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Voriconazole Treatment of Invasive Aspergillosis : Real-World versus Health-Economic Model Results.
Clin Drug Investig. 2008; 28(8): 509-521
Van Campenhout H, Marbaix S, Derde MP, Annemans L
OBJECTIVE: The objective of this study was to assess, in a real-world setting, the predictive validity (in terms of clinical outcome and treatment cost) of the voriconazole arm of a health-economic model applied in the Belgian reimbursement submission for use of voriconazole in the treatment of invasive aspergillosis. METHODS: A non-interventional study was designed to prospectively collect clinical response and direct costs data related to the treatment of invasive aspergillosis with voriconazole (oral, intravenous) in real-world practice. The outcomes of this study were compared with the inputs and outputs of the health-economic model. For the analysis, unit costs of 2002 from the public payer's perspective, as used in the model, were applied. RESULTS: Data from 116 patients with invasive aspergillosis starting treatment with voriconazole were collected. At 12 weeks, there were similar rates of satisfactory clinical response for the observational study and the model, the latter based on the results of a clinical study (50% vs 53%, respectively). Overall mortality rates at 84 days were 42% in the observational study and 29% in the model. Average total healthcare cost associated with voriconazole treatment was lower in the observational study compared with the model for all patients. When the cost for all hospitalization days from the start until the end of the fungal infection was included in the analysis, the average total cost was euro19 674. When the cost for only those hospitalization days solely related to the fungal infection was included in the analysis, the average total cost was euro12 376. These costs are below the cost predicted by the model of euro21 298. CONCLUSIONS: This analysis demonstrates that the results provided in the voriconazole arm of the health-economic model were valid estimates with regard to real-world outcomes but with a slightly better survival rate and higher costs than in real life.
Diagn Microbiol Infect Dis. 2008 Jun 30;
Rautemaa R, Richardson M, Pfaller MA, Perheentupa J, Saxén H
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, APS-I) is exceptionally common in Finland. Most patients have chronic oral candidiasis since childhood. Thus, most patients receive repeated courses of antifungals throughout their life. Eleven of our patients (31.4%) have become colonized with Candida albicans with decreased sensitivity to fluconazole. A total of 43 isolates of C. albicans from 23 APECED patients isolated during the years 1994 to 2004 were divided into 2 groups: fluconazole-susceptible dose-dependent (MIC, 16-32 mug/mL, 18 isolates) and fluconazole-susceptible (MIC
Curr Opin Infect Dis. 2008 Aug; 21(4): 409-14
Marr KA
PURPOSE OF REVIEW: Infectious complications after hematopoietic stem cell transplant, especially those caused by fungi, contribute to poor outcomes. Availability of new antifungal drugs has led to creative attempts to prevent infections caused by both yeasts and molds with new antifungal prophylaxis strategies; these studies will be reviewed. RECENT FINDINGS: Trials evaluating mold-active azoles, posaconazole and voriconazole, demonstrate that invasive aspergillosis infections can be prevented by prophylactic therapy in patients with hematologic malignancies and after allogeneic hematopoietic stem cell transplant. However, issues arise regarding appropriate dosing and levels, drug interactions, and the importance of breakthrough infections caused by organisms that demonstrate microbiologic resistance. Other recent studies evaluating efficacy and safety of aerosolized lipid formulations of amphotericin B demonstrate promise with directed delivery to the lungs; more long-term follow-up safety information is needed to be assured that this strategy is safe late after allogeneic hematopoietic stem cell transplant, in the setting of acute and chronic graft vs. host disease. SUMMARY: Clinicians should consider using new mold-active azole drugs for prophylaxis instead of fluconazole in allogeneic hematopoietic stem cell transplant recipients that have high risks due to prolonged neutropenia and severe graft vs. host disease. More investigations are needed to support other preventive strategies that utilize diagnostic tests and aerosolized delivery of amphotericin B formulations.
Nihon Kokyuki Gakkai Zasshi. 2008 Jun; 46(6): 448-54
Kiyokawa H, Nakashima R, Takafuji S, Suzuki Y, Ito A
A 58-year-old Japanese man was admitted with high fever, productive cough, marked leukocytosis, and chest X-ray findings of infiltration and fluid levels within lung cysts. He had been treated for pulmonary tuberculosis for 6 months. He was also receiving home oxygen therapy for chronic obstructive pulmonary disease and 10 mg prednisolone daily for rheumatoid arthritis. Aspergillus fumigatus was cultured from bronchial washing fluid and we diagnosed chronic necrotizing pulmonary aspergillosis (CNPA). Micafungin was initially effective but 9 weeks later the symptoms recurred. Micafungin was stopped and after combination therapy of intravenous liposomal amphotericin B and oral itraconazole capsule was started his symptoms and laboratory data markedly improved. Fifteen weeks later his medication was switched to oral voriconazole and he was discharged. CNPA is a chronic infectious disease with poor prognostic and no standard therapy has been confirmed. Each antifungal drug has different mechanisms and sites of action. In the case of treatment failure with several drugs, combination therapy to achieve drug interaction can be a treatment option.
Intern Med J. 2008 Jun; 38(6b): 477-495
Morrissey CO, Bardy PG, Slavin MA, Ananda-Rajah MR, Chen SC, Kirsa SW, Ritchie DS, Upton A
Persistent or recurrent fevers of unknown origin (PFUO) in neutropenic patients on broad-spectrum antibiotics have traditionally been treated with empirical antifungal therapy (EAFT). The lack of survival benefit seen with the use of amphotericin B deoxycholate (AmB-D) as EAFT has been attributed to its toxicities. More recently, newer, less toxic and more expensive antifungal agents such as the lipid formulations of AmB, the newer azoles (fluconazole, itraconazole and voriconazole) and caspofungin have been analysed in a number of EAFT trials. Compared with AmB-D the newer agents have superior safety but are of equivalent efficacy. This lack of survival advantage is related to the fact that the trigger for commencement of EAFT is late and non-specific. Thus, alternative approaches are required. New sensitive serological and molecular tests for the detection of Aspergillus antigens and genomic DNA have been developed and evaluated in accuracy studies. These tests have been incorporated into management strategies (i.e. pre-emptive strategies) to direct antifungal therapy. The pre-emptive approach has been shown to be safe and feasible but its impact on clinically important patient outcomes such as survival is less clear. Other advances include the introduction of effective, non-toxic mould-active antifungal prophylaxis and patient risk-group stratification. In this paper we provide new evidence-based algorithms for the diagnosis and treatment of PFUO in adult patients undergoing stem cell transplantation and chemotherapy for haematological malignancy which incorporate these newer diagnostic tests and are directed by the risk category of the patient and type of antifungal prophylaxis the patient is receiving.
Voriconazole in the treatment of fungal eye infections: a review of current literature.
Br J Ophthalmol. 2008 Jul; 92(7): 871-8
Hariprasad SM, Mieler WF, Lin TK, Sponsel WE, Graybill JR
BACKGROUND: Voriconazole has an important role to play in the prophylaxis and management of fungal endophthalmitis and keratitis. New-generation triazoles, including voriconazole, posaconazole and ravuconazole, have been shown in laboratory studies and clinical experience to have very good safety profiles with few side effects. Fungal eye infections, while not common in temperate climates, have been notoriously difficult to diagnose and treat, and generally result in protracted therapy with poor final outcomes. Current treatment options are far from optimal. AIMS: This paper will review studies and clinical case reports published in the ophthalmic literature that address the safety of these drugs in the eye, penetration and concentration in ocular tissues and media, and efficacy in treating common pathogens implicated in fungal keratitis and endophthalmitis. CONCLUSIONS: Over 40 clinical case reports of treatment with voriconazole suggest that it may be used safely and effectively against a broad range of fungal pathogens.
Visual disturbance comorbid with hallucination caused by voriconazole in the Japanese population.
Int J Hematol. 2008 Jun 24;
Imataki O, Ohnishi H, Kitanaka A, Kubota Y, Ishida T, Tanaka T
Voriconazole (VRCZ) has a curious visual adverse event that is completely reversible, but its mechanism has not been fully addressed. We observed 20 consecutive patients treated with VRCZ after chemotherapy for hematological malignancy. Six of these cases experienced visual disturbance, and all cases among those treated with oral VRCZ. The authors discuss a relatively higher frequency of visual events complicated with hallucination, which might be associated with a special metabolism of VRCZ in Japanese patients with hematological malignancies. Hallucination and oral administration were specific clinical features for the patients presenting with visual adverse events in response to VRCZ.
Antifungal activity of 25-azalanosterol against Candida species.
Eur J Clin Microbiol Infect Dis. 2008 Jun 24;
Wang J, Wu J
The antifungal properties of 25-azalanosterol was investigated. Compared to normal antifungal reagents, fluoconazole, clotrimazole and voriconazole, it exhibited significant anti-Candida activity (the minimum inhibitory concentration [MIC] ranges were 0.125-8, 0.5-8 and 0.5-32 microg/mL against C. albicans, C. krusei and C. glabrata, respectively), but showed little toxicity to mice liver cells at clinical dosage after 24 h of exposure, with the lowest lactate dehydrogenase and the highest ED(50) compared to four other azoles antifungal agents. 25-Azalanosterol inhibited the incorporation of [methyl-(3)H(3)] AdoMet into the C-24 of ergosterol in whole cells of C. albicans. Thus, 25-azalanosterol, as an inhibitor of the growth of C. albicans in vitro, may have considerable potential as a new class of anti-Candida agent that lacks toxic side effects in the mammalian host.
Eur J Clin Microbiol Infect Dis. 2008 Jun 18;
Nomura K, Fujimoto Y, Kanbayashi Y, Ikawa K, Taniwaki M
Voriconazole has been shown to be safe and effective for fungal infection. However, its population pharmacokinetics for patients with hematological malignancies remains unknown. We performed a population pharmacokinetics study of nine hematological patients with 36 points samples. We approximated the drug concentration curve using a linear one-compartment model. The distribution of volume (Vd), elimination rate constant, and clearance (CL) were 68.7 L, 0.163 h(-1), and 11.2 L/h, respectively. By coincidence, our study has verified that the current administration is enough to treat fungus infections by using Monte Carlo simulation. Our data demonstrated that the current administration method is appropriate and effective. Our results may prove to be useful as a basic reference for the clinical usage of voriconazole.
J Clin Microbiol. 2008 Jun 18;
Pfaller MA, Messer SA, Boyken L, Rice C, Tendolkar S, Hollis RJ, Diekema DJ
Few data exist to describe in vitro patterns of cross resistance among large collections of clinical Aspergillus, including species other than A. fumigatus. We examined 771 Aspergillus spp. clinical isolates collected from 2000-2006 as part of a global antifungal surveillance program (553 A. fumigatus, 76 A. flavus, 59 A. niger, 35 A. terreus, 24 A. versicolor, and 24 other Aspergillus species). Antifungal susceptibility testing was performed by the Clinical and Laboratory Standards Institute (CLSI) M38-A broth dilution method against itraconazole( ITR), posaconazole (POS), ravuconazole (RAV) and voriconazole (VOR). We examined the potential for cross-resistance using measures of correlation overall and by species. Most Aspergillus had MICs of 2 microg/mL to VOR or POS remain extremely rare (