Disease relevance of Voriconazole

• We evaluated, retrospectively, the outcome and survival of 81 patients who were treated with voriconazole for definite (n = 48) or probable (n = 33) CNS aspergillosis [1].
• An exception was 1 patient with a brain abscess, successfully treated with voriconazole and surgical drainage [2].
• Successful treatment with voriconazole of invasive aspergillosis in chronic granulomatous disease [3].
• OBJECTIVE: Voriconazole is a broad-spectrum triazole antifungal agent under investigation for opportunistic infections that often target immunosuppressed patients [4].
• In the present studies, we evaluated topical voriconazole as therapy for P. lilacinus keratitis in rabbits [5].

Psychiatry related information on Voriconazole

• After discontinuing voriconazole the hallucinations decreased in intensity by the 2nd day and ceased altogether by the 3rd day [6].
• From a medical perspective, confirmation of the diagnosis, the need for long-term antifungal therapy, the need for long-term patient compliance, and the use of the new antifungal agent voriconazole are emphasized [7].
• In multivariable models, salvage therapy with the combination of voriconazole and caspofungin was associated with reduced mortality, compared with therapy with voriconazole (HR, 0.28; 95% CI, 0.28-0.92; P=.011), independent of other prognostic variables (e.g., receipt of transplant and type of conditioning therapy) [8].

High impact information on Voriconazole

• Improved outcome in central nervous system aspergillosis, using voriconazole treatment [1].
• This study thus assessed the effect of the potent CYP3A4 inhibitor ritonavir after short-term administration on voriconazole pharmacokinetics in extensive metabolizers (EMs) and poor metabolizers (PMs) of CYP2C19 [9].
• This reduction occurred in all CYP2C19 genotypes (463+/-168 mL/min versus 305+/-112 mL/min [P = .023] for *1/*1, 343+/-127 mL/min versus 190+/-93 mL/min [P = .008] for *1/*2, and 158+/-54 mL/min versus 22+/-11 mL/min for *2/*2) and is probably caused by inhibition of CYP3A4-mediated voriconazole metabolism [9].
• It is reasonable to assume that patients receiving voriconazole require 70% to 90% less alfentanil for the maintenance of analgesia than patients who are not receiving concomitant CYP3A inhibitors [10].
• Effect of voriconazole on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam [11].

Chemical compound and disease context of Voriconazole

• The second-generation triazole, voriconazole, was superior to conventional amphotericin B as primary therapy for invasive aspergillosis, and is the new standard of care for this infection [12].
• Newer antifungals such as voriconazole and caspofungin, which are more potent in vitro and have a broader spectrum of activity, including activity against fluconazole-resistant Candida species are a welcome addition to the antifungal armamentarium that may be used in the management of refractory mucosal candidiasis [13].
• It is concluded that voriconazole is highly efficacious in the prevention and treatment of Aspergillus endocarditis in the guinea pig and is superior to itraconazole in these respects [14].
• We evaluated combinations of voriconazole (VRC) and liposomal amphotericin B (L-AMB) in a guinea pig invasive aspergillosis model [15].
• Synergism of voriconazole and terbinafine against Candida albicans isolates from human immunodeficiency virus-infected patients with oropharyngeal candidiasis [16].

Biological context of Voriconazole

• METHODS: In a controlled, open-label study, single oral doses of 400 mg voriconazole were administered to 16 healthy men stratified for CYP2C19 genotype before and on day 1 and day 15 of concomitant SJW intake (300 mg LI 160 3 times daily) [17].
• CONCLUSIONS: In this population of severely immunocompromised patients with life-threatening IFI who have failed or were intolerant to standard antifungal therapy, voriconazole demonstrated substantial efficacy and an acceptable level of toxicity [18].
• Voriconazole has several important safety issues, including visual adverse events, hepatic enzyme elevation and skin reactions, as well as a number of drug interactions [19].
• The voriconazole free drug AUC/MIC ratios were similar for all of the organisms studied (range, 11 to 58; mean +/- standard deviation, 24 +/- 17 [P = 0.45]) [20].
• Voriconazole is rapidly absorbed within 2 hours after oral administration and the oral bioavailability is over 90%, thus allowing switching between oral and intravenous formulations when clinically appropriate [21].

Anatomical context of Voriconazole

• Voriconazole was measured in tissue samples of brain, liver, kidney, heart, lung as well as cerebrospinal fluid [21].
• Voriconazole Concentration in Human Aqueous Humor and Plasma during Topical or Combined Topical and Systemic Administration for Fungal Keratitis [22].
• The antifungal activity of voriconazole (VCZ) was tested against Candida albicans in the absence or presence of polymorphonuclear neutrophils (PMN) or monocytes [23].
• Clinically relevant concentrations of voriconazole inhibited the metabolism of tacrolimus in human liver microsomes [24].
• We demonstrate that while both antifungal drugs are inhibitory, only voriconazole completely inhibited fungal growth, allowing long-term maintenance of T-cell cultures [25].

Associations of Voriconazole with other chemical compounds

• RESULTS: Voriconazole decreased the mean plasma clearance of intravenous alfentanil by 85%, from the control value of 4.4 +/- 2.4 mL . min(-1). kg(-1) to 0.67 +/- 0.27 mL . min(-1). kg(-1) (P < .001), and prolonged its elimination half-life from 1.5 +/- 0.49 hours to 6.6 +/- 1.8 hours (P < .001) [10].
• Voriconazole and fluconazole had only weak effects on the pharmacokinetics of R-(-)-ibuprofen [26].
• All Aspergillus isolates were inhibited by </=1 microg of voriconazole/ml, including isolates with increased resistance to amphotericin B and itraconazole [27].
• Only minor differences between the tested antifungals were observed since 16 of 20 and 17 of 20 of the isolates of Aspergillus spp. tested appeared to be killed by voriconazole and itraconazole, respectively [28].
• The MICs and fractional inhibitory concentrations of posaconazole (POS) and voriconazole (VRZ), alone and in combination with amphotericin B (AMB), for the conidia and hyphae of 100 Aspergillus isolates were evaluated [29].
• Exposure of Rhizopus oryzae to itraconazole, amphotericin B, or caspofungin and exposure of Aspergillus fumigatus to voriconazole did not alter the virulence of these isolates in fruit flies [30].

Gene context of Voriconazole

• Activity against C. krusei in the presence of voriconazole was greatest when MDM were activated with IFN-gamma rather than GM-CSF [31].
• Five hematopoietic stem cell transplant recipients that developed breakthrough Candida glabrata bloodstream infections while receiving voriconazole are described and the clinical management and susceptibility profiles of their isolates are reported [32].
• These results were confirmed by expressing the CYP51 genes from C. krusei and C. albicans in Saccharomyces cerevisiae and determining the susceptibility of the transformants to voriconazole and fluconazole [33].
• Using different inoculation models of IA, we found that Toll-deficient Drosophila flies exposed to voriconazole (VRC), the preferred drug for the treatment of IA in humans, had significantly better survival rates and lower tissue fungal burdens than did those not exposed to VRC [34].
• Our primary objective was to compare the results of voriconazole disk diffusion testing of Candida spp. performed by centers participating in the ARTEMIS program with disk diffusion and MIC results obtained by the central reference laboratory [35].

Analytical, diagnostic and therapeutic context of Voriconazole

• Plasma and urine concentrations of voriconazole were determined by liquid chromatography with mass-spectrometric detection [17].
• SJW might put CYP2C19 wild-type individuals at highest risk for potential voriconazole treatment failure [17].
• Close monitoring of the blood concentration and adjustment in the dose of tacrolimus are warranted in transplant recipients treated with voriconazole [24].
• The predictive pharmacokinetic/pharmacodynamic parameter for voriconazole treatment efficacy in Candida infections is the free drug AUC from 0 to 24 hour : minimum inhibitory concentration ratio [21].
• Steady-state plasma concentrations are reached approximately 5 days after both intravenous and oral administration; however, steady state is reached within 24 hours with voriconazole administered as an intravenous loading dose [21].

References