrations: subtherapeutic drug exposure may result in a lack of response to therapy and emergence of fungal resistance, while overexposure may increase the risk of toxicity (21, 48, 57, 59). There is therefore increasing clinical evidence of the usefulness of therapeutic drug monitoring (TDM), which allows real-time adjustment of antifungal dosing aimed at optimizing the individual drug''s pharmacokinetic/pharmacodynamic profile. This may be especially helpful for severely ill patients with multiple organ dysfunctions and comedications, when drug absorption is uncertain, in infections not responding to therapy, or when severe toxicity is suspected (1, 11, 24, 35, 46, 50, 55). Tentative recommendations for timing of measurement and therapeutic concentration intervals in TDM for azole antifungals have been proposed (1). For echinocandins, experimental in vitro and in vivo studies have determined the pharmacokinetic/pharmacodynamic parameters associated with therapeutic success. Clinical studies are ongoing for the assessment of the relationships between exposure to echinocandins and efficacy or safety. Moreover, combinations of these compounds with azoles or polyenes are used for salvage therapy of refractory infections and are being investigated for first-line therapy (13, 18, 31).Analytical methods using liquid chromatography coupled with triple-quadrupole mass spectrometry (LC-MS/MS) have been reported for the quantification of single antifungals in biological fluids, including fluconazole (FLC) (14, 34, 49), itraconazole (ITZ) (39, 62) and its active metabolite (hydroxyitraconazole [OH-ITZ]) (4, 6, 27, 53), voriconazole (VRC) (2, 15, 26, 54, 63), posaconazole (PSC) (10, 40a, 44, 52), caspofungin (CASPO) (7, 16, 40), and anidulafungin (ANI) (13). LC-MS/MS assays were recently reported for the simultaneous quantification of posaconazole, voriconazole, isavuconazole, caspofungin, anidulafungin, and micafungin in different peripheral blood compartments (19) and of itraconazole, voriconazole, and posaconazole in blood (3).Ultra-performance liquid chromatography coupled with tandem mass spectrometry (ULPC-MS/MS) allows the selective and sensitive quantification of structurally unrelated drugs in a single analytical run, resulting in substantial reductions in analytical time, turnaround time, and costs. An analytical method using a simple extraction procedure followed by simultaneous quantification of multiple antifungal agents would be most efficient for rapidly providing TDM results, including those for patients receiving combination antifungal therapy (13, 18, 31), and for maximizing lab resource utilization.We aimed at developing and validating a simple, sensitive, and robust multiplex UPLC-MS/MS method for the simultaneous analysis in human plasma of six recommended and frequently used antifungal drugs and two metabolites: fluconazole, itraconazole and its active metabolite (hydroxyitraconazole), posaconazole, voriconazole, voriconazole-N-oxide (VRC-NO; the principal metabolite of voriconazole, produced by cytochrome P450 2C19 [CYP2C19] [23, 41]), caspofungin, and anidulafungin.     

In Vitro Susceptibility of Aspergillus fumigatus to Isavuconazole: Correlation with Itraconazole,Voriconazole, and Posaconazole

Triazoles are first-line agents for treating aspergillosis. The prevalence of azole resistance in Aspergillus fumigatus is increasing, and cross-resistance is a growing concern. In this study, the susceptibilities of 40 A. fumigatus clinical isolates were tested by using the CLSI method with amphotericin B, itraconazole, voriconazole, posaconazole, and the new triazole isavuconazole. Isavuconazole MICs were higher in strains with reduced susceptibilities to other triazoles, mirroring changes in voriconazole susceptibility. Isavuconazole MICs differed depending on the Cyp51A substitution.     

伊曲康唑对比氟康唑治疗老年恶性肿瘤合并深部真菌感染的研究

目的对比观察伊曲康唑和氟康唑治疗老年恶性肿瘤患者合并深部真菌感染的疗效和安全性。方法选择2003年～2007年老年恶性肿瘤合并深部真菌感染患者共46例,其中伊曲康唑组和氟康唑组各23例,分别按照相应的指导用法进行治疗。结果伊曲康唑组总有效率为78．3％,氟康唑总有效率仅为47．8％,二者之间差异有显著性（P〈0．05）,而伊曲康唑组的不良反应率为26．1％,氟康唑组的不良反应率为13．0％,二者之间差异无显著性（P〉0．05）。结论对老年恶性肿瘤合并深部真菌感染患者,应用伊曲康唑治疗较氟康唑治疗更有效,副作用却未明显增加。     

米卡芬净在造血干细胞移植二级预防中的临床应用分析

目的 探讨米卡芬净在有侵袭性真菌感染(invasive fungal infection,IFI)病史的患者行造血干细胞移植(haematopoietic stem cell transplantation,HSCT)时二级预防(secondary anti-fungal prophylaxis,SAP)的有效性和安全...     

Multilaboratory Study of Epidemiological Cutoff Values for Detection of Resistance in Eight Candida Species to Fluconazole,Posaconazole, and Voriconazole

Although epidemiological cutoff values (ECVs) have been established for Candida spp. and the triazoles, they are based on MIC data from a single laboratory. We have established ECVs for eight Candida species and fluconazole, posaconazole, and voriconazole based on wild-type (WT) MIC distributions for isolates of C. albicans (n = 11,241 isolates), C. glabrata (7,538), C. parapsilosis (6,023), C. tropicalis (3,748), C. krusei (1,073), C. lusitaniae (574), C. guilliermondii (373), and C. dubliniensis (162). The 24-h CLSI broth microdilution MICs were collated from multiple laboratories (in Canada, Brazil, Europe, Mexico, Peru, and the United States). The ECVs for distributions originating from ≥6 laboratories, which included ≥95% of the modeled WT population, for fluconazole, posaconazole, and voriconazole were, respectively, 0.5, 0.06 and 0.03 μg/ml for C. albicans, 0.5, 0.25, and 0.03 μg/ml for C. dubliniensis, 8, 1, and 0.25 μg/ml for C. glabrata, 8, 0.5, and 0.12 μg/ml for C. guilliermondii, 32, 0.5, and 0.25 μg/ml for C. krusei, 1, 0.06, and 0.06 μg/ml for C. lusitaniae, 1, 0.25, and 0.03 μg/ml for C. parapsilosis, and 1, 0.12, and 0.06 μg/ml for C. tropicalis. The low number of MICs (<100) for other less prevalent species (C. famata, C. kefyr, C. orthopsilosis, C. rugosa) precluded ECV definition, but their MIC distributions are documented. Evaluation of our ECVs for some species/agent combinations using published individual MICs for 136 isolates (harboring mutations in or upregulation of ERG11, MDR1, CDR1, or CDR2) and 64 WT isolates indicated that our ECVs may be useful in distinguishing WT from non-WT isolates.     

A Reference Laboratory Experience of Clinically Achievable Voriconazole,Posaconazole, and Itraconazole Concentrations within the Bloodstream and Cerebral Spinal Fluid

Interest in antifungal therapeutic-drug monitoring has increased due to studies demonstrating associations between concentrations and outcomes. We reviewed the antifungal drug concentration database at our institution to gain a better understanding of achievable triazole drug levels. Antifungal concentrations were measured by high-performance liquid chromatography (HPLC), ultraperformance liquid chromatography and single-quadrupole mass spectrometry (UPLC/MS), or a bioassay. For this study, only confirmed human bloodstream (serum or plasma) and cerebral spinal fluid (CSF) concentrations of voriconazole, posaconazole, and itraconazole were analyzed. The largest numbers of bloodstream and CSF samples were found for voriconazole (14,370 and 173, respectively). Voriconazole bloodstream concentrations within the range of 1 to 5.5 μg/ml represented 50.6% of samples. Levels below the lower limit of quantification (0.2 μg/ml) were observed in 14.6% of samples, and 10.4% of samples had levels of ≥5.5 μg/ml. CSF voriconazole levels ranged from undetectable to 15.3 μg/ml and were <0.2 μg/ml in 11% of samples. Posaconazole bloodstream concentrations were ≥0.7 and ≥1.25 μg/ml in 41.6% and 18.9% of samples, respectively. Posaconazole was detected in only 4 of 22 CSF samples (undetectable to 0.56 μg/ml). Itraconazole levels, as measured by UPLC/MS, were ≥0.5 μg/ml in 43.3% and were undetectable in 33.9% of bloodstream samples. In contrast, when measured by a bioassay, itraconazole/hydroxyitraconazole bloodstream concentrations were ≥1.0 μg/ml in 72.9% of samples and were undetectable in 18% of samples. These results indicate that there is marked variability in bloodstream concentrations achieved with these three azoles. In addition, many levels within the bloodstream for each azole and for voriconazole and posaconazole in the CSF were undetectable or below thresholds associated with efficacy.     

In Vitro Activities of Voriconazole, Fluconazole, and Itraconazole against 566 Clinical Isolates of Cryptococcus neoformans from the United States and Africa

We investigated the in vitro activity of voriconazole compared to those of fluconazole and itraconazole against 566 clinical isolates of Cryptococcus neoformans from Africa (164) and the United States (402). Isolates were obtained from cerebrospinal fluid (362), blood (139), and miscellaneous sites (65). Voriconazole (MIC at which 90% of the isolates are inhibited [MIC₉₀], 0.12 to 0.25 μg/ml) was more active than either itraconazole (MIC₉₀, 0.5 μg/ml) or fluconazole (MIC₉₀, 8.0 to 16 μg/ml) against both African and U.S. isolates. Isolates inhibited by ≥16 μg of fluconazole per ml were almost all (99%) inhibited by ≤1 μg of voriconazole per ml. These results suggest that voriconazole may be useful in the treatment of cryptococcosis.     

Heteroresistance to Fluconazole and Voriconazole in Cryptococcus neoformans

Cryptococcus neoformans isolates that exhibited unusual patterns of resistance to fluconazole and voriconazole were isolated from seven isolates from two different geographical regions: one isolate from an Israeli non-AIDS patient and six serial isolates from an Italian AIDS patient who had suffered six recurrent episodes of cryptococcal meningitis. Each isolate produced cultures with heterogeneous compositions in which most of the cells were susceptible, but cells highly resistant to fluconazole (MICs, >/=64 microg/ml) were recovered at a variable frequency (7 x 10(-3) to 4.6 x 10(-2)). Evidence showed that this type of resistance is innate and is unrelated to drug exposure since the Israeli patient had never been treated with azoles or any other antimycotic agents. Analysis of clonal subpopulations of these two strains showed that they exhibited heterogeneous patterns of resistance. The number of subpopulations which grew on fluconazole or voriconazole agar declined progressively with increasing azole concentration without a sharp cutoff point. For the Italian serial isolates, the number of clonal populations resistant to fluconazole (64 microg/ml) and voriconazole (1 microg/ml) increased steadily, yielding the highest number for the isolate from the last episode. Attempts to purify a sensitive subpopulation failed, but clones highly resistant to fluconazole (100 microg/ml) and moderately resistant to voriconazole (1 microg/ml) always produced a homogeneous population of resistant cells. Upon maintenance on drug-free medium, however, the majority of the homogeneously resistant cells of these subclones lost their resistance and returned to the stable initial heteroresistant phenotype. The pattern of heteroresistance was not affected by the pH or osmolarity of the medium but was influenced by temperature. The resistance appeared to be suppressed at 35 degrees C and was completely abolished at 40 degrees C. Although heterogeneity in azole resistance among subpopulations of single isolates has been reported for Candida species, the transient changes in expression of resistance under different growth conditions reported here have not been observed in fungal pathogens.     

Evaluation of the Efficacies of Amphotericin B,Posaconazole, Voriconazole,and Anidulafungin in a Murine Disseminated Infection by the Emerging Opportunistic Fungus Sarocladium (Acremonium) kiliense

We evaluated and compared the efficacies of different antifungal drugs against Sarocladium kiliense (formerly Acremonium kiliense), a clinically relevant opportunistic fungus, in a murine model of systemic infection. Three clinical strains of this fungus were tested, and the therapy administered was as follows: posaconazole at 20 mg/kg of body weight (twice daily), voriconazole at 40 mg/kg, anidulafungin at 10 mg/kg, or amphotericin B at 0.8 mg/kg. The efficacy was evaluated by prolonged animal survival, tissue burden reduction, and (1→3)-β-d-glucan serum levels. In general, the four antifungal drugs showed high MICs and poor in vitro activity. The efficacy of the different treatments was only modest, since survival rates were never higher than 40% and no drug was able to reduce fungal load in all the organs for the three strains tested. Posaconazole, in spite of its high MICs (≥16 μg/ml), showed the highest efficacy. The (1→3)-β-d-glucan serum levels were equally reduced by all drugs evaluated.     

Development,Validation, and Routine Application of a High-Performance Liquid Chromatography Method Coupled with a Single Mass Detector for Quantification of Itraconazole,Voriconazole, and Posaconazole in Human Plasma

We have developed and validated a high-performance liquid chromatography method coupled with a mass detector to quantify itraconazole, voriconazole, and posaconazole using quinoxaline as the internal standard. The method involves protein precipitation with acetonitrile. Mean accuracy (percent deviation from the true value) and precision (relative standard deviation percentage) were less than 15%. Mean recovery was more than 80% for all drugs quantified. The lower limit of quantification was 0.031 μg/ml for itraconazole and posaconazole and 0.039 μg/ml for voriconazole. The calibration range tested was from 0.031 to 8 μg/ml for itraconazole and posaconazole and from 0.039 to 10 μg/ml for voriconazole.The incidence of mycoses has continued to increase over the past 2 decades, especially in immunocompromised patients. Notwithstanding the fact that in the last decades new antifungal agents have been approved, there is still a therapeutic need for azole compounds, such as itraconazole (ITC), posaconazole (PSC), and voriconazole (VRC), which inhibit 14a-demethylase, a key enzyme in the ergosterol biosynthesis of yeasts and molds (40).Antifungal prophylaxis, empirical therapy, and treatment of established fungal infections in the hematology patient population may be associated with significant toxicity or drug interactions, leading to subtherapeutic antifungal drug concentrations and poorer clinical outcomes (47). For example, a relationship between plasma concentrations and antifungal efficacy was shown for ITC (19), and the ratio between the area under the concentration-time curve (AUC) and MIC was identified to be predictive for the treatment efficacy of voriconazole and posaconazole, as well (1, 2). Antifungal therapeutic drug monitoring (TDM) could be an important tool in clinical practice if compliance is poor, the therapeutic window is narrow, or drug interactions and toxicity are common adverse effects. Therefore, quantification of drug in plasma samples is an important issue in clinical practice to improve efficacy and to decrease toxicity.Many methods to individually quantify ITZ (6, 7, 9, 17, 18, 26, 31-34, 37, 45, 46), PSC (8, 35, 39), and VRC (11, 20, 24, 25, 28, 29, 36, 38) in human plasma have been published. Only one method described the quantification of the three triazoles plus fluconazole, ITC metabolite, and ketokonazole in human plasma using a solid-phase extraction procedure.The aim of this study was to develop and validate a high-performance liquid chromatography-mass spectrometry (HPLC-MS) method useful in routine TDM for quantitation of ITC, PSC, and VRC in human plasma using a protein precipitation extraction procedure and direct injection in an HPLC system.     

Phase 1b Study of New Posaconazole Tablet for Prevention of Invasive Fungal Infections in High-Risk Patients with Neutropenia

Posaconazole tablets, a new oral formulation of posaconazole, can be effective when given as antifungal prophylaxis to neutropenic patients at high risk for invasive fungal infection (e.g., those with acute myelogenous leukemia or myelodysplastic syndrome). Such effectiveness might be specifically important to patients with poor oral intake because of nausea, vomiting, or chemotherapy-associated mucositis. This was a prospective, global study in high-risk patients to characterize the pharmacokinetics and safety profile of posaconazole tablets and to identify the dose of posaconazole tablets that would provide exposure within a predefined range of exposures (steady-state average concentration [area under the concentration-time curve/24 h] of ≥500 ng/ml and ≤2,500 ng/ml in >90% of patients). The study evaluated two sequential dosing cohorts: 200 mg posaconazole once daily (n = 20) and 300 mg posaconazole once daily (n = 34) (both cohorts had a twice-daily loading dose on day 1) taken without regard to food intake during the neutropenic period for ≤28 days. The exposure target was reached (day 8) in 15 of 19 (79%) pharmacokinetic-evaluable patients taking 200 mg posaconazole once daily and in 31 of 32 (97%) patients taking 300 mg posaconazole once daily; 300 mg posaconazole once daily achieved the desired exposure target. Posaconazole tablets were generally well tolerated in high-risk neutropenic patients. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01777763","term_id":"NCT01777763"}}NCT01777763.)     

Cost-Effectiveness of Posaconazole Tablets for Invasive Fungal Infections Prevention in Acute Myelogenous Leukemia or Myelodysplastic Syndrome Patients in Spain

Introduction

Posaconazole is superior to fluconazole (FLU) and itraconazole (ITRA) in the prevention of invasive fungal diseases (IFDs) in neutropenic patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). A new tablet formulation of posaconazole with improved pharmacokinetic and pharmacodynamic properties compared to posaconazole oral solution has recently been approved. The objective of this study is to estimate the cost-effectiveness of the newly developed posaconazole tablets versus FLU oral suspension or ITRA oral solution for preventing IFDs in high-risk neutropenic patients with AML or MDS and from the perspective of the Spanish National Health System (NHS).

Methods

A previously validated economic model was used. The probabilities of experiencing an IFD, an IFD-related death or death from other causes over 100 days were based on clinical trial data and input into a decision tree. Surviving patients were entered into a Markov model to calculate total costs, number of IFDs and number of life-years gained per patient over a lifetime horizon in each disease and treatment group. Two health states, alive and dead, were considered. Health effects were discounted using a rate of 3%. Univariate and probabilistic sensitivity analyses were conducted.

Results

During the first 100 days, posaconazole tablets were associated with a lower risk of IFDs (0.046 vs. 0.111), longer life expectancy (2.92 vs. 2.69 years) and lower total costs (€5906.06 vs. €7847.20 per patient) over the patients’ lifetimes compared to FLU or ITRA treatments. Thus, posaconazole tablets were more effective and less costly than FLU or ITRA. Probabilistic sensitivity analysis indicated that there was a 79.9% probability of posaconazole tablets being cost-saving compared to FLU or ITRA.

Conclusion

From the Spanish NHS perspective, posaconazole tablets are cost-effective compared to FLU or ITRA in AML or MSD patients with chemotherapy-induced neutropenia and at high risk for IFDs.

Funding

MSD Sharp & Dohme.

     

Efficacy of Posaconazole as Treatment and Prophylaxis against Fusarium solani

Invasive fusariosis is a highly aggressive fungal infection associated with high mortality in heavily immunocompromised patients. Although posaconazole is efficacious as salvage therapy against infections caused by Fusarium species, concerns remain regarding this agent in the setting of reduced potency. To evaluate the efficacy of posaconazole as treatment or prophylaxis against invasive fusariosis caused by Fusarium solani, we utilized a neutropenic murine model of disseminated disease. ICR mice were administered escalating doses of posaconazole (6.25, 12.5, 25, or 50 mg/kg of body weight twice daily [BID]) by oral gavage beginning 2 days prior to inoculation in the prophylaxis studies or beginning 12 h after inoculation as treatment. Therapy was continued until day 9 postinoculation, and animals were monitored off therapy until day 15 for survival. Fungal burden was assessed as CFU in the kidneys. A clear dose-response relationship was observed, as the highest dose of posaconazole (50 mg/kg) was the most effective in prolonging survival and reducing tissue fungal burden both as prophylaxis and as treatment. This dose response was associated with high posaconazole serum concentrations as measured by bioassay. However, the extent of efficacy was also dependent on the infecting inoculum, as greater increases in survival and reductions in fungal burden were observed with the lower inocula tested. In this model high dosages of posaconazole were effective as treatment and prophylaxis against disseminated fusariosis caused by F. solani.Fusarium species are among the leading causes of invasive mold infections among patients with hematologic malignancies and those undergoing hematopoietic stem cell transplantation (HSCT), with mortality exceeding 70% (1, 2, 15). Risk factors for disseminated infection include neutropenia, lymphopenia, graft-versus-host disease, corticosteroids, and immunosuppressive therapy (1, 2). In vitro studies have reported moderate to negligible activity of available antifungals against Fusarium, with amphotericin B and itraconazole having minimal activity (3, 8, 16). Reduced in vitro potency has also been reported for voriconazole and posaconazole when measured by standard microdilution methodology (3, 8, 16). However, both voriconazole and posaconazole have been shown to be effective in animal models of invasive fusariosis, including infections caused by isolates with reduced in vitro susceptibility (4, 10, 20).Modifications to testing parameters used in determining the in vitro activity (e.g., inoculum size and incubation period) may greatly affect the MIC against Fusarium isolates (8, 16). This suggests that the in vitro activity as measured by standard microdilution methodology may not be predictive of in vivo efficacy. Our objective was to assess the in vivo efficacy of posaconazole against disseminated fusariosis caused by Fusarium solani, both as treatment and as prophylaxis, and to compare this activity to the in vitro potency measured at 24 and 48 h against different starting inocula. In addition, posaconazole concentrations were measured in animals that were administered the same dosages used for treatment and prophylaxis.     

高龄危重患者继发侵袭性真菌感染34例临床分析

目的:观察高龄危重患者继发侵袭性真菌感染(IFI)的临床特征及病原学特点,为早期经验性治疗提供依据.方法:对2006年10月～2007年10月我院ICU病房34例高龄IFI患者的病原学结果及临床特征进行回顾性分析.结果:34例IFI中并发气道痉挛22例、呼吸道出血及皮疹各19例、多器官功能障碍15例、消化道出血10例、血尿6例.共培养出菌株134株,其中白色念珠菌90株、光滑球念珠菌20株、热带念珠菌15株、克柔念珠菌2株、曲霉菌7株.结论:高龄IFI患者主要的致病菌仍然为念珠菌,尤其是白色念珠菌,但曲霉菌也有上升趋势.提示对具有高危因素的高龄患者,在原发病病情稳定后,突发气道痉挛、不明原因的呼吸道和消化道出血、皮疹等临床表现,应注意继发IFI的可能,早期经验性治疗以覆盖念珠菌为主,之后根据病原学选择敏感药物,且需视患者肝、肾功能变化及时调整药物剂量.     

Susceptibilities of Clinical and Laboratory Isolates of Blastomyces dermatitidis to Ketoconazole, Itraconazole, and Fluconazole

Eighteen isolates of Blastomyces dermatitidis were evaluated for their in vitro susceptibilities to ketoconazole, itraconazole, and fluconazole. The MIC ranges were 0.1 to 0.4 μg/ml for ketoconazole, ≤0.018 to 0.07 μg/ml for itraconazole, and 2.5 to 4.0 μg/ml for fluconazole. The ranges for the minimal lethal concentrations were 0.2 to 0.8 μg/ml for ketoconazole, ≤0.018 to 0.07 μg/ml for itraconazole, and 10 to 40 μg/ml for fluconazole. Itraconazole was the most active agent against B. dermatitidis in vitro, while fluconazole was the least active. These results correlate with the clinical efficacies noted to date with doses of these agents used to treat blastomycosis.     

Phase 1B Study of the Pharmacokinetics and Safety of Posaconazole Intravenous Solution in Patients at Risk for Invasive Fungal Disease

This was a phase 1B, dose-ranging, multicenter, pharmacokinetics, and safety study of cyclodextrin-based posaconazole intravenous (i.v.) solution administered through a central line to subjects at high risk for invasive fungal disease (part 1 of a 2-part study [phase 1B/3]). Initially, the safety and tolerability of single-dose posaconazole i.v. 200 mg (n = 10) were compared with those of a placebo (n = 11). Subsequently, 2 doses were evaluated, posaconazole i.v. 200 mg once daily (q.d.) (n = 21) and 300 mg q.d. (n = 24). The subjects received twice-daily (b.i.d.) posaconazole i.v. on day 1, followed by 13 days of posaconazole i.v. q.d., then 14 days of posaconazole oral suspension 400 mg b.i.d. The steady-state (day 14) exposure target (average concentration [areas under concentration-time curve {AUCs}/24 h, average concentrations at steady state {C_avgs}], of ≥500 to ≤2,500 ng/ml in ≥90% of the subjects) was achieved by 94% of the subjects for 200 mg posaconazole q.d. and by 95% of subjects for 300 mg posaconazole q.d. The desired exposure target (mean steady-state C_avg, ∼1,200 ng/ml) was 1,180 ng/ml in the 200-mg dosing cohort and was exceeded in the 300-mg dosing cohort (1,430 ng/ml). Posaconazole i.v. was well tolerated. Posaconazole i.v. 300 mg q.d. was selected for the phase 3 study segment. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01075984","term_id":"NCT01075984"}}NCT01075984.)