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Rachel Harrington, Edward Lee, Hongbo Yang, Jin Wei, Andrew Messali, Nkechi Azie, Eric Q Wu, James Spalding
INTRODUCTION: Invasive aspergillosis (IA) is associated with a significant clinical and economic burden. The phase III SECURE trial demonstrated non-inferiority in clinical efficacy between isavuconazole and voriconazole. No studies have evaluated the cost-effectiveness of isavuconazole compared to voriconazole. The objective of this study was to evaluate the costs and cost-effectiveness of isavuconazole vs. voriconazole for the first-line treatment of IA from the US hospital perspective...
December 2, 2016: Advances in Therapy
Markus Ruhnke, Stefan Schwartz
Patients with hematological cancer have a high risk of invasive fungal diseases (IFDs). These infections are mostly life threatening and an early diagnosis and initiation of appropriate antifungal therapy are essential for the clinical outcome. Most commonly, Aspergillus and Candida species are involved. However, other non-Aspergillus molds are increasingly be identified in cases of documented IFDs. Important risk factors are long lasting granulocytopenia with neutrophil counts below 500/μl for more than 10 days or graft-versus-host disease resulting from allogeneic stem-cell transplantation...
December 2016: Therapeutic Advances in Hematology
Jingjing Yu, Zhu Zhou, Katie H Owens, Tasha K Ritchie, Isabelle Ragueneau-Majlessi
As a follow-up to previous reviews, the aim of the present analysis was to systematically examine all drug metabolism, transport, PK, and DDI data available in the 33 NDAs and 12 BLAs approved by the FDA in 2015, using the University of Washington Drug Interaction Database©, and to highlight the significant findings. All of the NDAs were well-characterized with regard to drug metabolism, transport, and/or organ impairment, and were fully analyzed in this review. In vitro, a majority of the NMEs were found to be substrates or inhibitors/inducers of at least one DME or transporter...
November 7, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Maiken Cavling Arendrup, Paul Verweij, Henrik Vedel Nielsen
We evaluated the "MIC Strip Isavuconazole" test against EUCAST E.Def 9.3 using 40 wild-type and 39 CYP51A mutant A. fumigatus Full (FIE) and 80% growth inhibition (80%-IE) strip endpoints were determined by two independent readers (R1/R2). The essential (within ±0, ±1 and ±2 two-fold dilutions) and categorical agreement were best for the FIE (R1/R2: 42%/41%, 75%/73% and 90%/89%, and 91.1%/92.4%, with 6.3/8.9% VMEs and 0/1.3% MEs, respectively). The isavuconazole strip test with FIE appears useful.
October 31, 2016: Antimicrobial Agents and Chemotherapy
Teclegiorgis Gebremariam, Nathan P Wiederhold, Abdullah Alqarihi, Priya Uppuluri, Nkechi Azie, John E Edwards, Ashraf S Ibrahim
OBJECTIVES: Previously we demonstrated the benefit of isavuconazole in treating murine mucormycosis due to Rhizopus. We wanted to determine the efficacy of isavuconazole in treating murine mucormycosis caused by Mucor, the second most common cause of the disease. Furthermore, because we previously determined that Rhizopus possesses the target enzyme for echinocandins and micafungin has activity against murine mucormycosis, we compared the activity of combination therapy (isavuconazole + micafungin) with placebo, either drug alone or standard therapy of liposomal amphotericin B (LAmB) in treating pulmonary murine mucormycosis caused by Rhizopus delemar...
October 24, 2016: Journal of Antimicrobial Chemotherapy
J Meletiadis, Klaus Leth Mortensen, Paul E Verweij, J W Mouton, M C Arendrup
OBJECTIVES: Given the increasing number of antifungal drugs and the emergence of resistant Aspergillus isolates, objective, automated and high throughput antifungal susceptibility testing is important. The EUCAST E.Def 9.3 reference method for MIC determination of Aspergillus species relies on visual reading. Spectrophotometric reading was not adopted due to a concern that non-uniform filamentous growth might lead to unreliable and non-reproducible results. We therefore evaluated spectrophotometric reading for the determination of MICs of antifungal azoles against Aspergillus fumigatus...
October 25, 2016: Clinical Microbiology and Infection
Ghady Haidar, Christa S Zerbe, Michelle Cheng, Adrian M Zelazny, Steven M Holland, Kathleen R Sheridan
Aspergillus spp. are a leading cause of mortality in chronic granulomatous disease (CGD), but other fungi have emerged in the era of mould prophylaxis. Of these, Phellinus spp. are an under-recognised cause of invasive fungal infections (IFIs) in CGD, and data on their presentation and management are scarce. We present a patient with CGD who developed disseminated IFI involving the lungs and brain. Surgical specimens grew a basidiomycete which was disregarded as a contaminant. After three months of progressive disease despite antifungals, he was diagnosed with Phellinus tropicalis by internal transcribed spacer (ITS) sequencing...
October 26, 2016: Mycoses
Matt Shirley, Lesley J Scott
Isavuconazole is a second-generation triazole with activity against a broad spectrum of clinically important fungi. Its water-soluble prodrug, isavuconazonium sulfate (Cresemba(®)), available in interchangeable intravenous and oral formulations, is approved in the USA and EU for the treatment of adults with invasive aspergillosis and mucormycosis. In international phase III clinical trials, isavuconazole was efficacious and generally well tolerated in the treatment of these life-threatening diseases. In the phase III SECURE trial, isavuconazole was non-inferior to voriconazole for the primary treatment of invasive mould disease (primarily aspergillosis) and was associated with fewer drug-related treatment-emergent adverse events (TEAEs) than voriconazole...
November 2016: Drugs
Daisuke Hagiwara, Akira Watanabe, Katsuhiko Kamei, Gustavo H Goldman
Invasive aspergillosis is a life-threatening mycosis caused by the pathogenic fungus Aspergillus. The predominant causal species is Aspergillus fumigatus, and azole drugs are the treatment of choice. Azole drugs approved for clinical use include itraconazole, voriconazole, posaconazole, and the recently added isavuconazole. However, epidemiological research has indicated that the prevalence of azole-resistant A. fumigatus isolates has increased significantly over the last decade. What is worse is that azole-resistant strains are likely to have emerged not only in response to long-term drug treatment but also because of exposure to azole fungicides in the environment...
2016: Frontiers in Microbiology
Alessandro Busca, Livio Pagano
Invasive fungal infections (IFI) represent a major hindrance to the success of hematopoietic stem cell transplantation (HSCT), contributing substantially to morbidity and infection-related mortality. During the most recent years several reports indicate an overall increase of IFI among hematologic patients, in particular, invasive aspergillosis, that may be explained, at least partially, by the fact that diagnoses only suspected in the past, are now more easily established due to the application of serum biomarkers and early use of CT scan...
2016: Mediterranean Journal of Hematology and Infectious Diseases
Tinashe K Nyazika, Patricia F Herkert, Ferry Hagen, Kudzanai Mateveke, Valerie J Robertson, Jacques F Meis
Cryptococcus neoformans is the leading cause of cryptococcosis in HIV-infected subjects worldwide. Treatment of cryptococcosis is based on amphotericin B, flucytosine, and fluconazole. In Zimbabwe, little is known about antifungal susceptibility of Cryptococcus. Sixty-eight genotyped Cryptococcus isolates were tested for antifungal profiles. Amphotericin B, isavuconazole, and voriconazole showed higher activity than other triazoles. Fluconazole and flucytosine were less effective, with geometric mean MICs of 2...
November 2016: Diagnostic Microbiology and Infectious Disease
Derek Murrell, John B Bossaer, Ronald Carico, Sam Harirforoosh, David Cluck
OBJECTIVE: To review the place in therapy of isavuconazole, the active metabolite of isavuconazonium sulfate, via a review of the available literature on drug chemistry, spectrum of activity, pharmacokinetic/pharmacodynamic profile and trials assessing clinical efficacy and safety. METHODS: Relevant data, original research articles and reviews, were gathered primarily through the use of a PubMed database search. The search was conducted without date restrictions in order to collect both historical and recent data regarding isavuconazole...
August 29, 2016: International Journal of Pharmacy Practice
Dustin T Wilson, V Paul Dimondi, Steven W Johnson, Travis M Jones, Richard H Drew
Despite recent advances in both diagnosis and prevention, the incidence of invasive fungal infections continues to rise. Available antifungal agents to treat invasive fungal infections include polyenes, triazoles, and echinocandins. Unfortunately, individual agents within each class may be limited by spectrum of activity, resistance, lack of oral formulations, significant adverse event profiles, substantial drug-drug interactions, and/or variable pharmacokinetic profiles. Isavuconazole, a second-generation triazole, was approved by the US Food and Drug Administration in March 2015 and the European Medicines Agency in July 2015 for the treatment of adults with invasive aspergillosis (IA) or mucormycosis...
2016: Therapeutics and Clinical Risk Management
J Steinmann, S Dittmer, J Houbraken, J Buer, P-M Rath
In vitro susceptibilities of a large collection of Rasamsonia isolates (n=47) belonging to seven species were determined for the novel triazole isavuconazole and six other antifungal agents. Isavuconazole and voriconazole had no in vitro activity (minimum inhibitory concentration >32 mg/liter) against isolates from the Rasamsonia argillacea species complex. The echinocandins were the most potent antifungal drugs against all isolates (minimum effective concentration ≤ 0.19 mg/liter).
August 15, 2016: Antimicrobial Agents and Chemotherapy
P F Herkert, F Hagen, G L de Oliveira Salvador, R R Gomes, M S Ferreira, V A Vicente, M D Muro, R L Pinheiro, J F Meis, F Queiroz-Telles
Cryptococcosis, caused by Cryptococcus gattii sensu lato, is an emerging disease that was initially found in (sub)tropical regions but recently expanded to temperate regions. Cryptococcus gattii s.l. infections are mostly encountered in healthy individuals, frequently affecting both lungs and the central nervous system (CNS). Usually, C. gattii s.l. is less susceptible to antifungal compounds than its counterpart, C. neoformans s.l. We studied 18 clinical C. gattii s.l. isolates with amplified fragment length polymorphism (AFLP) fingerprinting, mating-typing, multi-locus sequence typing (MLST) and antifungal susceptibility testing...
November 2016: European Journal of Clinical Microbiology & Infectious Diseases
Aradhana Masih, Pradeep K Singh, Shallu Kathuria, Kshitij Agarwal, Jacques F Meis, Anuradha Chowdhary
Aspergillus species cause a wide spectrum of clinical infections. Although Aspergillus fumigatus and Aspergillus flavus remain the most commonly isolated species in aspergillosis, in the last decade, rare and cryptic Aspergillus species have emerged in diverse clinical settings. The present study analyzed the distribution and in vitro antifungal susceptibility profiles of rare Aspergillus species in clinical samples from patients with suspected aspergillosis in 8 medical centers in India. Further, a matrix-assisted laser desorption ionization-time of flight mass spectrometry in-house database was developed to identify these clinically relevant Aspergillus species...
September 2016: Journal of Clinical Microbiology
Amit Desai, Laura Kovanda, Donna Kowalski, Qiaoyang Lu, Robert Townsend, Peter L Bonate
Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent used for the treatment of invasive fungal infections. The objective of this analysis was to develop a population pharmacokinetic (PPK) model to identify covariates that affect isavuconazole pharmacokinetics and to determine the probability of target attainment (PTA) for invasive aspergillosis patients. Data from nine phase 1 studies and one phase 3 clinical trial (SECURE) were pooled to develop the PPK model (NONMEM, version 7...
September 2016: Antimicrobial Agents and Chemotherapy
Anne Schmitt-Hoffmann, Amit Desai, Donna Kowalski, Helene Pearlman, Takao Yamazaki, Robert Townsend
OBJECTIVE/METHODS: Two openlabel, single-dose, randomized crossover studies and one open-label, multiple-dose, parallel group study in healthy volunteers were conducted with the prodrug, isavuconazonium sulfate, to determine absolute bioavailability of the active triazole, isavuconazole (EudraCT 2007-004949-15; n = 14), and the effect of food (EudraCT 2007- 004940-63; n = 26), and pH (NCT02128893; n = 24) on the absorption of isavuconazole. Isavuconazonium sulfate 744 mg designed to deliver 400 mg of the active triazole isavuconazole was administered in the absolute bioavailability (oral or intravenous (IV) (2-hour infusion)) and food-effect studies (oral)...
August 2016: International Journal of Clinical Pharmacology and Therapeutics
Monica A Donnelley, Elizabeth S Zhu, George R Thompson
We have a limited arsenal with which to treat invasive fungal infections caused by Aspergillus and Mucorales. The morbidity and mortality for both pathogens remains high. A triazole antifungal, isavuconazole, was recently granted approval by the US Food and Drug Administration and the European Medicines Agency for the treatment of invasive aspergillosis and mucormycosis. A randomized double-blind comparison trial for the treatment of invasive aspergillosis found isavuconazole noninferior to voriconazole. A separate, open-label study evaluating the efficacy of isavuconazole in the treatment of mucormycosis found comparable response rates to amphotericin B and posaconazole treated historical controls...
2016: Infection and Drug Resistance
Nathan P Wiederhold, Laura Kovanda, Laura K Najvar, Rosie Bocanegra, Marcos Olivo, William R Kirkpatrick, Thomas F Patterson
We evaluated the efficacy of isavuconazole against cryptococcal meningitis. Treatment with either oral isavuconazole (120 mg/kg and 240 mg/kg twice a day [BID]) or fluconazole as the positive control significantly improved survival in mice infected intracranially with either Cryptococcus neoformans USC1597 or H99 and significantly reduced brain fungal burdens for both isolates. Concentrations of isavuconazole in plasma and brain tissue also demonstrated that the greatest improvements in survival and fungal burden were associated with elevated exposures...
September 2016: Antimicrobial Agents and Chemotherapy
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