BACKGROUND: Voriconazole therapeutic drug monitoring (TDM) is increasingly used in clinical practice. However, the utility of voriconazole TDM to guide therapy remains uncertain and controversial. We conducted a meta-analysis of studies assessing the relationship between voriconazole serum concentration and clinical outcomes of success and toxicity. METHODS: We searched bibliographic databases for studies on voriconazole serum concentrations and clinical outcomes. We compared success outcomes between patients with therapeutic and subtherapeutic voriconazole serum concentrations, and toxicity outcomes between patients with and without supratherapeutic serum concentrations. RESULTS: Twenty-four studies were analysed. Pooled analysis for efficacy endpoint demonstrated that patients with therapeutic voriconazole serum concentrations (1.0-2.2 mg/L) were more likely to have successful outcomes compared with those with subtherapeutic voriconazole serum concentrations (OR 2.30; 95% CI 1.39-3.81). A therapeutic threshold of 1.0 mg/L was most predictive of successful outcome (OR 1.94; 95% CI 1.04-3.62). Patients with therapeutic concentrations did not have better survival rates. Pooled analysis for toxicity endpoint demonstrated that patients with supratherapeutic voriconazole serum concentrations (4.0-6.0 mg/L) were at increased risk of toxicity (OR 4.17; 95% CI 2.08-8.36). A supratherapeutic threshold of 6.0 mg/L was most predictive of toxicity (OR 4.60; 95% CI 1.49-14.16). CONCLUSIONS: Patients with therapeutic voriconazole serum concentrations were twice as likely to achieve successful outcomes. The likelihood of toxicity associated with supratherapeutic voriconazole serum concentrations was 4-fold that of therapeutic concentrations. Our findings suggest that the use of voriconazole TDM to aim for serum concentrations between 1.0 and 6.0 mg/L during therapy may be warranted to optimize clinical success and minimize toxicity.

• MeSH
• antifungální látky škodlivé účinky   krev   terapeutické užití   MeSH
• invazivní mykotické infekce farmakoterapie   prevence a kontrola   MeSH
• lidé MeSH
• monitorování léčiv * MeSH
• mykózy farmakoterapie   MeSH
• vorikonazol škodlivé účinky   krev   terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH

This study aimed to explore pharmacokinetics of voriconazole and its covariates in lung transplant recipients using population approach in order to propose dosing individualization. Data from routine therapeutic drug monitoring in adult lung transplant recipients treated with oral voriconazole were analysed with a three-stage population pharmacokinetic model using nonlinear mixed-effects modelling. Monte Carlo simulations based on final voriconazole pharmacokinetic model were used to generate the theoretical distribution of pharmacokinetic profiles at various dosing regimens. A total of 78 voriconazole serum concentrations collected from 40 patients were included in pharmacokinetic analysis. The only significant covariate was age for voriconazole clearance. Population voriconazole apparent clearance started at 32.26 L/h and decreased by 0.021 L/h with each year of patient's age, while population apparent volume of distribution was 964.46 L. Based on this model, we have proposed an easy-to-use dosing regimen consisting of a loading dose of 400 mg every 12 h for the first 48 h of treatment followed by maintenance dose of 300 mg every 12 h in patients aged up to 59 years, or by maintenance dose of 200 mg every 12 h in patients aged above 59 years.

• MeSH
• biologické modely MeSH
• dospělí MeSH
• lidé MeSH
• metoda Monte Carlo MeSH
• monitorování léčiv * MeSH
• plíce MeSH
• příjemce transplantátu * MeSH
• senioři MeSH
• vorikonazol farmakokinetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH

Voriconazole and posaconazole are azole broadspectrum pharmaceuticals used in treatment and prophylaxis of invasive fungal infections. Determination of both the antifungals in blood plasma in the course of treatment makes it possible to achieve optimal dosing. Our aim was to integrate voriconazole and posaconazole monitoring in the treatment of fungal infections in hematooncological patients. At present the simple and rapid ultra performance liquid chromatography (UPLC) monitoring of both the antifungal is a part of daily routine.

• MeSH
• antifungální látky terapeutické užití   MeSH
• autoimunitní nemoci MeSH
• financování organizované MeSH
• lidé MeSH
• monitorování léčiv metody   MeSH
• triazoly analýza   krev   MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• Check Tag
• lidé MeSH

• MeSH
• antifungální látky aplikace a dávkování   krev   MeSH
• azoly krev   MeSH
• lidé MeSH
• monitorování léčiv metody   MeSH
• výsledek terapie MeSH
• vysokoúčinná kapalinová chromatografie metody   MeSH
• Check Tag
• lidé MeSH

• Klíčová slova
• posakonazol,
• MeSH
• antifungální látky * škodlivé účinky   terapeutické užití   MeSH
• dospělí MeSH
• fluoridy krev   MeSH
• hematologické nádory * komplikace   terapie   MeSH
• homologní transplantace MeSH
• itrakonazol škodlivé účinky   terapeutické užití   MeSH
• kosterní svaly patologie   MeSH
• lidé MeSH
• nemoci kostí * epidemiologie   chemicky indukované   MeSH
• pyrimidiny škodlivé účinky   terapeutické užití   MeSH
• retrospektivní studie MeSH
• transplantace hematopoetických kmenových buněk MeSH
• triazoly škodlivé účinky   terapeutické užití   MeSH
• vorikonazol MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• souhrny MeSH

The distribution for voriconazole and fluconazole susceptibility was determined by Etest and disk diffusion test in 143 clinical isolates. The majority of the strains of Aspergillus spp., Candida krusei, C. inconspicua, C norvegensis and Saccharomyces cerevisiae displayed resistance or decreased susceptibility to fluconazole in contrast to voriconazole. The absolute categorical agreement for voriconazole and fluconazole susceptibility results by the disk method and Etest was 90.5 and 74.8 % respectively. The error rate bounding analysis showed only 0.7 % of false susceptible results ( very major error) with voriconazole, but 2.8 % with fluconazole. Fluconazole can be used as a surrogate factor to predict voriconazole susceptibility but with lower reliability for susceptible-dose dependent and resistance category, especially in Candida glabrata isolates. The results of the disk method were not substantially influenced by the composition of media (Mueller-Hinton agar vs antimycotic Sensitivity Test agar), even if with the latter the results had fewer tendencies to produce false susceptibility of C.glabrata isolates to both of the triazole drugs. Disk test as well as Etest were shown to represent suitable methods for routine evaluation of susceptibility of clinical isolates of pathogenic fungi, including aspergilli, to fluconazole and voriconazole.

• MeSH
• antifungální látky farmakologie   MeSH
• diskové difúzní antimikrobiální testy metody   MeSH
• flukonazol farmakologie   MeSH
• fungální léková rezistence MeSH
• houby izolace a purifikace   účinky léků   MeSH
• kultivační média chemie   MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• mykózy farmakoterapie   mikrobiologie   MeSH
• pyrimidiny farmakologie   MeSH
• triazoly farmakologie   MeSH
• Check Tag
• lidé MeSH

The objective of this retrospective study was to evaluate results from voriconazole therapeutic drug monitoring (TDM) in haematological patients in routine clinical practice. Between 2005 and 2010, 1228 blood samples were obtained from 264 haematological patients (median 3 samples/patient; range 1-27) receiving voriconazole for targeted/preemptive treatment of invasive aspergillosis (IA) (46.3% of samples), empirical therapy (12.9%) or prophylaxis (40.8%). A high-pressure liquid chromatography assay was used to analyse voriconazole concentrations. Clinical and laboratory data were analysed retrospectively. The median of the detected voriconazole plasma concentration was 1.00 μg ml(-1) (range <0.20-13.47 μg ml(-1)). Significant inter- and intra-patients variability of measured concentrations (81.9% and 50.5%) were identified. With the exception of omeprazole administration, there was no relevant relationship between measured voriconazole concentrations and drug dose, route administration, age, gender, CYP2C19*2 genotype, gastrointestinal tract abnormality, administration via nasogastric tube, serum creatinine, and liver enzymes. However, per patient analysis identified significant role of individual voriconazole dose and drug form change on measured plasma concentration. Measured voriconazole concentrations did not correlate with the treatment outcome of patients with IA. We only identified a limited number of adverse events related to voriconazole therapy; however, the median plasma concentration was not different from concentrations measured in samples without reported toxicity. Our retrospective study has suggested that routine monitoring of voriconazole plasma concentrations has probably only a limited role in daily haematological practice.

• MeSH
• antifungální látky aplikace a dávkování   škodlivé účinky   krev   MeSH
• aromatické hydroxylasy genetika   MeSH
• aspergilóza komplikace   farmakoterapie   genetika   MeSH
• dospělí MeSH
• jednonukleotidový polymorfismus MeSH
• krevní nemoci komplikace   farmakoterapie   genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• monitorování léčiv * MeSH
• pyrimidiny aplikace a dávkování   škodlivé účinky   krev   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• triazoly aplikace a dávkování   škodlivé účinky   krev   MeSH
• výsledek terapie MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

INTRODUCTION: Voriconazole represents an essential part of antimicrobial therapy in critically ill patients. The aim of this study was to exclude a significant alteration in voriconazole pharmacokinetics in critically ill patients undergoing continuous venovenous hemofiltration (CVVH). METHODS: Six patients dependent on CVVH with evidence of an invasive mycotic infection treated with intravenous voriconazole at the standard dosing regimen were investigated. The total serum concentration of voriconazole in arterial blood and the concentration in ultrafiltrate were measured by reverse-phase high-performance liquid chromatography with ultraviolet detection. The authors profiled a 5-point pharmacokinetic concentration-time curve during the 12-hour standard maintenance dosing interval and derived the basic pharmacokinetic parameters. RESULTS: The serum voriconazole concentration did not decrease <1.0 mg/L at any time point, and the mean was 4.3 ± 2.6 mg/L and the median (range) 3.6 (9.0) mg/L. The sieving coefficient of the drug did not exceed 0.30 in any patient (0.22 ± 0.08). The mean serum AUC0-12, the mean total clearance, and the mean clearance via CVVH were 53.52 ± 29.97 mg·h/L [the median (range) of 57.74 (62.34) mg·h/L], 0.11 ± 0.07 L·h-1·kg-1, and 0.007 ± 0.003 L·h-1·kg-1, respectively. The clearance by the CVVH method ranged from 4% to 20% of the total drug clearance. The disposition of voriconazole was not compromised. The mean elimination half-life was 27.58 ± 35.82 hours [the median of 13.10 (92.21) hours], and the mean distribution volume value was 3.28 ± 3.10 L/kg [the median of 2.01 (8.10) L/kg]. Marked variability in serum concentrations, elimination half-life, distribution volume, and total clearance was seen. Half of the patients showed some drug accumulation. CONCLUSIONS: The clearance of voriconazole by CVVH is not clinically significant. In view of this finding, voriconazole dose adjustment in patients undergoing the standard method of CVVH is not required. However, the observed potential for an unpredictable voriconazole accumulation suggests the usefulness for monitoring its levels in critically ill patients.

• MeSH
• antiinfekční látky aplikace a dávkování   krev   farmakokinetika   MeSH
• hemofiltrace MeSH
• kritický stav MeSH
• lidé MeSH
• monitorování léčiv metody   MeSH
• mykózy krev   farmakoterapie   metabolismus   MeSH
• plocha pod křivkou MeSH
• poločas MeSH
• pyrimidiny aplikace a dávkování   krev   farmakokinetika   MeSH
• triazoly aplikace a dávkování   krev   farmakokinetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• práce podpořená grantem MeSH

BACKGROUND: Data on safety and efficacy of voriconazole for invasive aspergillosis (IA) and invasive candidiasis/esophageal candidiasis (IC/EC) in pediatric patients are limited. METHODS: Patients aged 2-<18 years with IA and IC/EC were enrolled in 2 prospective open-label, non-comparative studies of voriconazole. Patients followed dosing regimens based on age, weight and indication, with adjustments permitted. Treatment duration was 6-12 weeks for IA patients, ≥14 days after last positive Candida culture for IC patients and ≥7 days after signs/symptoms resolution for EC patients. Primary analysis for both the studies was safety and tolerability of voriconazole. Secondary end points included global response success at week 6 and end of treatment (EOT), all-causality mortality and time to death. Voriconazole exposure-response relationship was explored. RESULTS: Of 53 voriconazole-treated pediatric patients (31 IA; 22 IC/EC), 14 had proven/probable IA, 7 had confirmed IC and 10 had confirmed EC. Treatment-related hepatic and visual adverse events, respectively, were reported in 22.6% and 16.1% of IA patients, and 22.7% and 27.3% of IC/EC patients. All-causality mortality in IA patients was 14.3% at week 6; no deaths were attributed to voriconazole. No deaths were reported for IC/EC patients. Global response success rate was 64.3% (week 6 and EOT) in IA patients and 76.5% (EOT) in IC/EC patients. There was no association between voriconazole exposure and efficacy; however, a slight positive association between voriconazole exposure and hepatic adverse events was established. CONCLUSIONS: Safety and efficacy outcomes in pediatric patients with IA and IC/EC were consistent with previous findings in adult patients.

• MeSH
• antifungální látky aplikace a dávkování   škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• aspergilóza farmakoterapie   MeSH
• dítě MeSH
• kandidóza invazivní farmakoterapie   MeSH
• kandidóza farmakoterapie   MeSH
• lidé MeSH
• mladiství MeSH
• předškolní dítě MeSH
• prospektivní studie MeSH
• vorikonazol aplikace a dávkování   škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH

There are only a few antifungal drugs used systemically in treatment, and invasive fungal infections that are resistant to these drugs are an emerging problem in health care. In this study, we performed a high-copy-number genomic DNA (gDNA) library screening to find and characterize genes that reduce susceptibility to amphotericin B, caspofungin, and voriconazole in Saccharomyces cerevisiae We identified the PDR16 and PMP3 genes for amphotericin B, the RMD9 and SWH1 genes for caspofungin, and the MRS3 and TRI1 genes for voriconazole. The deletion mutants for PDR16 and PMP3 were drug susceptible, but the other mutants had no apparent susceptibility. Quantitative-PCR analyses suggested that the corresponding drugs upregulated expression of the PDR16, PMP3, SWH1, and MRS3 genes. To further characterize these genes, we also profiled the global expression patterns of the cells after treatment with the antifungals and determined the genes and paths that were up- or downregulated. We also cloned Candida albicans homologs of the PDR16, PMP3, MRS3, and TRI1 genes and expressed them in S. cerevisiae Heterologous expression of Candida homologs also provided reduced drug susceptibility to the budding yeast cells. Our analyses suggest the involvement of new genes in antifungal drug resistance.

• MeSH
• amfotericin B farmakologie   MeSH
• antifungální látky farmakologie   MeSH
• Candida albicans účinky léků   genetika   metabolismus   MeSH
• fungální léková rezistence genetika   MeSH
• kaspofungin farmakologie   MeSH
• mikrobiální testy citlivosti MeSH
• Saccharomyces cerevisiae - proteiny genetika   metabolismus   MeSH
• Saccharomyces cerevisiae účinky léků   genetika   metabolismus   MeSH
• Saccharomycetales účinky léků   genetika   metabolismus   MeSH
• vorikonazol farmakologie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH