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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
Treavor T Riley, Christina A Muzny, Edwin Swiatlo, Davey P Legendre
OBJECTIVE: To review the current literature for the pathogenesis of mucormycosis, discuss diagnostic strategies, and evaluate the efficacy of polyenes, triazoles, and echinocandins as pharmacological treatment options. DATA SOURCES: An electronic literature search was conducted in PubMed using the MESH terms Rhizopus, zygomycetes, zygomycosis, Mucorales and mucormycosis, with search terms amphotericin B, micafungin, anidulafungin, caspofungin, extended infusion amphotericin B, liposomal amphotericin B, combination therapy, triazole, posaconazole, isavuconazole, diagnosis, and clinical manifestations...
September 2016: Annals of Pharmacotherapy
Amit Desai, Takao Yamazaki, Albert J Dietz, Donna Kowalski, Christopher Lademacher, Helene Pearlman, Shahzad Akhtar, Robert Townsend
This phase I trial evaluated pharmacokinetic and pharmacodynamic interactions between the novel triazole antifungal agent, isavuconazole, and warfarin in healthy adults. Multiple doses of isavuconazole were administered as the oral prodrug, isavuconazonium sulfate (372 mg three times a day for two days loading dose, then 372 mg once-daily thereafter; equivalent to isavuconazole 200 mg) in the presence and absence of single doses of oral warfarin sodium 20 mg. Co-administration with isavuconazole increased the mean area under the plasma concentration-time curves from time zero to infinity of S- and R-warfarin by 11% and 20%, respectively, but decreased the mean maximum plasma concentrations of S- and R-warfarin by 12% and 7%, respectively, relative to warfarin alone...
June 9, 2016: Clinical Pharmacology in Drug Development
Robert Townsend, Albert Dietz, Christine Hale, Shahzad Akhtar, Donna Kowalski, Christopher Lademacher, Kenneth Lasseter, Helene Pearlman, Diane Rammelsberg, Anne Schmitt-Hoffmann, Takao Yamazaki, Amit Desai
This report describes the phase I trials that evaluated the metabolism of the novel triazole antifungal, isavuconazole, by cytochrome P450 3A4 (CYP3A4) and isavuconazole's effects on CYP3A4-mediated metabolism in healthy adults. Co-administration of oral isavuconazole (100 mg once daily) with oral rifampin (600 mg once daily; CYP3A4 inducer) decreased isavuconazole area under the concentration-time curve (AUCtau ) during a dosing interval by 90% and maximum concentration (Cmax ) by 75%. Conversely, co-administration of isavuconazole (200 mg single dose) with oral ketoconazole (200 mg twice daily; CYP3A4 inhibitor) increased isavuconazole AUC from time zero to infinity (AUC0-∞ ) and Cmax by 422% and 9%, respectively...
June 8, 2016: Clinical Pharmacology in Drug Development
Andreas H Groll, Amit Desai, David Han, Corrie Howieson, Kota Kato, Shahzad Akhtar, Donna Kowalski, Christopher Lademacher, William Lewis, Helene Pearlman, Debra Mandarino, Takao Yamazaki, Robert Townsend
This report summarizes phase 1 studies that evaluated pharmacokinetic interactions between the novel triazole antifungal agent isavuconazole and the immunosuppressants cyclosporine, mycophenolic acid, prednisolone, sirolimus, and tacrolimus in healthy adults. Healthy subjects received single oral doses of cyclosporine (300 mg; n = 24), mycophenolate mofetil (1000 mg; n = 24), prednisone (20 mg; n = 21), sirolimus (2 mg; n = 22), and tacrolimus (5 mg; n = 24) in the presence and absence of clinical doses of oral isavuconazole (200 mg 3 times daily for 2 days; 200 mg once daily thereafter)...
June 8, 2016: Clinical Pharmacology in Drug Development
Takao Yamazaki, Amit Desai, David Han, Kota Kato, Donna Kowalski, Shahzad Akhtar, Christopher Lademacher, Laura Kovanda, Robert Townsend
This phase I, open-label study evaluated the pharmacokinetic effects of co-administration of the antifungal agent, isavuconazole (administered as its water-soluble prodrug isavuconazonium sulfate) with the antiretroviral agent, lopinavir/ritonavir, in healthy adults. In Part 1, 13 subjects were randomized to two arms to receive multiple doses of oral isavuconazole 100 mg either alone or with lopinavir/ritonavir 400/100 mg. In Part 2, a different group of 55 subjects were randomized to three arms to receive multiple doses of oral isavuconazole 200 mg, either alone or with lopinavir/ritonavir 400/100 mg, or to receive oral lopinavir/ritonavir 400/100 mg alone...
June 8, 2016: Clinical Pharmacology in Drug Development
Takao Yamazaki, Amit Desai, Ronald Goldwater, David Han, Corrie Howieson, Shahzad Akhtar, Donna Kowalski, Christopher Lademacher, Helene Pearlman, Diane Rammelsberg, Robert Townsend
This report describes phase I clinical trials performed to assess interactions of oral isavuconazole at the clinically targeted dose (200 mg [administered as isavuconazonium sulfate 372 mg] three times a day for 2 days; 200 mg once daily thereafter) with single oral doses of the cytochrome P450 (CYP) substrates: bupropion hydrochloride (CYP2B6; 100 mg; n = 24), repaglinide (CYP2C8/CYP3A4; 0.5 mg; n = 24), caffeine (CYP1A2; 200 mg; n = 24), dextromethorphan hydrobromide (CYP2D6/CYP3A4; 30 mg; n = 24), and methadone (CYP2B6/CYP2C19/CYP3A4; 10 mg; n = 23)...
June 8, 2016: Clinical Pharmacology in Drug Development
Takao Yamazaki, Amit Desai, Ronald Goldwater, David Han, Kenneth C Lasseter, Corrie Howieson, Shahzad Akhtar, Donna Kowalski, Christopher Lademacher, Diane Rammelsberg, Robert Townsend
This article summarizes 4 phase 1 trials that explored interactions between the novel, triazole antifungal isavuconazole and substrates of the drug transporters breast cancer resistance protein (BCRP), multidrug and toxin extrusion protein-1 (MATE1), organic anion transporters 1/3 (OAT1/OAT3), organic anion-transporting polypeptide 1B1 (OATP1B1), organic cation transporters 1/2 (OCT1/OCT2), and P-glycoprotein (P-gp). Healthy subjects received single doses of atorvastatin (20 mg; OATP1B1 and P-gp substrate), digoxin (0...
June 8, 2016: Clinical Pharmacology in Drug Development
Maria N Chitasombat, Dimitrios P Kontoyiannis
PURPOSE OF REVIEW: Mucormycosis is an opportunistic mold infection whose management is difficult, as there is a paucity of evidence-based data. We summarize the latest advances in diagnosis and management of mucormycosis in transplant recipients. RECENT FINDINGS: There is promise for improvement in nonculture-based diagnostics with new biomarkers of Mucorales DNA that can be used for early diagnosis, and monitoring of response. Antifungal treatment consists of high-dose lipid formulations of amphotericin B or isavuconazole as the first-line therapy and posaconazole as salvage therapy...
August 2016: Current Opinion in Infectious Diseases
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