314 results on '"Kontoyiannis, Dimitrios P"'
Search Results
2. The modern face of esophageal candidiasis in an oncology center: Correlating clinical manifestations, endoscopic grade, and pathological data in 323 contemporary cancer patients.
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Matsuo T, Singh BS, Wurster S, Jiang Y, Bhutani MS, Chatterjee D, and Kontoyiannis DP
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- Humans, Male, Female, Middle Aged, Retrospective Studies, Aged, Adult, Aged, 80 and over, Risk Factors, Neoplasms complications, Neoplasms pathology, Candida isolation & purification, Candida classification, Esophageal Diseases pathology, Esophageal Diseases microbiology, Esophageal Diseases drug therapy, Treatment Failure, Esophageal Neoplasms pathology, Esophageal Neoplasms microbiology, Candidiasis microbiology, Candidiasis pathology, Candidiasis drug therapy, Candidiasis epidemiology, Fluconazole therapeutic use, Antifungal Agents therapeutic use
- Abstract
Objectives: Clinical presentation and outcomes of esophageal candidiasis (EC) in cancer patients are scarcely studied in the azole era, as is the correlation between clinical, endoscopic, and histopathological EC manifestations., Methods: We retrospectively reviewed the risk factors, clinical features, and outcomes of pathology-documented EC cases at MD Anderson Cancer Center. We further assessed associations between presence of symptoms, standardized 4-stage endoscopic grade (Kodsi classification), histopathological data, and fluconazole treatment failure., Results: Among 323 cancer patients with EC, 89% had solid tumors, most commonly esophageal cancer (29%). Thirty-three percent of EC patients were asymptomatic. The proportion of symptomatic EC patients significantly increased with endoscopic grade (P = 0.005). Among 202 patients receiving oral fluconazole, 27 (13%) had treatment failure. Underlying esophageal disease was the only independent predictor of fluconazole treatment failure (odds ratio: 3.88, P = 0.005). Endoscopic grade correlated significantly with Candida organism burden (Correlation coefficient [ρ] = 0.21, P < 0.01) and neutrophilic inflammation (ρ = 0.18, P < 0.01). Candida invasion of the squamous mucosal layer was associated with treatment failure (P = 0.049)., Conclusions: EC was predominantly encountered in patients with solid tumors. One-third of EC patients were asymptomatic, challenging traditional symptom-based diagnosis. The development of integrated clinicopathological scoring systems could further guide the therapeutic management of cancer patients with EC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. D.P.K reports honoraria and research support from Gilead Sciences and Astellas Pharma. He received consultant fees from Astellas Pharma, Merck, and Gilead Sciences, Knight and is a member of the Data Review Committee of Cidara Therapeutics, AbbVie, Scynexis and the Mycoses Study Group. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed, (Copyright © 2024. Published by Elsevier Ltd.)
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- 2024
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3. Investigational Antifungal Agents for Invasive Mycoses: A Clinical Perspective.
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Lamoth F, Lewis RE, and Kontoyiannis DP
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- Aspergillus, Azoles pharmacology, Azoles therapeutic use, Drug Resistance, Fungal, Fungi, Humans, Microbial Sensitivity Tests, Antifungal Agents pharmacology, Antifungal Agents therapeutic use, Invasive Fungal Infections drug therapy
- Abstract
Treatment of invasive fungal infections (IFIs) remains challenging, because of the limitations of the current antifungal agents (ie, mode of administration, toxicity, and drug-drug interactions) and the emergence of resistant fungal pathogens. Therefore, there is an urgent need to expand our antifungal armamentarium. Several compounds are reaching the stage of phase II or III clinical assessment. These include new drugs within the existing antifungal classes or displaying similar mechanism of activity with improved pharmacologic properties (rezafungin and ibrexafungerp) or first-in-class drugs with novel mechanisms of action (olorofim and fosmanogepix). Although critical information regarding the performance of these agents in heavily immunosuppressed patients is pending, they may provide useful additions to current therapies in some clinical scenarios, including IFIs caused by azole-resistant Aspergillus or multiresistant fungal pathogens (eg, Candida auris, Lomentospora prolificans). However, their limited activity against Mucorales and some other opportunistic molds (eg, some Fusarium spp.) persists as a major unmet need., Competing Interests: Potential conflicts of interest. F. L. has received research grants from the Swiss National Science Foundation, the Santos-Suarez Foundation, Novartis, Pfizer, and Merck and has participated on advisory boards for Gilead and Pfizer. R. E. L. has received research grants from Merck and Gilead; has participated on advisory boards for Gilead and Cidara therapeutics; and reports consulting fees from Cidara Therapeutics and F2G Therapeutics. D. P. K. has received research support from Astellas, Merck, T2 Biosystems, Pfizer, and Gilead and honoraria from Merck, Astellas, Gilead, and Cidara; serves on data review committee for Cidara, Scynegis, and AbbVie; and has received consulting fees from Amplyx, Scynexis, Jazz Pharmaceuticals, and Gilead. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)
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- 2022
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4. Clumping Morphology Influences Virulence Uncoupled from Echinocandin Resistance in Candida glabrata.
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Hu C, Fong G, Wurster S, Kontoyiannis DP, and Beyda ND
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- Animals, Candida glabrata drug effects, Candida glabrata genetics, Fungal Proteins genetics, Fungal Proteins metabolism, Humans, Moths microbiology, Antifungal Agents pharmacology, Candida glabrata growth & development, Candida glabrata pathogenicity, Candidiasis microbiology, Drug Resistance, Fungal, Echinocandins pharmacology
- Abstract
Here, we report two paired sets of an index wild-type Candida glabrata bloodstream isolate and subsequent echinocandin-resistant FKS mutant. One paired set exhibited a higher proportion of clumping cells and was more virulent in the invertebrate host Galleria mellonella than the other paired set. No virulence difference between the paired index and FKS strains was observed. These findings imply a potential link of clumping morphology with virulence in C. glabrata that is uncoupled from FKS-mediated echinocandin resistance. IMPORTANCE Candida glabrata is a leading cause of invasive candidiasis. In contrast to other species, it has a high propensity for developing resistance to echinocandins, which are the first-line treatment. Unlike the dimorphic Candida albicans which can grow invasive filamentous hyphae, C. glabrata lacks this ability. Here, we report a link between virulence and clumping cell morphology in two different sets of clinical C. glabrata strains obtained from patients failing echinocandin therapy. One set of paired strains (echinocandin-susceptible and subsequent resistant mutant) had a high proportion of clumping cells in the population and were significantly more virulent than another set which had fewer clumping cells. Additionally, we corroborate that echinocandin resistance does not impart a significant fitness cost. Our findings suggest that clumping morphology may be an important but previously underestimated virulence factor for C. glabrata and also aid our understand for the high prevalence of resistance observed in this species.
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- 2022
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5. Systemic antifungal therapy with isavuconazonium sulfate or other agents in adults with invasive mucormycosis or invasive aspergillosis (non-fumigatus): A multicentre, non-interventional registry study.
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Thompson GR 3rd, Garcia-Diaz J, Miceli MH, Nguyen MH, Ostrosky-Zeichner L, Young JH, Fisher CE, Clark NM, Greenberg RN, Spec A, Kovanda L, Croos-Dabrera R, and Kontoyiannis DP
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- Adult, Humans, Nitriles adverse effects, Nitriles therapeutic use, Pyridines adverse effects, Pyridines therapeutic use, Registries, Triazoles adverse effects, Triazoles therapeutic use, Antifungal Agents adverse effects, Antifungal Agents therapeutic use, Aspergillosis drug therapy, Invasive Fungal Infections drug therapy, Mucormycosis drug therapy
- Abstract
Background: Isavuconazole, administered as isavuconazonium sulfate (ISAVUSULF), is a broad-spectrum triazole agent for the treatment of invasive fungal disease. In phase 3 studies, ISAVUSULF showed comparable efficacy to voriconazole and amphotericin B for the treatment of invasive aspergillosis (IA) and invasive mucormycosis (IM), respectively., Objectives: The objective of this study is to determine all-cause mortality and safety outcomes among adults with IM and/or IA non-fumigatus (nf) treated with ISAVUSULF or other antifungal therapies (AFT)., Patients and Methods: This multicentre, non-interventional registry enrolled patients aged ≥18 years with IM or IA-nf who received systemic AFT from January 2016 to November 2018. Patients received primary ISAVUSULF, non-primary ISAVUSULF, or other AFT, as monotherapy or combination therapy. The primary end point was all-cause mortality at Days 42 and 84; safety outcomes were adverse drug reactions (ADRs) to ISAVUSULF., Results: Of 204 patients enrolled, 74 received primary ISAVUSULF, 30 non-primary ISAVUSULF, and 100 other AFT. All-cause mortality through Day 42 was numerically lower in the non-primary ISAVUSULF group than in the primary ISAVUSULF and other AFT groups, for patients with IM (20.0% vs. 33.3% and 41.3%, respectively) or IA-nf (0% vs. 14.8% and 17.8%, respectively). All-cause mortality tended to be lower with combination therapy than with monotherapy, except for patients with IM receiving primary ISAVUSULF. Of 111 patients receiving ISAVUSULF, 14 (12.6%) reported ADRs, of whom three (2.7%) developed serious ADRs. There were no drug-related deaths., Conclusions: This study supports the effectiveness and tolerability of ISAVUSULF in clinical practice. Further research is required to confirm the value of ISAVUSULF combination therapy over monotherapy., (© 2021 Wiley-VCH GmbH.)
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- 2022
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6. Effect of High-Dose Posaconazole on Serum Levels in Adult Patients with Hematologic Malignancy.
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DiPippo AJ, McDaneld PM, Tverdek FP, and Kontoyiannis DP
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- Administration, Oral, Adult, Humans, Retrospective Studies, Triazoles, Antifungal Agents therapeutic use, Hematologic Neoplasms drug therapy
- Abstract
Posaconazole (POS) appears to have dose-proportional pharmacokinetics; however, there is a paucity of real-life data. We retrospectively evaluated 67 patients with hematologic cancer who had POS dose increases from 300 mg/day to either 400 mg/day ( n = 52) or 300 mg twice daily (BID) ( n = 15) and for whom POS serum levels were measured. Median POS levels were 840 ng/ml, 1,625 ng/ml, and 2,710 ng/ml for the dosages of 300 mg/day, 400 mg/day, and 300 mg BID, respectively. Significant interpatient variability in serum levels was noted.
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- 2021
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7. Resistance to Antifungal Drugs.
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Ben-Ami R and Kontoyiannis DP
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- Antifungal Agents pharmacology, Humans, Antifungal Agents therapeutic use, Drug Resistance, Microbial, Fungi drug effects, Mycoses drug therapy
- Abstract
Pathogenic fungi have several mechanisms of resistance to antifungal drugs, driven by the genetic plasticity and versatility of their homeostatic responses to stressful environmental cues. We critically review the molecular mechanisms of resistance and cellular adaptations of pathogenic fungi in response to antifungals and discuss the factors contributing to such resistance. We offer suggestions for the translational and clinical research agenda of this rapidly evolving and medically important field. A better understanding of antifungal resistance should assist in developing better detection tools and inform optimal strategies for preventing and treating refractory mycoses in the future., Competing Interests: Disclosure R. Ben-Ami has received consulting fees from Merck & Co., Pfizer and Gilead. D.P. Kontoyiannis has received research support from Gilead and honoraria from Astellas Pharma US; Gilead Sciences, Inc and Mayne, Inc.; He is member of the Cidara, Inc Data review Committee., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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8. How I perform hematopoietic stem cell transplantation on patients with a history of invasive fungal disease.
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Puerta-Alcalde P, Champlin RE, and Kontoyiannis DP
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- Aged, Allografts, Humans, Male, Antifungal Agents therapeutic use, Hematologic Neoplasms immunology, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Transplantation, Invasive Fungal Infections drug therapy, Invasive Fungal Infections immunology
- Abstract
Hematopoietic transplantation is the preferred treatment for many patients with hematologic malignancies. Some patients may develop invasive fungal diseases (IFDs) during initial chemotherapy, which need to be considered when assessing patients for transplantation and treatment posttransplantation. Given the associated high risk of relapse and mortality in the post-hematopoietic stem cell transplantation (HSCT) period, IFDs, especially invasive mold diseases, were historically considered a contraindication for HSCT. Over the last 3 decades, advances in antifungal drugs and early diagnosis have improved IFD outcomes, and HSCT in patients with a recent IFD has become increasingly common. However, an organized approach for performing transplantation in patients with a prior IFD is scarce, and decisions are highly individualized. Patient-, malignancy-, transplantation procedure-, antifungal treatment-, and fungus-specific issues affect the risk of IFD relapse. Effective surveillance to detect IFD relapse post-HSCT and careful drug selection for antifungal prophylaxis are of paramount importance. Antifungal drugs have their own toxicities and interact with immunosuppressive drugs such as calcineurin inhibitors. Immune adjunct cytokine or cellular therapy and surgery can be considered in selected cases. In this review, we critically evaluate these factors and provide guidance for the complex decision making involved in the peri-HSCT management of these patients., (© 2020 by The American Society of Hematology.)
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- 2020
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9. Protective Activity of Programmed Cell Death Protein 1 Blockade and Synergy With Caspofungin in a Murine Invasive Pulmonary Aspergillosis Model.
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Wurster S, Robinson P, Albert ND, Tarrand JJ, Goff M, Swamydas M, Lim JK, Lionakis MS, and Kontoyiannis DP
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- Animals, Disease Models, Animal, Dose-Response Relationship, Drug, Female, Immunohistochemistry, Invasive Pulmonary Aspergillosis drug therapy, Mice, Microbial Sensitivity Tests, Programmed Cell Death 1 Receptor metabolism, Antifungal Agents pharmacology, Aspergillus drug effects, Caspofungin pharmacology, Immune Checkpoint Inhibitors pharmacology, Invasive Pulmonary Aspergillosis metabolism, Invasive Pulmonary Aspergillosis microbiology, Programmed Cell Death 1 Receptor antagonists & inhibitors
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Pharmacological immune checkpoint blockade has revolutionized oncological therapies, and its remarkable success has sparked interest in expanding checkpoint inhibitor therapy in infectious diseases. Herein, we evaluated the efficacy of programmed cell death protein 1 (PD-1) blockade in a murine invasive pulmonary aspergillosis model. We found that, compared with isotype-treated infected control mice, anti-PD-1-treated mice had improved survival, reduced fungal burden, increased lung concentrations of proinflammatory cytokines and neutrophil-attracting chemokines, and enhanced pulmonary leukocyte accumulation. Furthermore, combined treatment with anti-PD-1 and caspofungin resulted in a significant survival benefit compared with caspofungin or anti-PD-1 therapy alone, indicating a synergistic effect between PD-1 inhibitors and immunomodulatory antifungal agents., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)
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- 2020
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10. Core Recommendations for Antifungal Stewardship: A Statement of the Mycoses Study Group Education and Research Consortium.
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Johnson MD, Lewis RE, Dodds Ashley ES, Ostrosky-Zeichner L, Zaoutis T, Thompson GR, Andes DR, Walsh TJ, Pappas PG, Cornely OA, Perfect JR, and Kontoyiannis DP
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- Antifungal Agents pharmacology, Clinical Competence, Drug Monitoring standards, Drug Prescriptions standards, Drug Resistance, Fungal, Humans, Inappropriate Prescribing prevention & control, Mycoses microbiology, Antifungal Agents therapeutic use, Antimicrobial Stewardship standards, Evidence-Based Medicine standards, Mycoses drug therapy, Practice Guidelines as Topic
- Abstract
In recent years, the global public health community has increasingly recognized the importance of antimicrobial stewardship (AMS) in the fight to improve outcomes, decrease costs, and curb increases in antimicrobial resistance around the world. However, the subject of antifungal stewardship (AFS) has received less attention. While the principles of AMS guidelines likely apply to stewarding of antifungal agents, there are additional considerations unique to AFS and the complex field of fungal infections that require specific recommendations. In this article, we review the literature on AMS best practices and discuss AFS through the lens of the global core elements of AMS. We offer recommendations for best practices in AFS based on a synthesis of this evidence by an interdisciplinary expert panel of members of the Mycoses Study Group Education and Research Consortium. We also discuss research directions in this rapidly evolving field. AFS is an emerging and important component of AMS, yet requires special considerations in certain areas such as expertise, education, interventions to optimize utilization, therapeutic drug monitoring, and data analysis and reporting., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)
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- 2020
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11. European confederation of medical mycology expert consult-An ECMM excellence center initiative.
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Koehler P, Denis B, Denning DW, Gangneux JP, Hoenigl M, Kontoyiannis DP, Krause R, Lagrou K, Lass-Flörl C, Maertens J, Mareković I, Meis JF, Molina JM, Pleško S, Prattes J, Rath PM, Rautemaa-Richardson R, Richardson M, Segal E, Seidel D, Spriet I, Steinmann J, Verweij PE, and Cornely OA
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- Europe, Guideline Adherence, Humans, Infectious Disease Medicine methods, Infectious Disease Medicine organization & administration, Mycology methods, Mycoses microbiology, Treatment Outcome, Antifungal Agents therapeutic use, Disease Management, Invasive Fungal Infections drug therapy, Mycology organization & administration, Mycoses drug therapy, Referral and Consultation organization & administration, Registries
- Abstract
Objectives: Difficult-to-treat invasive fungal infections require infectious diseases expert consultation to improve treatment outcome and increase survival rates., Methods: The European Confederation of Medical Mycology (ECMM) intends to provide expert help free of charge by a newly founded ECMM Expert Consultation Service for medical centres around the globe seeking advice when there is no fungal infection consultant available. The expert consult will provide recommendations and broad expertise on difficult-to-treat invasive fungal infections (eg azole-resistant Aspergillus species, Candida auris, mucormycosis) to improve diagnostic and therapeutic management and outcome., Results: The initiative plans global outreach through video conferencing between ECMM Excellence Centers and treating physicians. FungiScope
® registries will be used to structure case information and to evaluate the impact of the collegial advice system at regular intervals. Advice will follow recent guidelines, and EQUAL Scores will be used to measure guideline adherence., Conclusions: Infectious diseases expert consultation should be an integral component of care for patients with difficult-to-treat invasive fungal infections. The ECMM Expert Consult will attend to this matter on a global scale., (© 2020 The Authors. Mycoses published by Blackwell Verlag GmbH.)- Published
- 2020
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12. Comparative in vitro pharmacodynamic analysis of isavuconazole, voriconazole, and posaconazole against clinical isolates of aspergillosis, mucormycosis, fusariosis, and phaeohyphomycosis.
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Lewis RE, Wurster S, Beyda ND, Albert ND, and Kontoyiannis DP
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- Humans, Microbial Sensitivity Tests, Species Specificity, Antifungal Agents pharmacology, Fungi drug effects, Fungi isolation & purification, Mycoses microbiology, Triazoles pharmacology
- Abstract
We compared the in vitro pharmacodynamics of isavuconazole, voriconazole, and posaconazole against 92 clinical isolates from documented cases of invasive aspergillosis, mucormycosis, fusariosis, and phaeohyphomycosis. Whereas inhibitory and fungicidal concentrations of these triazoles were predictably similar with the exception of Mucorales, isavuconazole appeared to have improved pharmacodynamics against Fusarium solani., (Copyright © 2019 Elsevier Inc. All rights reserved.)
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- 2019
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13. Therapeutic Challenges of Non- Aspergillus Invasive Mold Infections in Immunosuppressed Patients.
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Lamoth F and Kontoyiannis DP
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- Drug Resistance, Fungal, Humans, Invasive Fungal Infections microbiology, Antifungal Agents therapeutic use, Immunocompromised Host, Invasive Fungal Infections drug therapy
- Abstract
While Aspergillus spp. remain the major cause of invasive mold infections in hematologic cancer patients and transplant recipients, other opportunistic molds, such as Mucorales , Fusarium , and Scedosporium spp. are increasingly encountered in an expanding population of patients with severe and prolonged immunosuppression. High potential for tissue invasion and dissemination, resistance to multiple antifungals and high mortality rates are hallmarks of these non- Aspergillus invasive mold infections (NAIMIs). Assessment of drug efficacy is particularly difficult in the complex treatment scenarios of NAIMIs. Specifically, correlation between in vitro susceptibility and in vivo responses to antifungals is hard to assess, in view of the multiple, frequently interrelated factors influencing outcomes, such as pharmacokinetic/pharmacodynamic parameters determining drug availability at the site of infection, the net state of immune suppression, delay in diagnosis, or surgical debulking of infectious foci. Our current therapeutic approach of NAIMIs should evolve toward a better integration of the dynamic interactions between the pathogen, the drug and the host. Innovative concepts of experimental research may consist in manipulating the host immune system to induce a specific antifungal response or targeted drug delivery. In this review, we discuss the challenges in the management of NAIMIs and provide an update about the latest advances in diagnostic and therapeutic approaches., (Copyright © 2019 American Society for Microbiology.)
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- 2019
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14. A murine model of cutaneous aspergillosis for evaluation of biomaterials-based local delivery therapies.
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Tatara AM, Watson E, Albert ND, Kontoyiannis PD, Kontoyiannis DP, and Mikos AG
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- Animals, Aspergillosis metabolism, Aspergillosis pathology, Biocompatible Materials pharmacokinetics, Biocompatible Materials pharmacology, Dermatomycoses metabolism, Dermatomycoses pathology, Disease Models, Animal, Drug Evaluation, Preclinical, Female, Mice, Mice, Inbred BALB C, Wound Infection metabolism, Wound Infection pathology, Antifungal Agents chemistry, Antifungal Agents pharmacokinetics, Antifungal Agents pharmacology, Aspergillosis drug therapy, Aspergillus fumigatus metabolism, Dermatomycoses drug therapy, Drug Delivery Systems, Wound Infection drug therapy
- Abstract
Cutaneous fungal infection is a challenging condition to treat that primarily afflicts immunocompromised patients. Local antifungal therapy may permit the delivery of high concentrations of antifungals directly to wounds while minimizing systemic toxicities. However, the field currently lacks suitable in vivo models. Therefore, a large cutaneous wound was created in immunosuppressed mice and inoculated with Aspergillus fumigatus. We fabricated biodegradable polymer microparticles (MPs) that were capable of locally delivering antifungal and characterized in vitro release kinetics. We compared wound bed size, fungal burden, and histological presence of fungi in mice treated with antifungal-loaded MPs. Mice with a cutaneous defect but no infection, mice with infected cutaneous defect but no treatment, and infected mice treated with blank MPs were used as controls. Infection of large wounds inhibited healing and resulted in tissue invasion in an inoculum-dependent manner. MPs were capable of releasing antifungals at concentrations above A. fumigatus Minimum Inhibitory Concentration (MIC) for at least 6 days. Wounds treated with MPs had significantly decreased size compared with no treatment (64.2% vs. 19.4% wound reduction, p = 0.002) and were not significantly different from uninfected controls (64.2% vs. 58.1%, p = 0.497). This murine model may serve to better understand cutaneous fungal infection and evaluate local biomaterials-based therapies. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1867-1874, 2019., (© 2019 Wiley Periodicals, Inc.)
- Published
- 2019
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15. Is Candida auris here to stay? An interview with Dimitrios Kontoyiannis.
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Kontoyiannis DP
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- Antifungal Agents therapeutic use, Candidiasis drug therapy, Candidiasis microbiology, Candidiasis transmission, Communicable Diseases, Emerging epidemiology, Communicable Diseases, Emerging microbiology, Communicable Diseases, Emerging transmission, Cross Infection drug therapy, Cross Infection microbiology, Cross Infection transmission, Disease Management, History, 20th Century, History, 21st Century, Prevalence, Texas, Antifungal Agents pharmacology, Candida drug effects, Candida isolation & purification, Candidiasis epidemiology, Cross Infection epidemiology, Disease Transmission, Infectious, Drug Resistance, Multiple, Fungal
- Abstract
In this exclusive interview, Dimitrios P Kontoyiannis discusses current mycology hot topic, Candida auris. With a focus on the current knowns and unknowns for the pathogenesis, resistance and transmission of this emerging fungal pathogen, in addition to a look at therapeutics and future perspectives. This interview was conducted by Ellen Colvin, Commissioning Editor of Future Microbiology. Dimitrios P Kontoyiannis is the Texas 4000 distinguished endowed professor and deputy head in the Division of Internal Medicine at MD Anderson Cancer Center in Houston (TX, USA). Dr Kontoyiannis has authored over 550 peer-reviewed manuscripts and has given over 330 lectures in national and international conferences and academic institutions in the USA and abroad. He is considered a leading mycology expert world-wide with an H index of 101 and over 43,000 citations. His research group is credited for many and sustained contributions to clinical, translational and experimental mycology. He is the recipient of many national and international awards and is the past president elect of Immunocompromised Host Society (2016-2018).
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- 2019
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16. A Novel Broad Allele-Specific TaqMan Real-Time PCR Method To Detect Triazole-Resistant Strains of Aspergillus fumigatus, Even with a Very Low Percentage of Triazole-Resistant Cells Mixed with Triazole-Susceptible Cells.
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Wang Q, Kontoyiannis DP, Li R, Chen W, Bu D, and Liu W
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- Alleles, Aspergillus fumigatus drug effects, Aspergillus fumigatus genetics, Cytochrome P-450 Enzyme System genetics, Fungal Proteins genetics, Genotyping Techniques methods, Humans, Sensitivity and Specificity, Time Factors, Antifungal Agents pharmacology, Aspergillosis diagnosis, Aspergillus fumigatus isolation & purification, Drug Resistance, Fungal, Molecular Diagnostic Techniques methods, Real-Time Polymerase Chain Reaction methods, Triazoles pharmacology
- Abstract
Invasive aspergillosis caused by triazole-resistant strains of Aspergillus fumigatus is a growing public health concern, as is the occurrence of mixed infections with triazole-resistant and -susceptible A. fumigatus strains. Therefore, it is crucial to develop robust methods to identify triazole-resistant strains of A. fumigatus , even in mixtures of triazole-resistant and -susceptible strains of A. fumigatus In this work, we developed a robust, highly selective, and broad-range allele-specific TaqMan real-time PCR platform consisting of 7 simultaneous assays that detect TR
34 (a 34-bp tandem repeat in the promoter region), TR46 , G54W (a change of G to W at position 54), G54R, L98H, Y121F, and M220I mutations in the cyp51A gene of A. fumigatus The method is based on the widely used TaqMan real-time PCR technology and combines allele-specific PCR with a blocking reagent (minor groove binder [MGB] oligonucleotide blocker) to suppress amplification of the wild-type cyp51A alleles. We used this method to detect triazole-resistant clinical strains of A. fumigatus with a variety of cyp51A gene mutations, as well as the triazole-resistant strains in mixtures of triazole-resistant and -susceptible strains of A. fumigatus The method had high efficiency and sensitivity (300 fg/well, corresponding to about 100 CFU per reaction mixture volume). It could promptly detect triazole resistance in a panel of 30 clinical strains of A. fumigatus within about 6 h. It could also detect cyp51A -associated resistance alleles, even in mixtures containing only 1% triazole-resistant A. fumigatus strains. These results suggest that this method is robustly able to detect cyp51A -associated resistance alleles even in mixtures of triazole-resistant and -susceptible strains of A. fumigatus and that it should have important clinical applications., (Copyright © 2019 American Society for Microbiology.)- Published
- 2019
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17. On the Emergence of Candida auris: Climate Change, Azoles, Swamps, and Birds.
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Casadevall A, Kontoyiannis DP, and Robert V
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- Animals, Candidiasis microbiology, Communicable Diseases, Emerging microbiology, Drug Resistance, Multiple, Fungal, Humans, Microbial Sensitivity Tests, Phylogeny, Antifungal Agents pharmacology, Azoles pharmacology, Birds microbiology, Candida drug effects, Candida pathogenicity, Climate Change, Temperature
- Abstract
The most enigmatic aspect of the rise of Candida auris as a human pathogen is that it emerged simultaneously on three continents, with each clade being genetically distinct. Although new pathogenic fungal species are described regularly, these are mostly species associated with single cases in individuals who are immunosuppressed. In this study, we used phylogenetic analysis to compare the temperature susceptibility of C. auris with those of its close relatives and to use these results to argue that it may be the first example of a new fungal disease emerging from climate change, with the caveat that many other factors may have contributed., (Copyright © 2019 Casadevall et al.)
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- 2019
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18. Drosophila melanogaster as a model to study virulence and azole treatment of the emerging pathogen Candida auris.
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Wurster S, Bandi A, Beyda ND, Albert ND, Raman NM, Raad II, and Kontoyiannis DP
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- Animals, Animals, Genetically Modified, Biopsy, Candida albicans drug effects, Candida albicans pathogenicity, Candidiasis pathology, Disease Models, Animal, Drosophila melanogaster, Microbial Sensitivity Tests, Virulence, Antifungal Agents pharmacology, Azoles pharmacology, Candida drug effects, Candida pathogenicity, Candidiasis drug therapy, Candidiasis microbiology
- Abstract
Objectives: Candida auris is an emerging, often MDR, yeast pathogen. Efficient animal models are needed to study its pathogenicity and treatment. Therefore, we developed a C. auris fruit fly infection model., Methods: TollI-RXA/Tollr632 female flies were infected with 10 different C. auris strains from the CDC Antimicrobial Resistance bank panel. We used three clinical Candida albicans strains as controls. For drug protection assays, fly survival was assessed along with measurement of fungal burden (cfu/g tissue) and histopathology in C. auris-infected flies fed with fluconazole- or posaconazole-containing food., Results: Despite slower in vitro growth, all 10 C. auris isolates caused significantly greater mortality than C. albicans in infected flies, with >80% of C. auris-infected flies dying by day 7 post-infection (versus 67% with C. albicans, P < 0.001-0.005). Comparison of C. auris isolates from different geographical clades revealed more rapid in vitro growth of South American isolates and greater virulence in infected flies, whereas the aggregative capacity of C. auris strains had minimal impact on their growth and pathogenicity. Survival protection and decreased fungal burden of fluconazole- or posaconazole-fed flies infected with two C. auris strains were in line with the isolates' disparate in vitro azole susceptibility. High reproducibility of survival curves for both non-treated and antifungal-treated infected flies was seen, with coefficients of variation of 0.00-0.31 for 7 day mortality., Conclusions: Toll-deficient flies could provide a fast, reliable and inexpensive model to study pathogenesis and drug activity in C. auris candidiasis., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2019
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19. Nitroglycerin-Citrate-Ethanol Catheter Lock Solution Is Highly Effective for In Vitro Eradication of Candida auris Biofilm.
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Vargas-Cruz N, Reitzel RA, Rosenblatt J, Chaftari AM, Wilson Dib R, Hachem R, Kontoyiannis DP, and Raad II
- Subjects
- Amphotericin B pharmacology, Anidulafungin pharmacology, Biofilms, Caspofungin pharmacology, Catheter-Related Infections prevention & control, Ethanol pharmacology, Fluconazole pharmacology, Micafungin pharmacology, Pharmaceutical Solutions, Voriconazole pharmacology, Antifungal Agents pharmacology, Candida drug effects, Catheters microbiology, Citric Acid pharmacology, Nitroglycerin pharmacology
- Abstract
Candida auris poses emerging risks for causing severe central line-associated bloodstream infections. We tested in vitro the ability of antifungal lock solutions to rapidly eradicate C. auris biofilms. Liposomal amphotericin B, amphotericin B deoxycholate, fluconazole, voriconazole, micafungin, caspofungin, and anidulafungin failed to completely eradicate all 10 tested C. auris biofilms. Conversely, nitroglycerin-citrate-ethanol (NiCE) catheter lock solution completely eradicated all replicates for all of C. auris biofilms tested., (Copyright © 2019 American Society for Microbiology.)
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- 2019
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20. Prolonged voriconazole treatment in a patient with chronic lymphocytic leukemia resulting in a litany of chronic overlapping toxicities.
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Rausch CR and Kontoyiannis DP
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- Humans, Male, Middle Aged, Antifungal Agents adverse effects, Coccidioidomycosis drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Meningitis, Fungal drug therapy, Voriconazole adverse effects
- Abstract
Voriconazole is a triazole antifungal with activity against a number of yeast and mold species including Candida, Aspergillosis, Fusarium, and Coccidioides. Invasive fungal infections are associated with high morbidity and mortality, prolonged treatment courses, and occasionally lifelong suppressive therapy. Voriconazole therapy can result in a number of acute toxicities that clinicians are frequently aware of including hepatotoxicity, visual disturbances, and hallucinations; however, there is limited experience with extended durations of voriconazole therapy. We describe the case of a 62-year-old man who developed Coccidioides meningitis as a result of prolonged neutropenia from treatment for chronic lymphocytic leukemia. He was initially treated with a number of different antifungal agents including voriconazole, liposomal amphotericin B, fluconazole, and itraconazole; however, he developed acute toxicity due to those agents. He was successfully re-challenged with voriconazole, and maintained therapeutic serum concentrations throughout treatment. As a result of prolonged voriconazole exposure of over 14 years, he has suffered a number of toxicities, most significantly including actinic keratosis, squamous cell carcinoma, and skeletal fluorosis. To our knowledge, this is the longest continuous use of voriconazole therapy currently in the literature.
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- 2019
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21. Rhodotorula infection in haematological patient: Risk factors and outcome.
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Potenza L, Chitasombat MN, Klimko N, Bettelli F, Dragonetti G, Del Principe MI, Nucci M, Busca A, Fracchiolla N, Sciumè M, Spolzino A, Delia M, Mancini V, Nadali GP, Dargenio M, Shadrivova O, Bacchelli F, Aversa F, Sanguinetti M, Luppi M, Kontoyiannis DP, and Pagano L
- Subjects
- Adolescent, Adult, Aged, Child, Female, Humans, Male, Middle Aged, Mycoses microbiology, Mycoses mortality, Prevalence, Retrospective Studies, Risk Factors, Survival Analysis, Tertiary Care Centers, Treatment Outcome, Young Adult, Antifungal Agents therapeutic use, Hematologic Neoplasms complications, Mycoses drug therapy, Mycoses epidemiology, Rhodotorula isolation & purification
- Abstract
Background: Rhodotorula spp are uncommon yeasts able to cause infections with high mortality rates. Rhodotorula infections have been associated with the presence of central venous catheter (CVC), immunosuppression, exposure to antifungals and the presence of either solid or haematologic malignancies. However, in this latter setting, only a few cases have so far been reported., Objectives: We have conducted a survey for Rhodotorula infections in haematologic patients., Methods: Patients' clinical and microbiological data were collected and correlated to the outcome., Results: A total of 27 cases were detected from 13 tertiary care hospitals. About 78% and 89% of patients had acute leukaemia and CVC. About 70% of patients were exposed to prophylaxis with azoles, mainly posaconazole (37%), 59% were severely neutropenic and 37% underwent allogeneic stem cell transplantation (alloSCT). The most frequent treatments were liposomal amphotericin B (L-AmB) and CVC removal in 17 and 16 patients, respectively. One month post-diagnosis, mortality was 26% and was associated with the presence of mucositis (P = 0.034)., Conclusions: Our study shows that Rhodotorula spp should be considered as aetiologic agents of breakthrough infections in acute leukaemia patients with a CVC, mucositis, who receive prophylaxis with azoles, including posaconazole, and/or undergo alloSCT. Prompt measures, such as L-AmB administration and CVC removal, should be carried out to avoid the high mortality risk of Rhodotorula infections., (© 2018 Blackwell Verlag GmbH.)
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- 2019
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22. Preexposure to Isavuconazole Increases the Virulence of Mucorales but Not Aspergillus fumigatus in a Drosophila melanogaster Infection Model.
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Wurster S, Lewis RE, Albert ND, and Kontoyiannis DP
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- Animals, Aspergillus fumigatus drug effects, Drosophila melanogaster, Female, Mucorales drug effects, Rhizopus drug effects, Rhizopus pathogenicity, Virulence, Antifungal Agents pharmacology, Aspergillus fumigatus pathogenicity, Mucorales pathogenicity, Nitriles pharmacology, Pyridines pharmacology, Triazoles pharmacology
- Abstract
Breakthrough mucormycosis in patients receiving isavuconazole prophylaxis or therapy has been reported. We compared the impact of isavuconazole and voriconazole exposure on the virulence of clinical isolates of Aspergillus fumigatus and different Mucorales species in a Drosophila melanogaster infection model. In contrast to A. fumigatus , a hypervirulent phenotype was found in all tested Mucorales upon preexposure to either voriconazole or isavuconazole. These findings may contribute to the explanation of breakthrough mucormycosis in isavuconazole-treated patients., (Copyright © 2019 American Society for Microbiology.)
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- 2019
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23. Breakthrough Fungal Infections in Patients With Leukemia Receiving Isavuconazole.
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Rausch CR, DiPippo AJ, Bose P, and Kontoyiannis DP
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- Adult, Aged, Aged, 80 and over, Candidemia drug therapy, Candidemia prevention & control, Electronic Health Records, Female, Humans, Male, Middle Aged, Retrospective Studies, Young Adult, Antifungal Agents therapeutic use, Invasive Fungal Infections drug therapy, Invasive Fungal Infections prevention & control, Leukemia complications, Leukemia microbiology, Nitriles therapeutic use, Pyridines therapeutic use, Triazoles therapeutic use
- Abstract
We retrospectively assessed breakthrough invasive fungal infections (b-IFIs) in 100 consecutive patients with leukemia receiving single-agent isavuconazole; 13 had documented b-IFIs (candidiasis in 6, mucormycosis in 4). All b-IFIs were observed in patients with prolonged neutropenia and active leukemia.
- Published
- 2018
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24. How to prophylax against invasive fungal infections in adult ALL? An unmet need.
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Cornely OA and Kontoyiannis DP
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents administration & dosage, Drug Interactions, Female, Humans, Male, Middle Aged, Young Adult, Antifungal Agents administration & dosage, Chemoprevention methods, Invasive Fungal Infections prevention & control, Precursor Cell Lymphoblastic Leukemia-Lymphoma complications
- Abstract
Although the benefit for any type of antifungal prophylaxis in patients with acute myelogenous leukaemia is well accepted, less is known about the risk for invasive fungal infections (IFIs) and the optimal prophylaxis strategies in patients with acute lymphocytic leukaemia (ALL). Based on recent studies, ALL is a disease that appears to be associated with significant risk for IFIs. The pharmacokinetic interactions between azoles and vincristine, an antineoplastic agent that is part of modern combination chemotherapies in ALL, results in clinically significant neurotoxicity that makes the use of azoles problematic. However, a number of questions regarding azole-vincristine interactions remain unanswered. In this viewpoint, we call for a renewed interest in antifungal prophylaxis studies in ALL in view of the availability of several non-azole novel antifungal agents that are under preclinical and/or clinical development. This is clearly a major unmet need in modern clinical mycology., (© 2018 Blackwell Verlag GmbH.)
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- 2018
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25. Advances in the diagnosis and treatment of fungal infections of the CNS.
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Schwartz S, Kontoyiannis DP, Harrison T, and Ruhnke M
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- Delayed Diagnosis, Humans, Risk Factors, Antifungal Agents therapeutic use, Central Nervous System Fungal Infections diagnosis, Central Nervous System Fungal Infections drug therapy
- Abstract
Fungal infections of the CNS are challenging to treat and their optimal management requires knowledge of their epidemiology, host characteristics, diagnostic criteria, and therapeutic options. Aspergillus and Cryptococcus species predominate among fungal infections of the CNS. Most of these fungi are ubiquitous, but some have restricted geographical distribution. Fungal infections of the CNS usually originate from primary sites outside the CNS (eg, fungal pneumonia) or occur after inoculation (eg, invasive procedures). Most patients with these infections have immunodeficiencies, but immunocompetent individuals can also be infected through heavy exposure. The infecting fungi can be grouped into moulds, yeasts, and dimorphic fungi. Substantial progress has been made with new diagnostic approaches and the introduction of novel antifungal drugs, but fungal infections of the CNS are frequently lethal because of diagnostic delays, impaired drug penetration, resistance to antifungal treatments, and inadequate restoration of immune function. To improve outcomes, future research should advance diagnostic methods (eg, molecular detection and fungus identification), develop antifungal compounds with enhanced CNS-directed efficacy, and further investigate crucial host defence mechanisms., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
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- 2018
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26. Impact of unresolved neutropenia in patients with neutropenia and invasive aspergillosis: a post hoc analysis of the SECURE trial.
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Kontoyiannis DP, Selleslag D, Mullane K, Cornely OA, Hope W, Lortholary O, Croos-Dabrera R, Lademacher C, Engelhardt M, and Patterson TF
- Subjects
- Adult, Aged, Aspergillus drug effects, Female, Humans, Invasive Pulmonary Aspergillosis complications, Male, Middle Aged, Neutropenia etiology, Neutropenia mortality, Nitriles therapeutic use, Pyridines therapeutic use, Treatment Outcome, Triazoles therapeutic use, Voriconazole therapeutic use, Antifungal Agents therapeutic use, Invasive Pulmonary Aspergillosis drug therapy, Invasive Pulmonary Aspergillosis immunology, Neutropenia microbiology
- Abstract
Background: Historically, baseline neutropenia and lack of neutrophil recovery have been associated with poor outcomes in invasive aspergillosis (IA). It is unclear how treatment with the new Aspergillus-active triazoles isavuconazole and voriconazole affects outcomes in neutropenic patients with IA., Methods: A post hoc analysis of the Phase 3 SECURE trial assessed patients with neutropenia (neutrophil count <0.5 × 109/L for >10 days at baseline) with IA (proven/probable) who had received either isavuconazole or voriconazole. The primary endpoint was all-cause mortality (ACM) through day 42. ACM in patients with resolved versus unresolved neutropenia at day 7 and overall success at end of treatment (EOT) were also assessed., Results: One hundred and forty-two patients with neutropenia and IA were included (isavuconazole n = 78, voriconazole n = 64). ACM through day 42 (primary endpoint), day 7 and EOT were higher for patients with unresolved versus resolved neutropenia at each timepoint (day 42, unresolved: 45.0% isavuconazole, 45.2% voriconazole; resolved: 5.0% isavuconazole, 5.9% voriconazole; day 7, unresolved: 31.0% isavuconazole, 29.8% voriconazole; resolved: 5.0% isavuconazole, 5.9% voriconazole; EOT, unresolved: 48.6% isavuconazole, 36.4% voriconazole; resolved: 5.0% isavuconazole, 14.3% voriconazole). ACM was significantly higher for isavuconazole-treated patients with unresolved versus resolved neutropenia (day 7, P = 0.031; day 42, P < 0.001; EOT, P < 0.001). In voriconazole-treated patients, ACM was significantly higher among patients with unresolved versus resolved neutropenia at day 42 (P = 0.002) and numerically higher at day 7 and EOT (P > 0.05 for both)., Conclusions: Isavuconazole had comparable efficacy and safety to voriconazole in neutropenic patients with IA. Resolution of neutropenia was associated with improved outcomes.
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- 2018
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27. Persistent CNS toxicity in a patient receiving posaconazole tablets after discontinuation of voriconazole due to supratherapeutic serum levels.
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Foolad F and Kontoyiannis DP
- Subjects
- Humans, Male, Middle Aged, Tablets administration & dosage, Tablets adverse effects, Voriconazole administration & dosage, Voriconazole adverse effects, Antifungal Agents administration & dosage, Antifungal Agents adverse effects, Brain Diseases chemically induced, Brain Diseases pathology, Serum chemistry, Triazoles administration & dosage, Triazoles adverse effects
- Published
- 2018
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28. Anidulafungin for the treatment of candidaemia caused by Candida parapsilosis: Analysis of pooled data from six prospective clinical studies.
- Author
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Kontoyiannis DP, Bassetti M, Nucci M, Capparella MR, Yan JL, Aram J, and Hogan PA
- Subjects
- Administration, Intravenous, Adult, Anidulafungin, Antifungal Agents administration & dosage, Antifungal Agents adverse effects, Azoles pharmacology, Azoles therapeutic use, Candidemia microbiology, Candidiasis, Invasive drug therapy, Clinical Trials as Topic, Echinocandins administration & dosage, Echinocandins adverse effects, Female, Fluconazole pharmacology, Fluconazole therapeutic use, Humans, Male, Microbial Sensitivity Tests, Middle Aged, Prospective Studies, Treatment Outcome, Antifungal Agents therapeutic use, Candida parapsilosis drug effects, Candidemia drug therapy, Echinocandins therapeutic use
- Abstract
Concerns with echinocandin use for infections caused by Candida parapsilosis complex species have driven the need for data to support echinocandin clinical efficacy in such patients. Data from six prospective studies were pooled to assess efficacy and safety of anidulafungin in patients with candidaemia caused by C. parapsilosis. Patient-level data were pooled from patients with microbiologically confirmed candidaemia due to C. parapsilosis treated with anidulafungin. Patients received a 200 mg intravenous (IV) loading dose of anidulafungin (day 1) and 100 mg daily thereafter. IV treatment could be switched to oral azole therapy after ≥5 or ≥10 days. Primary endpoint was global response at end of IV therapy (EOIVT). Seventy patients had candidaemia caused by C. parapsilosis. Global response was 77.1% (95% CI: 67.3, 87.0) at EOIVT and 70.0% (95% CI: 59.3, 80.7) at end of treatment. Three of 55 isolates (with MICs available) were resistant to anidulafungin (MIC ≥8 mg/L). All-cause mortality was 5.7% (n=4/70) by day 14 and 14.3% (n=10/70) by day 28. IV anidulafungin was effective for the treatment of C. parapsilosis candidaemia in this population, consistent with efficacy previously demonstrated for other Candida species. (ClinicalTrials.gov identifiers: NCT00496197, NCT00548262, NCT00537329, NCT00689338, NCT00806351, NCT00805740)., (© 2017 Blackwell Verlag GmbH.)
- Published
- 2017
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29. Epidemiology of antifungal resistance in human pathogenic yeasts: current viewpoint and practical recommendations for management.
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Farmakiotis D and Kontoyiannis DP
- Subjects
- Humans, Prevalence, Yeasts isolation & purification, Antifungal Agents administration & dosage, Antifungal Agents pharmacology, Antimicrobial Stewardship methods, Drug Resistance, Fungal, Mycoses epidemiology, Mycoses microbiology, Yeasts drug effects
- Abstract
In this review, we describe the epidemiology and clinical significance of resistance in Candida spp. and other non-Cryptococcus yeasts. The rise in echinocandin resistance, azole resistance and cross-resistance to two or more antifungal classes [multidrug resistance (MDR)] has been a worrisome trend, mainly in US large tertiary and oncology centres, particularly as it relates to Candida glabrata. Candida kefyr is also a concern as it can be resistant to echinocandins and polyenes, especially in patients with haematological malignancies. Lately, Candida auris has drawn a lot of attention: this uncommon Candida spp. is the first globally emerging fungal pathogen that exhibits MDR and strong potential for nosocomial transmission. Its almost simultaneous spread in four continents could be indicative of increasing selection pressures from the use of antifungal agents. Echinocandin non-susceptibility is also common among non-Candida, non-Cryptococcus yeasts. As Candida resistance patterns reflect, in part, institutional practices of antifungal administration, the benefits of antifungal stewardship protocols are increasingly recognised and endorsed in recent guidelines. Development of rapid diagnostic methods for detecting or ruling out the presence of candidaemia and antifungal resistance, as well as discovery of novel antifungals, are key priorities in medical mycology research., (Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)
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- 2017
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30. Antifungal Resistance: An Emerging Reality and A Global Challenge.
- Author
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Kontoyiannis DP
- Subjects
- Animals, Antifungal Agents therapeutic use, Candida drug effects, Disease Models, Animal, Global Health, Humans, Microbial Sensitivity Tests, Mycoses diagnosis, Antifungal Agents pharmacology, Drug Resistance, Fungal, Mycoses drug therapy
- Published
- 2017
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31. Novel Agents and Drug Targets to Meet the Challenges of Resistant Fungi.
- Author
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McCarthy MW, Kontoyiannis DP, Cornely OA, Perfect JR, and Walsh TJ
- Subjects
- Animals, Disease Models, Animal, Fungi genetics, Humans, Invasive Fungal Infections drug therapy, Signal Transduction, Antifungal Agents pharmacology, Drug Resistance, Multiple, Fungal, Fungi drug effects
- Abstract
The emergence of drug-resistant fungi poses a major threat to human health. Despite advances in preventive, diagnostic, and therapeutic interventions, resistant fungal infections continue to cause significant morbidity and mortality in patients with compromised immunity, underscoring the urgent need for new antifungal agents. In this article, we review the challenges associated with identifying broad-spectrum antifungal drugs and highlight novel targets that could enhance the armamentarium of agents available to treat drug-resistant invasive fungal infections., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)
- Published
- 2017
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32. The quinoline bromoquinol exhibits broad-spectrum antifungal activity and induces oxidative stress and apoptosis in Aspergillus fumigatus.
- Author
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Ben Yaakov D, Shadkchan Y, Albert N, Kontoyiannis DP, and Osherov N
- Subjects
- Animals, Aspergillosis drug therapy, Aspergillosis microbiology, Disease Models, Animal, Lepidoptera, Microbial Sensitivity Tests, Survival Analysis, Antifungal Agents pharmacology, Apoptosis, Aspergillus fumigatus drug effects, Aspergillus nidulans drug effects, Oxidative Stress, Quinolines pharmacology
- Abstract
Objectives: Over the last 30 years, the number of invasive fungal infections among immunosuppressed patients has increased significantly, while the number of effective systemic antifungal drugs remains low. The aim of this study was to identify and characterize antifungal compounds that inhibit fungus-specific metabolic pathways not conserved in humans., Methods: We screened a diverse compound library for antifungal activity in the pathogenic mould Aspergillus fumigatus . We determined the in vitro activity of bromoquinol by MIC determination against a panel of fungi, bacteria and cell lines. The mode of action of bromoquinol was determined by screening an Aspergillus nidulans overexpression genomic library for resistance-conferring genes and by RNAseq analysis in A. fumigatus . In vivo efficacy was tested in Galleria mellonella and murine models of A. fumigatus infection., Results: Screening of a diverse chemical library identified three compounds interfering with fungal iron utilization. The most potent, bromoquinol, shows potent wide-spectrum antifungal activity that was blocked in the presence of exogenous iron. Mode-of-action analysis revealed that overexpression of the dba secondary metabolite cluster gene dbaD , encoding a metabolite transporter, confers bromoquinol resistance in A. nidulans , possibly by efflux. RNAseq analysis and subsequent experimental validation revealed that bromoquinol induces oxidative stress and apoptosis in A. fumigatus . Bromoquinol significantly reduced mortality rates of G. mellonella infected with A. fumigatus , but was ineffective in a murine model of infection., Conclusions: Bromoquinol is a promising antifungal candidate with a unique mode of action. Its activity is potentiated by iron starvation, as occurs during in vivo growth., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2017
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33. Real-Life Assessment of the Safety and Effectiveness of the New Tablet and Intravenous Formulations of Posaconazole in the Prophylaxis of Invasive Fungal Infections via Analysis of 343 Courses.
- Author
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Tverdek FP, Heo ST, Aitken SL, Granwehr B, and Kontoyiannis DP
- Subjects
- Administration, Intravenous, Administration, Oral, Algorithms, Antifungal Agents administration & dosage, Antifungal Agents blood, Cohort Studies, Drug Compounding, Female, Humans, Invasive Fungal Infections microbiology, Male, Middle Aged, Pre-Exposure Prophylaxis, Retrospective Studies, Tablets therapeutic use, Tertiary Care Centers, Treatment Outcome, Triazoles administration & dosage, Triazoles blood, Antifungal Agents therapeutic use, Hematologic Neoplasms drug therapy, Invasive Fungal Infections drug therapy, Leukemia, Myeloid, Acute drug therapy, Triazoles therapeutic use
- Abstract
Posaconazole is the preferred mold-active azole for prophylaxis against invasive fungal infections (IFIs) in patients with hematological malignancy. Delayed-release tablet and intravenous formulations of posaconazole have recently become available, but clinical data are limited. We sought to examine the real-world pharmacokinetics and prophylactic effectiveness of the new formulations of posaconazole given as prophylaxis for patients with hematological malignancy. A retrospective cohort of all consecutive adult inpatients with hematological malignancy who received ≥3 days of tablet or intravenous posaconazole therapy for primary IFI prophylaxis at the M. D. Anderson Cancer Center between 1 December 2013 and 31 December 2015 was established. Clinical information was collected and correlated with low posaconazole serum levels (<700 ng/ml). Rates of IFIs and safety events were assessed. A total of 1,321 courses of posaconazole were administered at the M. D. Anderson Cancer Center during the study period, of which 343 courses were assessed for prophylactic safety and effectiveness. Seventy-nine patients (23%) had posaconazole serum level measurements available for interpretation. Acute myeloid leukemia was the primary malignancy (62%), with 20% of all patients having previously received a stem cell transplant. The median posaconazole level was 1,380 ng/ml (interquartile range, 864 to 1,860 ng/ml). Low posaconazole levels (<700 ng/ml) were observed for 14 patients (18%). Proven or probable breakthrough IFIs occurred in 8 patients (2%); posaconazole therapeutic drug monitoring (TDM) was performed for 6 of those patients, all with levels above 700 ng/ml. Overall, 19% of patients experienced grade 3 or 4 liver injury, manifesting primarily as hyperbilirubinemia and being correlated with serum levels of >1,830 ng/ml. Although hepatotoxicity in a small percentage of patients is of concern, posaconazole tablets appeared to be generally safe and effective. As all breakthrough IFIs for which TDM was performed occurred in patients with levels of >700 ng/ml, and a posaconazole level of >1,830 ng/ml was correlated with grade 3 or 4 liver toxicity, further studies are needed to assess the role of TDM., (Copyright © 2017 American Society for Microbiology.)
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- 2017
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34. Initial Treatment of Cancer Patients with Fluconazole-Susceptible Dose-Dependent Candida glabrata Fungemia: Better Outcome with an Echinocandin or Polyene Compared to an Azole?
- Author
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Le A, Farmakiotis D, Tarrand JJ, and Kontoyiannis DP
- Subjects
- Candida glabrata isolation & purification, Candidemia microbiology, Candidemia mortality, Drug Resistance, Fungal, Female, Humans, Male, Middle Aged, Neoplasms drug therapy, Retrospective Studies, Amphotericin B therapeutic use, Antifungal Agents therapeutic use, Azoles therapeutic use, Candida glabrata drug effects, Candidemia drug therapy, Echinocandins therapeutic use, Fluconazole therapeutic use, Polyenes therapeutic use
- Abstract
The 28-day crude mortality rate in 68 cancer patients with fluconazole-susceptible dose-dependent Candida glabrata fungemia started on treatment (within 48 h after blood culture collection) with an echinocandin or liposomal amphotericin-B was better (30%) than those treated with azole monotherapy (52%) ( P = 0.07). After adjusting for confounders, azole monotherapy also was associated with worse 28-day survival (hazard ratio, 3.8; P = 0.003)., (Copyright © 2017 American Society for Microbiology.)
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- 2017
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35. Changes in In Vitro Susceptibility Patterns of Aspergillus to Triazoles and Correlation With Aspergillosis Outcome in a Tertiary Care Cancer Center, 1999-2015.
- Author
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Heo ST, Tatara AM, Jiménez-Ortigosa C, Jiang Y, Lewis RE, Tarrand J, Tverdek F, Albert ND, Verweij PE, Meis JF, Mikos AG, Perlin DS, and Kontoyiannis DP
- Subjects
- Adult, Antifungal Agents therapeutic use, Aspergillosis drug therapy, Aspergillosis microbiology, Aspergillus genetics, Aspergillus isolation & purification, Aspergillus fumigatus drug effects, Cohort Studies, Cytochrome P-450 Enzyme System genetics, Drug Resistance, Fungal genetics, Ergosterol biosynthesis, Female, Fungal Proteins genetics, Hematologic Neoplasms complications, Hematologic Neoplasms microbiology, Hematopoietic Stem Cell Transplantation adverse effects, Humans, Invasive Pulmonary Aspergillosis drug therapy, Invasive Pulmonary Aspergillosis mortality, Male, Microbial Sensitivity Tests, Polymorphism, Genetic, Prospective Studies, Treatment Outcome, Triazoles therapeutic use, Voriconazole pharmacology, Voriconazole therapeutic use, Young Adult, Antifungal Agents pharmacology, Aspergillus drug effects, Invasive Pulmonary Aspergillosis microbiology, Tertiary Healthcare, Triazoles pharmacology
- Abstract
Background: Azole-resistant aspergillosis in high-risk patients with hematological malignancy or hematopoietic stem cell transplantation (HSCT) is a cause of concern., Methods: We examined changes over time in triazole minimum inhibitory concentrations (MICs) of 290 sequential Aspergillus isolates recovered from respiratory sources during 1999-2002 (before introduction of the Aspergillus-potent triazoles voriconazole and posaconazole) and 2003-2015 at MD Anderson Cancer Center. We also tested for polymorphisms in ergosterol biosynthetic genes (cyp51A, erg3C, erg1) in the 37 Aspergillus fumigatus isolates isolated from both periods that had non-wild-type (WT) MICs. For the 107 patients with hematologic cancer and/or HSCT with invasive pulmonary aspergillosis, we correlated in vitro susceptibility with 42-day mortality., Results: Non-WT MICs were found in 37 (13%) isolates and was only low level (MIC <8 mg/L) in all isolates. Higher-triazole MICs were more frequent in the second period and were Aspergillus-species specific, and only encountered in A. fumigatus. No polymorphisms in cyp51A, erg3C, erg1 genes were identified. There was no correlation between in vitro MICs with 42-day mortality in patients with invasive pulmonary aspergillosis, irrespective of antifungal treatment. Asian race (odds ratio [OR], 20.9; 95% confidence interval [CI], 2.5-173.5; P = .005) and azole exposure in the prior 3 months (OR, 9.6; 95% CI, 1.9-48.5; P = .006) were associated with azole resistance., Conclusions: Non-WT azole MICs in Aspergillus are increasing and this is associated with prior azole exposure in patients with hematologic cancer or HSCT. However, no correlation of MIC with outcome of aspergillosis was found in our patient cohort., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)
- Published
- 2017
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36. The anti-Aspergillus drug pipeline: Is the glass half full or empty?
- Author
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Osherov N and Kontoyiannis DP
- Subjects
- Animals, Biological Products isolation & purification, Biological Products pharmacology, Clinical Trials as Topic, Drug Compounding, Drug Evaluation, Preclinical, Drug Repositioning, Drug Therapy methods, Humans, Immunotherapy methods, Antifungal Agents isolation & purification, Antifungal Agents pharmacology, Aspergillosis therapy, Aspergillus drug effects, Aspergillus immunology, Drug Discovery trends
- Abstract
Aspergillosis has emerged as important human mycoses, in view of the ever expanding population at risk. The emergence of resistance to the most commonly used drugs for aspergillosis, the azoles, the mediocre activity, and frequent toxicity of the current antifungal armamentarium, support the need for development of novel antifungals for treatment of this disease. In this minireview, we describe recent efforts by small drug companies and University research labs to develop novel therapies for invasive aspergillus infections. We specifically discuss four small-molecule antifungals (T-2307, E1210/APX001, ASP2397, and F901318) with novel modes-of-action, which are currently entering phase I clinical trials. In addition, we provide a nonexhaustive discussion of some interesting, yet early developments in the quest for improved therapeutic strategies such as (i) novel formulations of amphotericin B including AMB nanoparticle suspensions and AMB-arabinogalactan or AMB-PEG conjugates that show low toxicity and high efficacy in preclinical animal models, (ii) repurposed drugs that synergize with existing antifungals (clozafimine, trichostatin A, MGCD290, geldanamycin, tacrolimus, cyclosporin), (iii) natural products (psoriasin, humidimycin), and (iv) immunotherapy using adoptive transfer of activated immune cells with antifungal activity. We argue that despite the plethora of candidates, the extremely low success rates of drug development leading to clinically useful drugs reinforces the need for continued clinical reliance on mainstream antifungals and their improved derivatives., (© The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2017
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37. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America.
- Author
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Patterson TF, Thompson GR 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht R, Kontoyiannis DP, Marr KA, Morrison VA, Nguyen MH, Segal BH, Steinbach WJ, Stevens DA, Walsh TJ, Wingard JR, Young JA, and Bennett JE
- Subjects
- Amphotericin B therapeutic use, Aspergillosis drug therapy, Aspergillosis epidemiology, Azoles therapeutic use, Echinocandins therapeutic use, Humans, Infectious Disease Medicine organization & administration, Societies, Medical, United States, Antifungal Agents therapeutic use, Aspergillosis diagnosis
- Abstract
It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances., (Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)
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- 2016
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38. Executive Summary: Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America.
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Patterson TF, Thompson GR 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht R, Kontoyiannis DP, Marr KA, Morrison VA, Nguyen MH, Segal BH, Steinbach WJ, Stevens DA, Walsh TJ, Wingard JR, Young JA, and Bennett JE
- Subjects
- Amphotericin B therapeutic use, Aspergillosis drug therapy, Aspergillosis epidemiology, Azoles therapeutic use, Echinocandins therapeutic use, Humans, Infectious Disease Medicine organization & administration, Societies, Medical, United States, Antifungal Agents therapeutic use, Aspergillosis diagnosis, Practice Guidelines as Topic standards
- Abstract
It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances., (Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)
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- 2016
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39. Antifungal agents and liver toxicity: a complex interaction.
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Tverdek FP, Kofteridis D, and Kontoyiannis DP
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- Animals, Antifungal Agents administration & dosage, Antifungal Agents pharmacokinetics, Antifungal Agents therapeutic use, Chemical and Drug Induced Liver Injury epidemiology, Dose-Response Relationship, Drug, Drug Interactions, Humans, Incidence, Invasive Fungal Infections epidemiology, Liver enzymology, Liver pathology, Liver Function Tests, Antifungal Agents adverse effects, Chemical and Drug Induced Liver Injury etiology, Invasive Fungal Infections drug therapy, Liver drug effects
- Abstract
Introduction: The number of antifungal agents has sharply increased in recent decades. Antifungals differ in their spectrum of activity, pharmacokinetic/pharmacodynamic properties, dosing, safety-profiles and costs. Risk of developing antifungal associated hepatotoxicity is multifactorial and is influenced by pre-existing liver disease, chemical properties of the drug, patient demographics, comorbidities, drug-drug interactions, environmental and genetic factors. Antifungal related liver injury typically manifests as elevations in serum aminotransferase levels, although the clinical significance of these biochemical alterations is not always clear. Incidence rates of hepatotoxicity induced by antifungal therapy range widely, occurring most frequently in patients treated with azole antifungals for documented fungal infections., Areas Covered: This review provides an update regarding the hepatotoxicity profiles of the modern systemic antifungals used in treatment of invasive fungal infections. Expert commentary: Understanding the likelihood and pattern of hepatotoxicity for all suspected drugs can aid the clinician in early detection of liver injury allowing for intervention and potential mitigation of liver damage. Therapeutic drug monitoring is emerging as a potential tool to assess risk for hepatotoxicity.
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- 2016
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40. Treatment of mucormycosis in transplant patients: role of surgery and of old and new antifungal agents.
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Chitasombat MN and Kontoyiannis DP
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- Amphotericin B therapeutic use, DNA, Fungal analysis, Humans, Mucorales genetics, Nitriles therapeutic use, Pyridines therapeutic use, Salvage Therapy, Triazoles therapeutic use, Antifungal Agents therapeutic use, Mucormycosis drug therapy, Mucormycosis surgery, Opportunistic Infections drug therapy, Opportunistic Infections surgery, Transplant Recipients
- Abstract
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. The new, pharmacokinetically more reliable formulations of posaconazole (intravenous, extended-release tablets) are welcomed improvements. Yet, the role of combination therapy is still uncertain. Surgery had a significant role in selected cases, such as in patients with rhinosinusitis form of mucormycosis, which nowadays can be performed with minimal invasive technique., Summary: Mucormycosis remain a life-threatening opportunistic mold infection among transplant patients. Early diagnosis, prompt treatment with effective antifungals in combination with surgery if feasible is essential. Immune adjunct therapy and improvement of early diagnostics are important areas for future research. There are good prospects of progress in diagnostics and management of mucormycosis in transplant patients.
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- 2016
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41. Statin Concentrations Below the Minimum Inhibitory Concentration Attenuate the Virulence of Rhizopus oryzae.
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Bellanger AP, Tatara AM, Shirazi F, Gebremariam T, Albert ND, Lewis RE, Ibrahim AS, and Kontoyiannis DP
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- Animals, Atorvastatin pharmacology, Atorvastatin therapeutic use, Diptera drug effects, Endoplasmic Reticulum Chaperone BiP, Female, Humans, Lovastatin pharmacology, Lovastatin therapeutic use, Mice, Microbial Sensitivity Tests, Simvastatin pharmacology, Simvastatin therapeutic use, Spores, Fungal drug effects, Texas, Antifungal Agents pharmacology, Antifungal Agents therapeutic use, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Mucormycosis drug therapy, Rhizopus drug effects, Virulence drug effects
- Abstract
Background: Mucormycosis is a destructive invasive mold infection afflicting patients with diabetes and hematologic malignancies. Patients with diabetes are often treated with statins, which have been shown to have antifungal properties. We sought to examine the effects of statins on Rhizopus oryzae, a common cause of mucormycosis., Methods: Clinical strains of R. oryzae were exposed to lovastatin, atorvastatin, and simvastatin and the minimum inhibitory concentrations (MICs) were determined. R. oryzae germination, DNA fragmentation, susceptibility to oxidative stress, and ability to damage endothelial cells were assessed. We further investigated the impact of exposure to lovastatin on the virulence of R. oryzae, Results: All statins had MICs of >64 µg/mL against R. oryzae Exposure of R. oryzae to statins decreased germling formation, induced DNA fragmentation, and attenuated damage to endothelial cells independently of the expression of GRP78 and CotH. Additionally, R. oryzae exposed to lovastatin showed macroscopic loss of melanin, yielded increased susceptibility to the oxidative agent peroxide, and had attenuated virulence in both fly and mouse models of mucormycosis., Conclusions: Exposure of R. oryzae to statins at concentrations below their MICs decreased virulence both in vitro and in vivo. Further investigation is warranted into the use of statins as adjunctive therapy in mucormycosis., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)
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- 2016
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42. Identification and characterization of haemofungin, a novel antifungal compound that inhibits the final step of haem biosynthesis.
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Ben Yaakov D, Rivkin A, Mircus G, Albert N, Dietl AM, Kovalerchick D, Carmeli S, Haas H, Kontoyiannis DP, and Osherov N
- Subjects
- Animals, Aspergillus nidulans drug effects, Aspergillus nidulans genetics, Bacteria drug effects, Bacteria growth & development, Cell Line, Drug Resistance, Fungal, Drug Synergism, Ferrochelatase antagonists & inhibitors, Fungi drug effects, Fungi growth & development, Humans, Insecta, Microbial Sensitivity Tests, Mycoses drug therapy, Mycoses microbiology, Protoporphyrins biosynthesis, Antifungal Agents pharmacology, Heme antagonists & inhibitors, Heme biosynthesis, Heterocyclic Compounds, 4 or More Rings pharmacology
- Abstract
Objectives: During recent decades, the number of invasive fungal infections among immunosuppressed patients has increased significantly, whereas the number of effective systemic antifungal drugs remains low and unsatisfactory. The aim of this study was to characterize a novel antifungal compound, CW-8/haemofungin, which we previously identified in a screen for compounds affecting fungal cell wall integrity., Methods: The in vitro characteristics of haemofungin were investigated by MIC evaluation against a panel of pathogenic and non-pathogenic fungi, bacteria and mammalian cells in culture. Haemofungin mode-of-action studies were performed by screening an Aspergillus nidulans overexpression genomic library for resistance-conferring plasmids and biochemical validation of the target. In vivo efficacy was tested in the Galleria mellonella and Drosophila melanogaster insect models of infection., Results: We demonstrate that haemofungin causes swelling and lysis of growing fungal cells. It inhibits the growth of pathogenic Aspergillus, Candida, Fusarium and Rhizopus isolates at micromolar concentrations, while only weakly affecting the growth of mammalian cell lines. Genetic and biochemical analyses in A. nidulans and Aspergillus fumigatus indicate that haemofungin primarily inhibits ferrochelatase (HemH), the last enzyme in the haem biosynthetic pathway. Haemofungin was non-toxic and significantly reduced mortality rates of G. mellonella and D. melanogaster infected with A. fumigatus and Rhizopus oryzae, respectively., Conclusions: Further development and in vivo validation of haemofungin is warranted., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
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- 2016
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43. Mucormycoses.
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Farmakiotis D and Kontoyiannis DP
- Subjects
- Humans, Immunocompromised Host, Mucormycosis immunology, Mucormycosis microbiology, Antifungal Agents therapeutic use, Mucormycosis diagnosis, Mucormycosis therapy
- Abstract
Life-threatening infections from virulent, angioinvasive molds of the order Mucorales are being recognized with increasing frequency in immunosuppressed hosts. Advances in the understanding of pathogenesis, early diagnosis, and the recent availability of active, nontoxic drugs have improved the prospects for effective control and even cure of this devastating infection. However, rates of delayed diagnosis and mortality are still high, partially because of the low yield and complexity of culture-based and molecular diagnostic methods. Therefore, there is an urgent need for novel diagnostic modalities and effective therapeutic approaches., (Copyright © 2016 Elsevier Inc. All rights reserved.)
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- 2016
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44. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial.
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Maertens JA, Raad II, Marr KA, Patterson TF, Kontoyiannis DP, Cornely OA, Bow EJ, Rahav G, Neofytos D, Aoun M, Baddley JW, Giladi M, Heinz WJ, Herbrecht R, Hope W, Karthaus M, Lee DG, Lortholary O, Morrison VA, Oren I, Selleslag D, Shoham S, Thompson GR 3rd, Lee M, Maher RM, Schmitt-Hoffmann AH, Zeiher B, and Ullmann AJ
- Subjects
- Administration, Oral, Adult, Aged, Antifungal Agents administration & dosage, Antifungal Agents adverse effects, Aspergillosis drug therapy, Aspergillosis mortality, Double-Blind Method, Drug Administration Schedule, Female, Humans, Injections, Intravenous, Male, Middle Aged, Mycoses mortality, Nitriles administration & dosage, Nitriles adverse effects, Pyridines administration & dosage, Pyridines adverse effects, Treatment Outcome, Triazoles administration & dosage, Triazoles adverse effects, Voriconazole administration & dosage, Voriconazole adverse effects, Antifungal Agents therapeutic use, Mycoses drug therapy, Nitriles therapeutic use, Pyridines therapeutic use, Triazoles therapeutic use, Voriconazole therapeutic use
- Abstract
Background: Isavuconazole is a novel triazole with broad-spectrum antifungal activity. The SECURE trial assessed efficacy and safety of isavuconazole versus voriconazole in patients with invasive mould disease., Methods: This was a phase 3, double-blind, global multicentre, comparative-group study. Patients with suspected invasive mould disease were randomised in a 1:1 ratio using an interactive voice-web response system, stratified by geographical region, allogeneic haemopoietic stem cell transplantation, and active malignant disease at baseline, to receive isavuconazonium sulfate 372 mg (prodrug; equivalent to 200 mg isavuconazole; intravenously three times a day on days 1 and 2, then either intravenously or orally once daily) or voriconazole (6 mg/kg intravenously twice daily on day 1, 4 mg/kg intravenously twice daily on day 2, then intravenously 4 mg/kg twice daily or orally 200 mg twice daily from day 3 onwards). We tested non-inferiority of the primary efficacy endpoint of all-cause mortality from first dose of study drug to day 42 in patients who received at least one dose of the study drug (intention-to-treat [ITT] population) using a 10% non-inferiority margin. Safety was assessed in patients who received the first dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00412893., Findings: 527 adult patients were randomly assigned (258 received study medication per group) between March 7, 2007, and March 28, 2013. All-cause mortality from first dose of study drug to day 42 for the ITT population was 19% with isavuconazole (48 patients) and 20% with voriconazole (52 patients), with an adjusted treatment difference of -1·0% (95% CI -7·8 to 5·7). Because the upper bound of the 95% CI (5·7%) did not exceed 10%, non-inferiority was shown. Most patients (247 [96%] receiving isavuconazole and 255 [98%] receiving voriconazole) had treatment-emergent adverse events (p=0·122); the most common were gastrointestinal disorders (174 [68%] vs 180 [69%]) and infections and infestations (152 [59%] vs 158 [61%]). Proportions of patients with treatment-emergent adverse events by system organ class were similar overall. However, isavuconazole-treated patients had a lower frequency of hepatobiliary disorders (23 [9%] vs 42 [16%]; p=0·016), eye disorders (39 [15%] vs 69 [27%]; p=0·002), and skin or subcutaneous tissue disorders (86 [33%] vs 110 [42%]; p=0·037). Drug-related adverse events were reported in 109 (42%) patients receiving isavuconazole and 155 (60%) receiving voriconazole (p<0·001)., Interpretation: Isavuconazole was non-inferior to voriconazole for the primary treatment of suspected invasive mould disease. Isavuconazole was well tolerated compared with voriconazole, with fewer study-drug-related adverse events. Our results support the use of isavuconazole for the primary treatment of patients with invasive mould disease., Funding: Astellas Pharma Global Development, Basilea Pharmaceutica International., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
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- 2016
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45. Primary antifungal prophylaxis during curative-intent therapy for acute myeloid leukemia.
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Halpern AB, Lyman GH, Walsh TJ, Kontoyiannis DP, and Walter RB
- Subjects
- Humans, Immunocompromised Host, Male, Middle Aged, Mycoses etiology, Mycoses immunology, Antifungal Agents therapeutic use, Leukemia, Myeloid, Acute complications, Mycoses prevention & control
- Published
- 2015
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46. Albumin Enhances Caspofungin Activity against Aspergillus Species by Facilitating Drug Delivery to Germinating Hyphae.
- Author
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Ioannou P, Andrianaki A, Akoumianaki T, Kyrmizi I, Albert N, Perlin D, Samonis G, Kontoyiannis DP, and Chamilos G
- Subjects
- Albumins metabolism, Anidulafungin, Aspergillosis microbiology, Aspergillus growth & development, Aspergillus isolation & purification, Caspofungin, Culture Media chemistry, Humans, Hyphae drug effects, Micafungin, Microbial Sensitivity Tests, Voriconazole pharmacology, Albumins pharmacology, Antifungal Agents pharmacology, Aspergillus drug effects, Echinocandins pharmacology, Lipopeptides pharmacology
- Abstract
The modest in vitro activity of echinocandins against Aspergillus implies that host-related factors augment the action of these antifungal agents in vivo. We found that, in contrast to the other antifungal agents (voriconazole, amphotericin B) tested, caspofungin exhibited a profound increase in activity against various Aspergillus species under conditions of cell culture growth, as evidenced by a ≥4-fold decrease in minimum effective concentrations (MECs) (P = 0. 0005). Importantly, the enhanced activity of caspofungin against Aspergillus spp. under cell culture conditions was strictly dependent on serum albumin and was not observed with the other two echinocandins, micafungin and anidulafungin. Of interest, fluorescently labeled albumin bound preferentially on the surface of germinating Aspergillus hyphae, and this interaction was further enhanced upon treatment with caspofungin. In addition, supplementation of cell culture medium with albumin resulted in a significant, 5-fold increase in association of fluorescently labeled caspofungin with Aspergillus hyphae (P < 0.0001). Collectively, we found a novel synergistic interaction between albumin and caspofungin, with albumin acting as a potential carrier molecule to facilitate antifungal drug delivery to Aspergillus hyphae., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
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47. Effect of Preexposure to Triazoles on Susceptibility and Virulence of Rhizopus oryzae.
- Author
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Bellanger AP, Albert ND, Lewis RE, Walsh TJ, and Kontoyiannis DP
- Subjects
- Agar, Animals, Culture Media chemistry, Disease Models, Animal, Drosophila melanogaster drug effects, Drosophila melanogaster microbiology, Female, Microbial Sensitivity Tests, Mucormycosis drug therapy, Mucormycosis microbiology, Mucormycosis mortality, Rhizopus growth & development, Rhizopus pathogenicity, Survival Analysis, Virulence, Antifungal Agents pharmacology, Fluconazole pharmacology, Itraconazole pharmacology, Rhizopus drug effects, Triazoles pharmacology, Voriconazole pharmacology
- Abstract
Triazole prophylaxis has become the norm in patients with hematological malignancies. Breakthrough infections caused by Mucorales during triazole prophylaxis remain a challenging problem. We found that preexposure of Rhizopus oryzae to antifungal triazoles (fluconazole, voriconazole, posaconazole, and itraconazole) did not modify the in vitro susceptibility of Rhizopus oryzae to posaconazole. In contrast, preexposure of Rhizopus to triazoles was associated with the enhanced in vitro susceptibility of R. oryzae to amphotericin B. Preexposure to posaconazole did not alter the virulence of R. oryzae in the fly model of mucormycosis., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
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48. Identification and characterization of a novel family of selective antifungal compounds (CANBEFs) that interfere with fungal protein synthesis.
- Author
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Mircus G, Albert N, Ben-Yaakov D, Chikvashvili D, Shadkchan Y, Kontoyiannis DP, and Osherov N
- Subjects
- Animals, Aspergillus drug effects, Aspergillus metabolism, Candida drug effects, Candida metabolism, Cell Line, Drosophila melanogaster drug effects, Female, Fusarium drug effects, Fusarium metabolism, Humans, Mice, Mice, Inbred ICR, Microbial Sensitivity Tests, Protein Biosynthesis drug effects, Rhizopus drug effects, Rhizopus metabolism, Saccharomyces cerevisiae drug effects, Saccharomyces cerevisiae metabolism, Antifungal Agents pharmacology, Fungal Proteins metabolism
- Abstract
Invasive mycotic infections have become more common during recent decades, posing an increasing threat to public health. However, despite the growing needs, treatments for invasive fungal infections remain unsatisfactory and are limited to a small number of antifungals. The aim of this study was to identify novel fungal cell wall inhibitors from a library of small chemical compounds using a conditional protein kinase C (PKC)-expressing strain of Aspergillus nidulans sensitive to cell wall-active agents. Eight "hit" compounds affecting cell wall integrity were identified from a screen of 35,000 small chemical compounds. Five shared a common basic molecular structure of 4-chloro-6-arylamino-7-nitro-benzofurazane (CANBEF). The most potent compound, CANBEF-24, was characterized further and was shown to inhibit the growth of pathogenic Aspergillus, Candida, Fusarium, and Rhizopus isolates at micromolar concentrations but not to affect the growth of mammalian cell lines. CANBEF-24 demonstrated strong synergy in combination with caspofungin, an antifungal that inhibits cell wall biosynthesis. Genetic and biochemical analyses with Aspergillus nidulans and Saccharomyces cerevisiae indicated that CANBEFs selectively inhibit fungal rRNA maturation and protein synthesis, suggesting that their effect on the cell wall is indirect. CANBEFs were nontoxic in insect (Galleria mellonella, Drosophila melanogaster) and mouse models of fungal infection. Preliminary evidence showing no therapeutic benefit in these models suggests that further cycles of optimization are needed for the development of this novel class of compounds for systemic use., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
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49. Correlation between Circulating Fungal Biomarkers and Clinical Outcome in Invasive Aspergillosis.
- Author
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Neofytos D, Railkar R, Mullane KM, Fredricks DN, Granwehr B, Marr KA, Almyroudis NG, Kontoyiannis DP, Maertens J, Fox R, Douglas C, Iannone R, Kauh E, and Shire N
- Subjects
- Adult, Aged, Aspergillus drug effects, Aspergillus growth & development, Aspergillus pathogenicity, Biomarkers blood, Female, Galactose analogs & derivatives, Humans, Invasive Pulmonary Aspergillosis blood, Invasive Pulmonary Aspergillosis mortality, Male, Middle Aged, Prognosis, Prospective Studies, Survival Analysis, Treatment Outcome, Antifungal Agents therapeutic use, Invasive Pulmonary Aspergillosis diagnosis, Invasive Pulmonary Aspergillosis drug therapy, Mannans blood, beta-Glucans blood
- Abstract
Objective means are needed to predict and assess clinical response in patients treated for invasive aspergillosis (IA). We examined whether early changes in serum galactomannan (GM) and/or β-D-glucan (BDG) can predict clinical outcomes. Patients with proven or probable IA were prospectively enrolled, and serial GM and BDG levels and GM optical density indices (GMI) were calculated twice weekly for 6 weeks following initiation of standard-of-care antifungal therapy. Changes in these biomarkers during the first 2 and 6 weeks of treatment were analyzed for associations with clinical response and survival at weeks 6 and 12. Among 47 patients with IA, 53.2% (25/47) and 65.9% (27/41) had clinical response by weeks 6 and 12, respectively. Changes in biomarkers during the first 2 weeks were associated with clinical response at 6 weeks (GMI, P = 0.03) and 12 weeks (GM+BDG composite, P = 0.05; GM, P = 0.04; GMI, P = 0.02). Changes in biomarkers during the first 6 weeks were also associated with clinical response at 6 weeks (GM, P = 0.05; GMI, P = 0.03) and 12 weeks (BDG+GM, P = 0.02; GM, P = 0.02; GMI, P = 0.01). Overall survival rates at 6 weeks and 12 weeks were 87.2% (41/47) and 79.1% (34/43), respectively. Decreasing biomarkers in the first 2 weeks were associated with survival at 6 weeks (BDG+GM, P = 0.03; BDG, P = 0.01; GM, P = 0.03) and at 12 weeks (BDG+GM, P = 0.01; BDG, P = 0.03; GM, P = 0.01; GMI, P = 0.007). Similar correlations occurred for biomarkers measured over 6 weeks. Patients with negative baseline GMI and/or persistently negative GMI during the first 2 weeks were more likely to have CR and survival. These results suggest that changes of biomarkers may be informative to predict and/or assess response to therapy and survival in patients treated for IA.
- Published
- 2015
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50. Clinical experience of the use of voriconazole, caspofungin or the combination in primary and salvage therapy of invasive aspergillosis in haematological malignancies.
- Author
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Raad II, Zakhem AE, Helou GE, Jiang Y, Kontoyiannis DP, and Hachem R
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antifungal Agents adverse effects, Caspofungin, Child, Drug Therapy, Combination adverse effects, Drug Therapy, Combination methods, Echinocandins adverse effects, Female, Hematologic Neoplasms complications, Humans, Lipopeptides, Male, Middle Aged, Retrospective Studies, Salvage Therapy adverse effects, Survival Analysis, Treatment Outcome, Voriconazole adverse effects, Young Adult, Antifungal Agents therapeutic use, Echinocandins therapeutic use, Invasive Pulmonary Aspergillosis drug therapy, Salvage Therapy methods, Voriconazole therapeutic use
- Abstract
Invasive aspergillosis (IA) is a life-threatening infection in severely immunocompromised haematological malignancy patients. In this study, the efficacy and safety of caspofungin, voriconazole or the combination as primary and salvage therapy in patients with IA were compared. The study included 181 patients with haematological malignancies and IA who received primary or salvage therapy with caspofungin, voriconazole or the combination. In total, 138 patients who received treatment for ≥7 days were analysed; 86 underwent primary antifungal therapy (15 with caspofungin, 38 with voriconazole and 33 with both). Among the salvage therapy patients, 17 received caspofungin, 24 received voriconazole and 35 received both. In the primary therapy group, no difference in therapy response was found, but caspofungin was associated with higher IA mortality rates. A multivariate competing risk analysis of primary antifungal therapy revealed that voriconazole was independently associated with lower IA-associated mortality rates than caspofungin (hazard ratio=0.2, 95% confidence interval 0.06-0.96; P=0.04). In the salvage therapy group, the three treatment groups had similar responses and IA-associated mortality rates. The combination of voriconazole and caspofungin did not result in better outcomes compared with voriconazole alone, as primary or salvage therapy, in haematological malignancy patients. However, voriconazole was associated with a lower Aspergillus-associated mortality rate compared with caspofungin monotherapy., (Copyright © 2014. Published by Elsevier B.V.)
- Published
- 2015
- Full Text
- View/download PDF
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