498 results on '"Perfect JR"'
Search Results
52. Curvularia alcornii Aortic Pseudoaneurysm Following Aortic Valve Replacement: Case Report and Review of the Literature.
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Narayanasamy S, Williams AR, Schell WA, Moehring RW, Alexander BD, Le T, Bharadwaj RA, McGauvran M, Schroder JN, and Perfect JR
- Abstract
We report the first case of Curvularia alcornii aortic pseudoaneurysm following bioprosthetic aortic valve replacement in an immunocompetent host. Infection was complicated by septic emboli to multiple organs. Despite aggressive surgical intervention and antifungal therapy, infection progressed. We review the literature on invasive Curvularia infection to inform diagnosis and management., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
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- 2021
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53. Cryptococcus gattii Species Complex as an Opportunistic Pathogen: Underlying Medical Conditions Associated with the Infection.
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Yang DH, England MR, Salvator H, Anjum S, Park YD, Marr KA, Chu LA, Govender NP, Lockhart SR, Desnos-Ollivier M, Chen S, Halliday C, Kan A, Chen J, Wollenberg KR, Zelazny A, Perfect JR, Chang YC, Bennett JE, Holland SM, Meyer W, Williamson PR, and Kwon-Chung KJ
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- Africa epidemiology, Autoantibodies blood, Autoantibodies immunology, Cryptococcosis immunology, Cryptococcosis microbiology, Cryptococcus gattii classification, Cryptococcus gattii genetics, Cryptococcus gattii immunology, HIV Infections complications, HIV Infections epidemiology, Humans, Immunocompetence, Immunocompromised Host, Opportunistic Infections immunology, Risk Factors, Cryptococcosis etiology, Cryptococcus gattii pathogenicity, Opportunistic Infections etiology, Opportunistic Infections microbiology
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The Cryptococcus gattii species complex has often been referred to as a primary pathogen due to its high infection frequency among apparently immunocompetent patients. In order to scrutinize the immune status of patients and the lineages of etiologic agents, we analyzed patient histories and the molecular types of etiologic agents from 135 global C. gattii cases. Eighty-six of 135 patients had been diagnosed as immunocompetent, although some of them had underlying medical issues, and 49 were diagnosed as immunocompromised with risk factors similar to those seen in Cryptococcus neoformans infection. We focused on the 86 apparently immunocompetent patients and were able to obtain plasma from 32 (37%) to analyze for the presence of autoantibodies against the granulocyte-macrophage colony-stimulating factor (GM-CSF) since these antibodies have been reported as a hidden risk factor for C. gattii infection. Among the 32 patients, 25 were free from any known other health issues, and 7 had various medical conditions at the time of diagnosis for cryptococcosis. Importantly, plasma from 19 (76%) of 25 patients with no recognized underlying medical condition showed the presence of GM-CSF autoantibodies, supporting this antibody as a major hidden risk factor for C. gattii infection. These data indicate that seemingly immunocompetent people with C. gattii infection warrant detailed evaluation for unrecognized immunologic risks. There was no relationship between molecular type and underlying conditions of patients. Frequency of each molecular type was related to its geographic origin exemplified by the overrepresentation of VGIV in HIV-positive (HIV+) patients due to its prevalence in Africa. IMPORTANCE The C. neoformans and C. gattii species complex causes cryptococcosis. The C. neoformans species complex is known as an opportunistic pathogen since it primarily infects immunocompromised patients. C. gattii species complex has been referred to as a primary pathogen due to its high infection frequency in apparently immunocompetent people. We analyzed 135 global cases of C. gattii infection with documented patient history. Eighty-six of 135 patients were originally diagnosed as immunocompetent and 49 as immunosuppressed with similar underlying conditions reported for C. neoformans infection. A significant number of C. gattii patients without known underlying conditions possessed autoantibodies against granulocytes-macrophage colony-stimulating factor (GM-CSF) in their plasma, supporting the presence of GM-CSF antibodies as a hidden risk factor for C. gattii infection. No relationship was found between C. gattii lineages and the underlying conditions except for overrepresentation of the molecular type VGIV among HIV+ patients due to the prevalence of VGIV in Africa.
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- 2021
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54. A randomized, double-blind, placebo-controlled clinical trial of fluconazole as early empiric treatment of coccidioidomycosis pneumonia (Valley Fever) in adults presenting with community-acquired pneumonia in endemic areas (FLEET-Valley Fever).
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Messina JA, Maziarz EK, Galgiani J, Truong JT, Htoo AK, Heidari A, Johnson RH, Narang AT, Donovan FM, Ewell M, Catanzaro A, Thompson GR 3rd, Ampel NM, Perfect JR, Naggie S, and Walter EB
- Abstract
Introduction: Coccidioidomycosis is a fungal infection endemic in the southwestern United States (US). Primary pulmonary coccidioidomycosis (PPC) is a leading cause of community-acquired pneumonia (CAP) in this region, although its diagnosis is often delayed, leading to lag in antifungal treatment and subsequent morbidity. The impact of early empiric antifungal therapy as part of treatment for CAP in endemic areas on clinical outcomes is unknown., Methods: Phase IV randomized, double-blind, placebo-controlled trial in individuals aged 18 years or older with CAP who met all eligibility criteria in Coccidioides endemic regions in the US. Eligible participants with CAP were randomized to receive either fluconazole (400 mg daily) or matching placebo for 42 days and were subsequently monitored for clinical resolution of their illness., Objectives: The primary objective was to assess the clinical response of early empiric antifungal therapy with fluconazole through Day 22 in subjects with PPC who were adherent to the study intervention. Secondary objectives included: assessments of the impact of early empiric antifungal therapy with fluconazole through Day 22 and 43 in subjects with PPC regardless of adherence, comparisons of the clinical response and its individual components over time by treatment group in subjects with PPC, assessments of days lost from work or school, hospitalization, and all-cause mortality., Discussion: This trial was halted early due to slow enrollment (72 participants in one year, 33 received fluconazole and 39 received placebo). Of those enrolled, eight (11%) met the study definition of PPC. The study design and challenges are discussed., Competing Interests: Julia A. Messina, MD, MHS, MSc: Nothing to report. Eileen K. Maziarz, MD: Nothing to report. John Galgiani, MD: Nothing to report. Jonathan T. Truong, MD: Nothing to report. Aung K. Htoo, MD: Nothing to report. Arash Heidari, MD: Nothing to report. Royce H. Johnson, MD: Nothing to report. Aneesh T. Narang, MD: Nothing to report. Fabria M. Donovan, MD, PhD: Nothing to report. Marion Ewell, ScD: Nothing to report. Antonino Catanzaro, MD: Nothing to report. George R. Thompson III, MD: Nothing to report. Neil M. Ampel, MD: Nothing to report. John R. Perfect, MD: reports research grants and consultation from the following: Astellas, Pfizer, Merck, Amplyx, Scynexis, Matinas, F2G, Appili and Minnetronix. Susanna Naggie, MD, MHS: Nothing to report. Emmanuel B. Walter, MD, MPH: has served as an investigator for clinical trials funded by Moderna and Pfizer., (© 2021 Published by Elsevier Inc.)
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- 2021
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55. MSG07: An International Cohort Study Comparing Epidemiology and Outcomes of Patients With Cryptococcus neoformans or Cryptococcus gattii Infections.
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Baddley JW, Chen SC, Huisingh C, Benedict K, DeBess EE, Galanis E, Jackson BR, MacDougall L, Marsden-Haug N, Oltean H, Perfect JR, Phillips P, Sorrell TC, and Pappas PG
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- Cohort Studies, Humans, Male, Middle Aged, Retrospective Studies, Cryptococcosis drug therapy, Cryptococcosis epidemiology, Cryptococcus gattii, Cryptococcus neoformans
- Abstract
Background: Cryptococcosis due to Cryptococcus neoformans and Cryptococcus gattii varies with geographic region, populations affected, disease manifestations, and severity of infection, which impact treatment., Methods: We developed a retrospective cohort of patients diagnosed with culture-proven cryptococcosis during 1995-2013 from 5 centers in North America and Australia. We compared underlying diseases, clinical manifestations, treatment, and outcomes in patients with C. gattii or C. neoformans infection., Results: A total of 709 patients (452 C. neoformans; 257 C. gattii) were identified. Mean age was 50.2 years; 61.4% were male; and 52.3% were white. Time to diagnosis was prolonged in C. gattii patients compared with C. neoformans (mean, 52.2 vs 36.0 days; P < .003), and there was a higher proportion of C. gattii patients without underlying disease (40.5% vs 10.2%; P < .0001). Overall, 59% had central nervous system (CNS) infection, with lung (42.5%) and blood (24.5%) being common sites. Pulmonary infection was more common in patients with C. gattii than in those with C. neoformans (60.7% vs 32.1%; P < .0001). CNS or blood infections were more common in C. neoformans-infected patients (P ≤ .0001 for both). Treatment of CNS disease with induction therapy of amphotericin B and flucytosine occurred in 76.4% of patients. Crude 12-month mortality was higher in patients with C. neoformans (28.4% vs 20.2%; odds ratio, 1.56 [95% confidence interval, 1.08-2.26])., Conclusions: This study emphasizes differences in species-specific epidemiology and outcomes of patients with cryptococcosis, including underlying diseases, site of infection, and mortality. Species identification in patients with cryptococcosis is necessary to discern epidemiologic patterns, guide treatment regimens, and predict clinical progression and outcomes., (© The Author(s) 2021. 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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- 2021
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56. Cryptococcal meningoencephalitis: time for action.
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Stott KE, Loyse A, Jarvis JN, Alufandika M, Harrison TS, Mwandumba HC, Day JN, Lalloo DG, Bicanic T, Perfect JR, and Hope W
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- Amphotericin B, Databases, Factual, Deoxycholic Acid, Drug Combinations, Drug Therapy, Combination, Fluconazole, Flucytosine pharmacology, Flucytosine therapeutic use, Humans, Meningoencephalitis microbiology, Meningoencephalitis pathology, Antifungal Agents therapeutic use, Cryptococcosis, Meningoencephalitis drug therapy, Meningoencephalitis mortality
- Abstract
Cryptococcal meningoencephalitis was first described over a century ago. This fungal infection is preventable and treatable yet continues to be associated with excessive morbidity and mortality. The largest burden of disease resides in people living with HIV in low-income and middle-income countries. In this group, mortality with the best antifungal induction regimen (7 days of amphotericin B deoxycholate [1·0 mg/kg per day] and flucytosine [100·0 mg/kg per day]) in a clinical trial setting was 24% at 10 weeks. The world is now at an inflection point in terms of recognition, research, and action to address the burden of morbidity and mortality from cryptococcal meningoencephalitis. However, the scope of interventional programmes needs to increase, with particular attention to implementation science that is specific to individual countries. This Review summarises causes of excessive mortality, interventions with proven survival benefit, and gaps in knowledge and practice that contribute to the ongoing high death toll from cryptococcal meningoencephalitis. TRANSLATIONS: For the Vietnamese and Chichewa translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests KES, AL, MA, TSH, HCM, and DGL declare no competing interests. TB has received research funding from Gilead Sciences and speaker fees from Gilead Sciences and Pfizer. JND has received fees for scientific consulting for Viamet Pharmaceuticals. JRP has research grants from, and does consultations for, Astellas, Pfizer, Merck, F2G, Amplyx, Matinas, Scynexis, Appili, and Minnetronix. WH holds, or has recently held, research grants with F2G, Astellas Pharma, Spero Therapeutics, Antabio, Allecra, Bugworks, and NAEJA-RGM. WH has received personal fees in his capacity as a consultant for F2G, Amplyx, Ausperix, Spero Therapeutics, VenatoRx, Pfizer, and BLC/TAZ. JNJ declares no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
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- 2021
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57. A link between urease and polyamine metabolism in Cryptococcus neoformans.
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Toplis B, Bosch C, Stander M, Taylor M, Perfect JR, and Botha A
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- Putrescine, Spermidine, Cryptococcus neoformans, Polyamines metabolism, Urease metabolism
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The urease enzyme of Cryptococcus neoformans is linked to different metabolic pathways within the yeast cell, several of which are involved in polyamine metabolism. Cryptococcal biogenic amine production is, however, largely unexplored and is yet to be investigated in relation to urease. The aim of this study was therefore to explore and compare polyamine metabolism in wild-type, urease-negative and urease-reconstituted strains of C. neoformans. Mass spectrometry analysis showed that agmatine and spermidine were the major extra- and intracellular polyamines of C. neoformans and significant differences were observed between 26 and 37 °C. In addition, compared to the wild-type, the relative percentages of extracellular putrescine and spermidine were found to be lower and agmatine higher in cultures of the urease-deficient mutant. The inverse was true for intracellular spermidine and agmatine. Cyclohexylamine was a more potent polyamine inhibitor compared to DL-α-difluoromethylornithine and inhibitory effects were more pronounced at 37 °C than at 26 °C. At both temperatures, the urease-deficient mutant was less susceptible to cyclohexylamine treatment compared to the wild-type. For both inhibitors, growth inhibition was alleviated with polyamine supplementation. This study has provided novel insight into the polyamine metabolism of C. neoformans, highlighting the involvement of urease in biogenic amine production., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
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- 2021
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58. Comparison of Cryptococcus gattii / neoformans Species Complex to Related Genera ( Papiliotrema and Naganishia ) Reveal Variances in Virulence Associated Factors and Antifungal Susceptibility.
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Oliveira LSS, Pinto LM, de Medeiros MAP, Toffaletti DL, Tenor JL, Barros TF, Neves RP, Neto RGL, Milan EP, Padovan ACB, Rocha WPDS, Perfect JR, and Chaves GM
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- Antifungal Agents pharmacology, Humans, Virulence, Virulence Factors, Basidiomycota, Cryptococcus gattii, Cryptococcus neoformans
- Abstract
Cryptococcosis is an infectious disease of worldwide distribution, caused by encapsulated yeasts belonging to the phylum Basidiomycota. The genus Cryptococcus includes several species distributed around the world. The C. gattii / neoformans species complex is largely responsible for most cases of cryptococcosis. However, clinical series have been published of infections caused by Papiliotrema ( Cryptococcus ) laurentii and Naganishia albida ( Cryptococcus albidus ), among other related genera. Here, we examined the pathogenic potential and antifungal susceptibility of C. gattii / neoformans species complex (clades I and II) and related genera ( Papiliotrema and Naganishia ) isolated from environmental and clinical samples. P . laurentii (clade III), N . liquefasciens/N. albidosimilis (clade IV) ; and N. adeliensis / N . albida (clade V) strains produced higher levels of phospholipase and hemolysins, whereas the C. gattii / neoformans species complex strains (clades I and II) had markedly thicker capsules, produced more biofilm biomass and melanin, which are known virulence attributes. Interestingly, 40% of C . neoformans strains (clade II) had MICs above the ECV established for this species to amphotericin B. Several non- C. gattii / neoformans species complex (clades III to V) had MICs equal to or above the ECVs established for C. deuterogattii and C. neoformans for all the three antifungal drugs tested. Finally, all the non- C. gattii/neoformans clinical isolates (clades III to V) produced more melanin than the environmental isolates might reflect their particularly enhanced need for melanin during in vivo protection. It is very clear that C. gattii / neoformans species complex (clades I and II) strains, in general, show more similar virulence phenotypes between each other when compared to non- C. gattii / neoformans species complex (clades III to V) isolates. These observations together with the fact that P . laurentii and Naganishia spp. (clades III to V) strains were collected from the outside of a University Hospital, identify features of these yeasts important for environmental and patient colonization and furthermore, define mechanisms for infections with these uncommon pathogens., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Oliveira, Pinto, de Medeiros, Toffaletti, Tenor, Barros, Neves, Neto, Milan, Padovan, Rocha, Perfect and Chaves.)
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- 2021
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59. Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance.
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Koehler P, Bassetti M, Chakrabarti A, Chen SCA, Colombo AL, Hoenigl M, Klimko N, Lass-Flörl C, Oladele RO, Vinh DC, Zhu LP, Böll B, Brüggemann R, Gangneux JP, Perfect JR, Patterson TF, Persigehl T, Meis JF, Ostrosky-Zeichner L, White PL, Verweij PE, and Cornely OA
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- Amphotericin B, Azoles pharmacology, Humans, Nitriles, Pyridines, SARS-CoV-2, Triazoles, Voriconazole therapeutic use, Antifungal Agents therapeutic use, COVID-19 complications, Coinfection drug therapy, Pulmonary Aspergillosis complications, Pulmonary Aspergillosis drug therapy
- Abstract
Severe acute respiratory syndrome coronavirus 2 causes direct damage to the airway epithelium, enabling aspergillus invasion. Reports of COVID-19-associated pulmonary aspergillosis have raised concerns about it worsening the disease course of COVID-19 and increasing mortality. Additionally, the first cases of COVID-19-associated pulmonary aspergillosis caused by azole-resistant aspergillus have been reported. This article constitutes a consensus statement on defining and managing COVID-19-associated pulmonary aspergillosis, prepared by experts and endorsed by medical mycology societies. COVID-19-associated pulmonary aspergillosis is proposed to be defined as possible, probable, or proven on the basis of sample validity and thus diagnostic certainty. Recommended first-line therapy is either voriconazole or isavuconazole. If azole resistance is a concern, then liposomal amphotericin B is the drug of choice. Our aim is to provide definitions for clinical research and up-to-date recommendations for clinical management of the diagnosis and treatment of COVID-19-associated pulmonary aspergillosis., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
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- 2021
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60. Amoeba Predation of Cryptococcus neoformans Results in Pleiotropic Changes to Traits Associated with Virulence.
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Fu MS, Liporagi-Lopes LC, Dos Santos SR Júnior, Tenor JL, Perfect JR, Cuomo CA, and Casadevall A
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- Acanthamoeba castellanii microbiology, Animals, Cryptococcosis immunology, Cryptococcus neoformans classification, Cryptococcus neoformans genetics, Cytokines immunology, Female, Humans, Larva microbiology, Macrophages microbiology, Mice, Inbred C57BL, Moths microbiology, Phagocytes microbiology, Phenotype, Virulence, Mice, Acanthamoeba castellanii physiology, Cryptococcosis microbiology, Cryptococcus neoformans pathogenicity, Phagocytosis
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Amoeboid predators, such as amoebae, are proposed to select for survival traits in soil microbes such as Cryptococcus neoformans ; these traits can also function in animal virulence by defeating phagocytic immune cells, such as macrophages. Consistent with this notion, incubation of various fungal species with amoebae enhanced their virulence, but the mechanisms involved are unknown. In this study, we exposed three strains of C. neoformans (1 clinical and 2 environmental) to predation by Acanthamoeba castellanii for prolonged times and then analyzed surviving colonies phenotypically and genetically. Surviving colonies comprised cells that expressed either pseudohyphal or yeast phenotypes, which demonstrated variable expression of traits associated with virulence, such as capsule size, urease production, and melanization. Phenotypic changes were associated with aneuploidy and DNA sequence mutations in some amoeba-passaged isolates, but not in others. Mutations in the gene encoding the oligopeptide transporter (CNAG_03013; OPT1 ) were observed among amoeba-passaged isolates from each of the three strains. Isolates derived from environmental strains gained the capacity for enhanced macrophage toxicity after amoeba selection and carried mutations on the CNAG_00570 gene encoding Pkr1 (AMP-dependent protein kinase regulator) but manifested reduced virulence in mice because they elicited more effective fungal-clearing immune responses. Our results indicate that C. neoformans survival under constant amoeba predation involves the generation of strains expressing pleiotropic phenotypic and genetic changes. Given the myriad potential predators in soils, the diversity observed among amoeba-selected strains suggests a bet-hedging strategy whereby variant diversity increases the likelihood that some will survive predation. IMPORTANCE Cryptococcus neoformans is a ubiquitous environmental fungus that is also a leading cause of fatal fungal infection in humans, especially among immunocompromised patients. A major question in the field is how an environmental yeast such as C. neoformans becomes a human pathogen when it has no need for an animal host in its life cycle. Previous studies showed that C. neoformans increases its pathogenicity after interacting with its environmental predator amoebae. Amoebae, like macrophages, are phagocytic cells that are considered an environmental training ground for pathogens to resist macrophages, but the mechanism by which C. neoformans changes its virulence through interactions with protozoa is unknown. Our study indicates that fungal survival in the face of amoeba predation is associated with the emergence of pleiotropic phenotypic and genomic changes that increase the chance of fungal survival, with this diversity suggesting a bet-hedging strategy to ensure that some forms survive., (Copyright © 2021 Fu et al.)
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- 2021
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61. Outcomes and Health Care Resource Utilization of Adult Bacterial Meningitis in the United States.
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Kiyani M, Hodges SE, Adil SM, Charalambous LT, Liu B, Lee HJ, Parente B, Perfect JR, and Lad SP
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Objective: To examine the longitudinal health care resource utilization, in-hospital mortality, and incidence of downstream complications of bacterial meningitis in the United States., Methods: Using IBM MarketScan, we retrieved data on adult patients with a diagnosis of bacterial meningitis admitted to a US hospital between 2008 and 2015. Patients were stratified into groups (1) with/without prior head trauma/neurosurgical complications, (2) nosocomial/community acquisition, and (3) Gram-negative/positive bacteria. Cost data were collected for up to 2 years and analyzed with descriptive statistics and longitudinal modeling., Results: Among 4,496 patients with bacterial meningitis, 16.5% and 4.6% had preceding neurosurgical complications and head injuries, respectively. Lumbar punctures were performed in 37.3% of patients without prior trauma/complications who went on to develop nosocomial meningitis, and those with prior head injuries or complications had longer initial hospital stays (17.0 days vs 8.0 days). Within a month of diagnosis, 29.2% of patients with bacterial meningitis had experienced downstream complications, most commonly hydrocephalus (12.7%). The worst 30-day mortality was due to tuberculous (12.3%) and streptococcal meningitis (7.2%). Overall, prior head trauma and complications were associated with higher costs. Community-acquired bacterial meningitis had lower median baseline costs relative to the nosocomial group (no head trauma/complication: $17,152 vs $82,778; head trauma/complication: $92,428 vs $168,309) but higher median costs within 3 months of diagnosis (no head trauma/complication: $47,911 vs $34,202; head trauma/complication: $89,207 vs $58,947). All costs demonstrated a sharp decline thereafter., Conclusions: Bacterial meningitis remains costly and devastating, especially for those who experience traumatic head injuries or have a complicated progress after neurosurgery., (© 2020 American Academy of Neurology.)
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- 2021
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62. Associations between Cryptococcus Genotypes, Phenotypes, and Clinical Parameters of Human Disease: A Review.
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Montoya MC, Magwene PM, and Perfect JR
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The genus Cryptococcus contains two primary species complexes that are significant opportunistic human fungal pathogens: C. neoformans and C . gattii . In humans, cryptococcosis can manifest in many ways, but most often results in either pulmonary or central nervous system disease. Patients with cryptococcosis can display a variety of symptoms on a spectrum of severity because of the interaction between yeast and host. The bulk of our knowledge regarding Cryptococcus and the mechanisms of disease stem from in vitro experiments and in vivo animal models that make a fair attempt, but do not recapitulate the conditions inside the human host. To better understand the dynamics of initiation and progression in cryptococcal disease, it is important to study the genetic and phenotypic differences in the context of human infection to identify the human and fungal risk factors that contribute to pathogenesis and poor clinical outcomes. In this review, we summarize the current understanding of the different clinical presentations and health outcomes that are associated with pathogenicity and virulence of cryptococcal strains with respect to specific genotypes and phenotypes.
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- 2021
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63. Paediatric bacterial meningitis in the USA: outcomes and healthcare resource utilization of nosocomial versus community-acquired infection.
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Adil SM, Hodges SE, Charalambous LT, Kiyani M, Liu B, Lee HJ, Parente BA, Perfect JR, and Lad SP
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- Adolescent, Bacteria classification, Bacteria genetics, Bacteria isolation & purification, Child, Child, Preschool, Community-Acquired Infections microbiology, Cross Infection microbiology, Female, Hospitals, Humans, Infant, Male, Meningitis, Bacterial microbiology, Pediatrics statistics & numerical data, United States, Community-Acquired Infections epidemiology, Cross Infection epidemiology, Meningitis, Bacterial epidemiology
- Abstract
Introduction. Paediatric bacterial meningitis remains a costly disease, both financially and clinically. Hypothesis/Gap Statement . Previous epidemiological and cost studies of bacterial meningitis (BM) have largely focused on adult populations or single pathogens. There have been few recent, large-scale studies of pediatric BM in the USA. Aim. We examined healthcare resource utilization (HCRU) and associated morbidity and mortality of community-acquired versus nosocomial bacterial infections in children across the USA. Methodology. The IBM MarketScan Research databases were used to identify patients <18 years old admitted to USA hospitals from 2008 to 2015 with a primary diagnosis of BM. Cases were categorized as either community-acquired or nosocomial. HCRU, post-diagnosis neurosurgical procedures, 30-day in-hospital mortality, and complications were compared between groups. Multivariable regression adjusted for sex, age and Gram staining was used to compare costs of nosocomial versus community-acquired infections over time. Results. We identified 1928 cases of paediatric BM without prior head trauma or neurological/systemic complications. Of these, 15.4 % were nosocomial and 84.6 % were community-acquired infections. After diagnostic lumbar puncture (37.1 %), the most common neurosurgical procedure was placement of ventricular catheter (12.6 %). The 30-day complication rates for nosocomial and community-acquired infections were 40.5 and 45.9 %, respectively. The most common complications were hydrocephalus (20.8 %), intracranial abscess (8.8 %) and cerebral oedema (8.1 %). The 30-day in-hospital mortality rates for nosocomial and community-acquired infections were 2.7 and 2.8 %, respectively.Median length of admission was 14.0 days (Q1: 7 days, Q3: 26 days). Median 90-day cost was $40 861 (Q1: $11 988, Q3: $114,499) for the nosocomial group and $56 569 (Q1: $26 127, Q3: $142 780) for the community-acquired group. In multivariable regression, the 90-day post-diagnosis total costs were comparable between groups (cost ratio: 0.89; 95 % CI: 0.70 to 1.13), but at 2 years post-diagnosis, the nosocomial group was associated with 137 % higher costs (CR: 2.37, 95 % CI: 1.51 to 3.70). Conclusion. In multivariable analysis, nosocomial infections were associated with significantly higher long-term costs up to 2 years post-infection. Hydrocephalus, intracranial epidural abscess and cerebral oedema were the most common complications, and lumbar punctures and ventricular catheter placement were the most common neurosurgical procedures. This study represents the first nation-wide, longitudinal comparison of the outcomes and considerable HCRU of nosocomial versus community-acquired paediatric BM, including characterization of complications and procedures contributing to the high costs of these infections.
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- 2021
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64. Emerging Issues in Antifungal Resistance.
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Perfect JR and Ghannoum M
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- Fungal Proteins genetics, Fungi drug effects, Gene Expression Regulation, Fungal drug effects, Humans, Immunocompromised Host, Invasive Fungal Infections microbiology, Antifungal Agents pharmacology, Drug Resistance, Fungal, Fungi genetics, Invasive Fungal Infections drug therapy
- Abstract
Invasive fungal diseases continue to cause substantial mortality in the enlarging immunocompromised population. It is fortunate that the field has moved past amphotericin B deoxycholate as the only available antifungal drug but despite new classes of antifungal agents both primary and secondary drug resistance in molds and yeasts abound. From the rise of multiple-drug-resistant Candida auris to the agrochemical selection of environmental azole-resistant Aspergillus fumigatus, it is and will be critical to understand antifungal drug resistance and both prevent and treat it with new strategies and agents., (Copyright © 2020 Elsevier Inc. All rights reserved.)
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- 2020
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65. Assessing the virulence of Cryptococcus neoformans causing meningitis in HIV infected and uninfected patients in Vietnam.
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Thanh LT, Toffaletti DL, Tenor JL, Giamberardino C, Sempowski GD, Asfaw Y, Phan HT, Van Duong A, Trinh NM, Thwaites GE, Ashton PM, Chau NVV, Baker SG, Perfect JR, and Day JN
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- AIDS-Related Opportunistic Infections pathology, Animals, Colony Count, Microbial, Cryptococcus neoformans genetics, Cytokines metabolism, Female, Fungal Capsules pathology, Genotype, Humans, Immunocompetence, Lung metabolism, Lung microbiology, Lung pathology, Male, Meningitis, Cryptococcal pathology, Mice, Phenotype, Vietnam epidemiology, Virulence, AIDS-Related Opportunistic Infections microbiology, Cryptococcus neoformans pathogenicity, Meningitis, Cryptococcal microbiology
- Abstract
We previously observed a substantial burden of cryptococcal meningitis in Vietnam atypically arising in individuals who are uninfected with human immunodeficiency virus (HIV). This disease was associated with a single genotype of Cryptococcus neoformans (sequence type [ST]5), which was significantly less common in HIV-infected individuals. Aiming to compare the phenotypic characteristics of ST5 and non-ST5 C. neoformans, we selected 30 representative Vietnamese isolates and compared their in vitro pathogenic potential and in vivo virulence. ST5 and non-ST5 organisms exhibited comparable characteristics with respect to in vitro virulence markers including melanin production, replication at 37°C, and growth in cerebrospinal fluid. However, the ST5 isolates had significantly increased variability in cellular and capsular sizing compared with non-ST5 organisms (P < .001). Counterintuitively, mice infected with ST5 isolates had significantly longer survival with lower fungal burdens at day 7 than non-ST5 isolates. Notably, ST5 isolates induced significantly greater initial inflammatory responses than non-ST5 strains, measured by TNF-α concentrations (P < .001). Despite being generally less virulent in the mouse model, we hypothesize that the significant within strain variation seen in ST5 isolates in the tested phenotypes may represent an evolutionary advantage enabling adaptation to novel niches including apparently immunocompetent human hosts., (© The Author(s) 2020. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)
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- 2020
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66. Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium.
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Donnelly JP, Chen SC, Kauffman CA, Steinbach WJ, Baddley JW, Verweij PE, Clancy CJ, Wingard JR, Lockhart SR, Groll AH, Sorrell TC, Bassetti M, Akan H, Alexander BD, Andes D, Azoulay E, Bialek R, Bradsher RW, Bretagne S, Calandra T, Caliendo AM, Castagnola E, Cruciani M, Cuenca-Estrella M, Decker CF, Desai SR, Fisher B, Harrison T, Heussel CP, Jensen HE, Kibbler CC, Kontoyiannis DP, Kullberg BJ, Lagrou K, Lamoth F, Lehrnbecher T, Loeffler J, Lortholary O, Maertens J, Marchetti O, Marr KA, Masur H, Meis JF, Morrisey CO, Nucci M, Ostrosky-Zeichner L, Pagano L, Patterson TF, Perfect JR, Racil Z, Roilides E, Ruhnke M, Prokop CS, Shoham S, Slavin MA, Stevens DA, Thompson GR, Vazquez JA, Viscoli C, Walsh TJ, Warris A, Wheat LJ, White PL, Zaoutis TE, and Pappas PG
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- Antifungal Agents therapeutic use, Consensus, Humans, Immunocompromised Host, Invasive Fungal Infections diagnosis, Invasive Fungal Infections drug therapy, Mycoses diagnosis, Mycoses drug therapy, Mycoses epidemiology, Neoplasms drug therapy
- Abstract
Background: Invasive fungal diseases (IFDs) remain important causes of morbidity and mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential., Methods: To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups' findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved., Results: There is no change in the classifications of "proven," "probable," and "possible" IFD, although the definition of "probable" has been expanded and the scope of the category "possible" has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses., Conclusions: These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)
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- 2020
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67. 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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68. Clinical mycology today: A synopsis of the mycoses study group education and research consortium (MSGERC) second biennial meeting, September 27-30, 2018, Big Sky, Montana, a proposed global research agenda.
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Pappas PG, Boulware DR, Kontoyiannis DP, Miceli MH, Ostrosky-Zeichner L, Spec A, Thompson GR, Chen S, and Perfect JR
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- Humans, Montana, Organizational Objectives, Biomedical Research organization & administration, Congresses as Topic, Mycology, Mycoses physiopathology, Research Report
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- 2020
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69. The virulence factor urease and its unexplored role in the metabolism of Cryptococcus neoformans.
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Toplis B, Bosch C, Schwartz IS, Kenyon C, Boekhout T, Perfect JR, and Botha A
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- Cryptococcus neoformans growth & development, Cryptococcus neoformans metabolism, Humans, Microbial Viability, Urease metabolism, Virulence, Cryptococcus neoformans enzymology, Cryptococcus neoformans pathogenicity, Metabolic Networks and Pathways, Urea metabolism, Urease genetics, Virulence Factors metabolism
- Abstract
Cryptococcal urease is believed to be important for the degradation of exogenous urea that the yeast encounters both in its natural environment and within the human host. Endogenous urea produced by the yeast's own metabolic reactions, however, may also serve as a substrate for the urease enzyme. Using wild-type, urease-deletion mutant and urease-reconstituted strains of Cryptococcus neoformans H99, we studied reactions located up- and downstream from endogenous urea. We demonstrated that urease is important for cryptococcal growth and that, compared to nutrient-rich conditions at 26°C, urease activity is higher under nutrient-limited conditions at 37°C. Compared to cells with a functional urease enzyme, urease-deficient cells had significantly higher intracellular urea levels and also showed more arginase activity, which may act as a potential source of endogenous urea. Metabolic reactions linked to arginase were also affected, since urease-positive and urease-negative cells differed with respect to agmatinase activity, polyamine synthesis, and intracellular levels of proline and reactive oxygen species. Lastly, urease-deficient cells showed higher melanin levels at 26°C than wild-type cells, while the inverse was observed at 37°C. These results suggest that cryptococcal urease is associated with the functioning of key metabolic pathways within the yeast cell., (© FEMS 2020.)
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- 2020
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70. Black mold takes hold and story told.
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Rolfe R Jr, Schell WA, Smith B, Klapper J, Perfect JR, and Messina JA
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We present a case of an invasive Curvularia infection in a patient who developed following bilateral orthotopic lung transplantation despite receiving post-transplant antifungal prophylaxis. This infection presented as mold colonies studding the interior surface of his chest tubes. Despite surgical washout of his bilateral pleural cavities and antifungal treatment with liposomal amphotericin B, micafungin, and isavuconazonium sulfate, the patient died., Competing Interests: Dr. Perfect has research grants and is a consultant for: Astellas, Pfizer, Merck, Scynexis, Amplyx, Matinas, Appili and Minnetronix. There are no other conflicts of interest to report., (© 2020 The Authors.)
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- 2020
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71. The robust and rapid role of molecular testing in precision fungal diagnostics: A case report.
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Steinbrink JM, Hong DK, Bergin SP, Al-Rohil RN, Perfect JR, and Maziarz EK
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Diagnosis of invasive fungal disease remains an ongoing challenge for clinicians, while continuously evolving treatment regimens increase patient risk for invasive infection. This case highlights how molecular testing led to the diagnosis of co-infection with two fungal pathogens producing invasive disease in a hematopoietic stem cell transplant recipient with graft-versus-host disease (GVHD)., Competing Interests: D.K.H was a previous employee of Karius. S.P.B. received salary support as principle investigator and site investigator in studies of the Karius test in immunocompromised pneumonia. He also is a consultant for pneumonia therapeutics program for Armata Pharmaceuticals. E.K.M. is serving on the Clinical Adjudication Committee for the Karius PICKUP study., (© 2020 The Author(s).)
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- 2020
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72. The longitudinal health economic impact of viral encephalitis in the United States.
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Kiyani M, Liu B, Charalambous LT, Adil SM, Hodges SE, Yang S, Pagadala P, Perfect JR, and Lad SP
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- Adult, Aged, Encephalitis, Viral diagnosis, Encephalitis, Viral mortality, Encephalitis, Viral virology, Female, Health Care Costs, Humans, Male, Middle Aged, Retrospective Studies, United States, Young Adult, Encephalitis, Viral economics
- Abstract
Introduction. Previous studies of viral encephalitis have focused on acute costs, estimating incidence at 7.3 per 100 000 and total US annual charges at $2 billion in 2010. Aim. We aim to quantify the most updated longitudinal health economic impact of viral encephalitis in the USA from 2008 to 2015. Methodology. Data on patients diagnosed with viral encephalitis were obtained from the Truven Health Analytics MarketScan database. Patients with a primary diagnosis of viral encephalitis, from herpetic viruses and other viral aetiologies (e.g. West Nile fever) were included in the analysis. Data concerning healthcare resource utilization, inpatient mortality, length of stay and accrued healthcare costs were collected for up to 5 years. Results. Among 3985 patients with continuous enrolment for 13 months prior to the encephalitis diagnosis, more non-herpes simplex encephalitis (61.7 %) than herpes simplex encephalitis (HSE; 38.3 %) cases were recorded, with the majority concentrated in the southern USA (29.2 %). One-year inpatient mortality was 6.2 %, which over a 5-year period rose to 8.9 % for HSE and 5.8 % for all other viral encephalitides. HSE resulted in longer cumulative stays in the hospital (11 days vs. 4 days; P =0.0025), and accrued 37 % higher first-year costs, after adjusting for known confounders [ P <0.001, cost ratio=1.37, 95 % confidence interval (1.20, 1.57)]. Additionally, HSE was associated with greater 5-year cumulative median charges ($125 338 vs. $82 317, P =0.0015). Conclusion. The health economic impact and long-term morbidity of viral encephalitis in the USA are substantial.
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- 2020
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73. Landscape of gene expression variation of natural isolates of Cryptococcus neoformans in response to biologically relevant stresses.
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Yu CH, Chen Y, Desjardins CA, Tenor JL, Toffaletti DL, Giamberardino C, Litvintseva A, Perfect JR, and Cuomo CA
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- Animals, Cell Line, Cryptococcus neoformans growth & development, Cryptococcus neoformans isolation & purification, Cryptococcus neoformans pathogenicity, Mice, RNA-Seq, Transcriptome, Virulence genetics, Cryptococcus neoformans genetics, Gene Expression Regulation, Fungal, Stress, Physiological genetics
- Abstract
Cryptococcus neoformans is an opportunistic fungal pathogen that at its peak epidemic levels caused an estimated million cases of cryptococcal meningitis per year worldwide. This species can grow in diverse environmental (trees, soil and bird excreta) and host niches (intracellular microenvironments of phagocytes and free-living in host tissues). The genetic basic for adaptation to these different conditions is not well characterized, as most experimental work has relied on a single reference strain of C. neoformans . To identify genes important for yeast infection and disease progression, we profiled the gene expression of seven C. neoformans isolates grown in five representative in vitro environmental and in vivo conditions. We characterized gene expression differences using RNA-Seq (RNA sequencing), comparing clinical and environmental isolates from two of the major lineages of this species, VNI and VNBI. These comparisons highlighted genes showing lineage-specific expression that are enriched in subtelomeric regions and in lineage-specific gene clusters. By contrast, we find few expression differences between clinical and environmental isolates from the same lineage. Gene expression specific to in vivo stages reflects available nutrients and stresses, with an increase in fungal metabolism within macrophages, and an induction of ribosomal and heat-shock gene expression within the subarachnoid space. This study provides the widest view to date of the transcriptome variation of C. neoformans across natural isolates, and provides insights into genes important for in vitro and in vivo growth stages.
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- 2020
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74. Invasive Fungal Infection After Lung Transplantation: Epidemiology in the Setting of Antifungal Prophylaxis.
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Baker AW, Maziarz EK, Arnold CJ, Johnson MD, Workman AD, Reynolds JM, Perfect JR, and Alexander BD
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- Antifungal Agents therapeutic use, Humans, Micafungin, Candidiasis drug therapy, Invasive Fungal Infections drug therapy, Invasive Fungal Infections epidemiology, Invasive Fungal Infections prevention & control, Lung Transplantation adverse effects
- Abstract
Background: Lung transplant recipients commonly develop invasive fungal infections (IFIs), but the most effective strategies to prevent IFIs following lung transplantation are not known., Methods: We prospectively collected clinical data on all patients who underwent lung transplantation at a tertiary care academic hospital from January 2007-October 2014. Standard antifungal prophylaxis consisted of aerosolized amphotericin B lipid complex during the transplant hospitalization. For the first 180 days after transplant, we analyzed prevalence rates and timing of IFIs, risk factors for IFIs, and data from IFIs that broke through prophylaxis., Results: In total, 156 of 815 lung transplant recipients developed IFIs (prevalence rate, 19.1 IFIs per 100 surgeries, 95% confidence interval [CI] 16.4-21.8%). The prevalence rate of invasive candidiasis (IC) was 11.4% (95% CI 9.2-13.6%), and the rate of non-Candida IFIs was 8.8% (95% CI 6.9-10.8%). First episodes of IC occurred a median of 31 days (interquartile range [IQR] 16-56 days) after transplant, while non-Candida IFIs occurred later, at a median of 86 days (IQR 40-121 days) after transplant. Of 169 IFI episodes, 121 (72%) occurred in the absence of recent antifungal prophylaxis; however, IC and non-Candida breakthrough IFIs were observed, most often representing failures of micafungin (n = 16) and aerosolized amphotericin B (n = 24) prophylaxis, respectively., Conclusions: Lung transplant recipients at our hospital had high rates of IFIs, despite receiving prophylaxis with aerosolized amphotericin B lipid complex during the transplant hospitalization. These data suggest benefit in providing systemic antifungal prophylaxis targeting Candida for up to 90 days after transplant and extending mold-active prophylaxis for up to 180 days after surgery., (© The Author(s) 2019. 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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75. A case of CNS aspergillosis in a patient with chronic lymphocytic leukemia on first-line ibrutinib therapy.
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Eichenberger EM, Saullo J, Brander D, Wang SH, Perfect JR, and Messina JA
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Ibrutinib has revolutionized the treatment of chronic lymphoid malignancies. Despite its success, ibrutinib has been linked with several reports of invasive fungal infections. We present a case of CNS aspergillosis in a CLL patient on first line ibrutinib therapy. We summarize existing case reports and case series of invasive aspergillosis in patients on ibrutinib, the pathogenesis of invasive aspergillosis, and discuss the clinical controversies regarding anti-fungal prophylaxis in this population., Competing Interests: JP discloses the following consulting/advisory committee/research grants: Astellas, Merck, F2G, Cidara, Pfizer, Scynexis, Viamet, Amplyx, Vical, Matinas, Minnetronix. DB discloses the following consulting/advisory committee/research grants: AbbVie, ArQule, AstraZeneca, BeiGene, DTRM, Genentech, Juno, MEI Pharma, Novartis, Pharmacyclics, Teva, TG Therapeutics, Tolero, Verastem. JM, EE, SW and JS have nothing to disclose., (© 2019 Published by Elsevier B.V. on behalf of International Society for Human and Animal Mycology.)
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- 2019
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76. Fluconazole Monotherapy Is a Suboptimal Option for Initial Treatment of Cryptococcal Meningitis Because of Emergence of Resistance.
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Hope W, Stone NRH, Johnson A, McEntee L, Farrington N, Santoro-Castelazo A, Liu X, Lucaci A, Hughes M, Oliver JD, Giamberardino C, Mfinanga S, Harrison TS, Perfect JR, and Bicanic T
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- Adult, Animals, Cryptococcus neoformans drug effects, Female, Humans, Male, Meningoencephalitis drug therapy, Meningoencephalitis microbiology, Mice, Microbial Sensitivity Tests methods, Middle Aged, Young Adult, Antifungal Agents therapeutic use, Drug Resistance, Fungal drug effects, Fluconazole therapeutic use, Meningitis, Cryptococcal drug therapy
- Abstract
Cryptococcal meningitis is a lethal disease with few therapeutic options. Induction therapy with fluconazole has been consistently demonstrated to be associated with suboptimal microbiological and clinical outcomes. Exposure to fluconazole causes dynamic changes in antifungal susceptibility, which are associated with the development of aneuploidy. The implications of this phenomenon for pharmacodynamics of fluconazole for cryptococcal meningitis are poorly understood. The pharmacodynamics of fluconazole were studied using a hollow-fiber infection model (HFIM) and a well-characterized murine model of cryptococcal meningoencephalitis. The relationship between drug exposure and both antifungal killing and the emergence of resistance was quantified. The same relationships were further evaluated in a recently described group of patients with cryptococcal meningitis undergoing induction therapy with fluconazole at 800 to 1,200 mg/day. The pattern of emergence of fluconazole resistance followed an "inverted U." Resistance amplification was maximal and suppressed at ratios of the area under the concentration-time curve for the free, unbound fraction of the drug to the MIC ( f AUC:MIC) of 34.5 to 138 and 305.6, respectively. Emergence of resistance was observed in vivo with an f AUC:MIC of 231.4. Aneuploidy with duplication of chromosome 1 was demonstrated to be the underlying mechanism in both experimental models. The pharmacokinetic (PK)-pharmacodynamic model accurately described the PK, antifungal killing, and emergence of resistance. Monte Carlo simulations from the clinical pharmacokinetic-pharmacodynamic model showed that only 12.8% of simulated patients receiving fluconazole at 1,200 mg/day achieved sterilization of the cerebrospinal fluid (CSF) after 2 weeks and that 83.4% had a persistent subpopulation that was resistant to fluconazole. Fluconazole is primarily ineffective due to the emergence of resistance. Treatment with 1,200 mg/day leads to the killing of a susceptible subpopulation but is compromised by the emergence of resistance. IMPORTANCE Cryptococcal meningitis is a lethal disease with few treatment options. The incidence remains high and intricately linked with the HIV/AIDS epidemic. In many parts of the world, fluconazole is the only agent that is available for the initial treatment of cryptococcal meningitis despite considerable evidence that it is associated with suboptimal microbiological and clinical outcomes. Fluconazole has a fungistatic mode of action: it predominantly inhibits growth rather than causing fungal killing. Our work shows that the pattern of fluconazole activity is caused by the emergence of resistance in Cryptococcus not detected by standard susceptibility tests, with chromosomal duplication/aneuploidy as the main mechanism. Resistance emergence is related to drug exposure and occurs with the use of clinically relevant regimens. Hence, fluconazole (and potentially other agents that target 14-alpha-demethylase) is compromised by an intrinsic property that limits its effectiveness. However, this resistance may be potentially overcome by dosage escalation or the use of combination therapy., (Copyright © 2019 Hope et al.)
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- 2019
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77. Regulatory Mechanism of the Atypical AP-1-Like Transcription Factor Yap1 in Cryptococcus neoformans.
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So YS, Maeng S, Yang DH, Kim H, Lee KT, Yu SR, Tenor JL, Giri VK, Toffaletti DL, Arras S, Fraser JA, Perfect JR, and Bahn YS
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- Animals, Cryptococcosis microbiology, DNA Mutational Analysis, Disease Models, Animal, Fungal Proteins genetics, Gene Expression Profiling, Mice, Inbred BALB C, Microbial Viability, Oxidative Stress, Protein Transport, Sequence Deletion, Transcription Factors genetics, Virulence, Cryptococcus neoformans genetics, Cryptococcus neoformans growth & development, Fungal Proteins metabolism, Gene Expression Regulation, Fungal, Stress, Physiological, Transcription Factors metabolism
- Abstract
AP-1-like transcription factors play evolutionarily conserved roles as redox sensors in eukaryotic oxidative stress responses. In this study, we aimed to elucidate the regulatory mechanism of an atypical yeast AP-1-like protein, Yap1, in the stress response and virulence of Cryptococcus neoformans YAP1 expression was induced and involved not only by oxidative stresses, such as H
2 O2 and diamide, but also by other environmental stresses, such as osmotic and membrane-destabilizing stresses. Yap1 was distributed throughout both the cytoplasm and the nucleus under basal conditions and more enriched within the nucleus in response to diamide but not to other stresses. Deletion of the C-terminal cysteine-rich domain (c-CRD), where the nuclear export signal resides, increased nuclear enrichment of Yap1 under basal conditions and altered resistance to oxidative stresses but did not affect the role of Yap1 in other stress responses and cellular functions. As a potential upstream regulator of Yap1, we discovered that Mpk1 is positively involved, but Hog1 is mostly dispensable. Pleiotropic roles for Yap1 in diverse biological processes were supported by transcriptome data showing that 162 genes are differentially regulated by Yap1, with further analysis revealing that Yap1 promotes cellular resistance to toxic cellular metabolites produced during glycolysis, such as methylglyoxal. Finally, we demonstrated that Yap1 plays a minor role in the survival of C. neoformans within hosts. IMPORTANCE The human meningitis fungal pathogen, Cryptococcus neoformans , contains the atypical yeast AP-1-like protein Yap1. Yap1 lacks an N-terminal cysteine-rich domain (n-CRD), which is present in other fungal Yap1 orthologs, but has a C-terminal cysteine-rich domain (c-CRD). However, the role of c-CRD and its regulatory mechanism remain unknown. Here, we report that Yap1 is transcriptionally regulated in response to oxidative, osmotic, and membrane-destabilizing stresses partly in an Mpk1-dependent manner, supporting its role in stress resistance. The c-CRD domain contributed to the role of Yap1 only in resistance to certain oxidative stresses and azole drugs but not in other cellular functions. Yap1 has a minor role in the survival of C. neoformans in a murine model of systemic cryptococcosis., (Copyright © 2019 So et al.)- Published
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78. Correction: Cryptococcus neoformans resists to drastic conditions by switching to viable but non-culturable cell phenotype.
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Hommel B, Sturny-Leclère A, Volant S, Veluppillai N, Duchateau M, Yu CH, Hourdel V, Varet H, Matondo M, Perfect JR, Casadevall A, Dromer F, and Alanio A
- Abstract
[This corrects the article DOI: 10.1371/journal.ppat.1007945.].
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79. Pharmacodynamics of Isavuconazole in a Rabbit Model of Cryptococcal Meningoencephalitis.
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Kovanda LL, Giamberardino C, McEntee L, Toffaletti DL, Franke KS, Bartuska A, Smilnak G, de Castro GC, Ripple K, Hope WW, and Perfect JR
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- Animals, Area Under Curve, Brain drug effects, Brain microbiology, Cryptococcus neoformans drug effects, Disease Models, Animal, Male, Meningitis, Cryptococcal microbiology, Meningoencephalitis microbiology, Microbial Sensitivity Tests, Models, Theoretical, Rabbits, Antifungal Agents pharmacokinetics, Meningitis, Cryptococcal drug therapy, Meningoencephalitis drug therapy, Nitriles pharmacokinetics, Pyridines pharmacokinetics, Triazoles pharmacokinetics
- Abstract
Cryptococcus spp., important fungal pathogens, are the leading cause of fungus-related mortality in human immunodeficiency virus-infected patients, and new therapeutic options are desperately needed. Isavuconazonium sulfate, a newer triazole antifungal agent, was studied to characterize the exposure-response relationship in a rabbit model of cryptococcal meningoencephalitis. Rabbits treated with isavuconazonium sulfate were compared with those treated with fluconazole and untreated controls. The fungal burden in the cerebrospinal fluid was measured serially over time, while the yeast concentrations in the brain and the eye (aqueous humor) were determined at the end of therapy. The exposure impact of isavuconazonium sulfate dosing in the rabbit was linked using mathematical modeling. Similar significant reductions in the fungal burden in the brain and cerebrospinal fluid in rabbits treated with isavuconazonium sulfate and fluconazole compared with that in the untreated controls were observed. No dose-dependent response was demonstrated with isavuconazonium sulfate treatment in this study. The treatment of cryptococcal meningoencephalitis with isavuconazonium sulfate was similar to that with fluconazole. Dose-dependent reductions in yeast over time were not demonstrated, which limited our ability to estimate the pharmacodynamic target. Further nonclinical and clinical studies are needed in order to characterize the extent of the exposure-response relationship in cryptococcal meningoencephalitis. However, this study suggests that isavuconazonium sulfate, like fluconazole, could be beneficial in the setting of consolidation and maintenance therapy, rather than induction monotherapy, in high-burden cryptococcal meningoencephalitis., (Copyright © 2019 Kovanda et al.)
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- 2019
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80. A Genome-Wide Functional Genomics Approach Identifies Susceptibility Pathways to Fungal Bloodstream Infection in Humans.
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Jaeger M, Matzaraki V, Aguirre-Gamboa R, Gresnigt MS, Chu X, Johnson MD, Oosting M, Smeekens SP, Withoff S, Jonkers I, Perfect JR, van de Veerdonk FL, Kullberg BJ, Joosten LAB, Li Y, Wijmenga C, Netea MG, and Kumar V
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- Alleles, Candida albicans pathogenicity, Candidemia microbiology, Chromosomes, Human, Pair 15, Cohort Studies, Cytokines blood, Cytokines genetics, Cytokines metabolism, Disease Susceptibility, Genetic Loci, Group IV Phospholipases A2 blood, Group IV Phospholipases A2 genetics, Group IV Phospholipases A2 metabolism, Homeostasis, Host-Pathogen Interactions genetics, Host-Pathogen Interactions immunology, Humans, Interleukin-6 genetics, Oxidative Stress, Reactive Oxygen Species metabolism, Candida albicans immunology, Candidemia genetics, Genome-Wide Association Study, Genomics
- Abstract
Background: Candidemia, one of the most common causes of fungal bloodstream infection, leads to mortality rates up to 40% in affected patients. Understanding genetic mechanisms for differential susceptibility to candidemia may aid in designing host-directed therapies., Methods: We performed the first genome-wide association study on candidemia, and we integrated these data with variants that affect cytokines in different cellular systems stimulated with Candida albicans., Results: We observed strong association between candidemia and a variant, rs8028958, that significantly affects the expression levels of PLA2G4B in blood. We found that up to 35% of the susceptibility loci affect in vitro cytokine production in response to Candida. Furthermore, potential causal genes located within these loci are enriched for lipid and arachidonic acid metabolism. Using an independent cohort, we also showed that the numbers of risk alleles at these loci are negatively correlated with reactive oxygen species and interleukin-6 levels in response to Candida. Finally, there was a significant correlation between susceptibility and allelic scores based on 16 independent candidemia-associated single-nucleotide polymorphisms that affect monocyte-derived cytokines, but not with T cell-derived cytokines., Conclusions: Our results prioritize the disturbed lipid homeostasis and oxidative stress as potential mechanisms that affect monocyte-derived cytokines to influence susceptibility to candidemia., (© The Author(s) 2019. 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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- 2019
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81. Cryptococcus neoformans resists to drastic conditions by switching to viable but non-culturable cell phenotype.
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Hommel B, Sturny-Leclère A, Volant S, Veluppillai N, Duchateau M, Yu CH, Hourdel V, Varet H, Matondo M, Perfect JR, Casadevall A, Dromer F, and Alanio A
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- Animals, Cryptococcosis microbiology, Cryptococcus neoformans genetics, Culture Media, Fatty Acids metabolism, Fungal Proteins metabolism, Humans, Mice, Microbial Viability, Mitochondria genetics, Mitochondria metabolism, Oxygen metabolism, Pantothenic Acid pharmacology, Phenotype, Transcriptome, Cryptococcus neoformans pathogenicity, Cryptococcus neoformans physiology
- Abstract
Metabolically quiescent pathogens can persist in a viable non-replicating state for months or even years. For certain infectious diseases, such as tuberculosis, cryptococcosis, histoplasmosis, latent infection is a corollary of this dormant state, which has the risk for reactivation and clinical disease. During murine cryptococcosis and macrophage uptake, stress and host immunity induce Cryptococcus neoformans heterogeneity with the generation of a sub-population of yeasts that manifests a phenotype compatible with dormancy (low stress response, latency of growth). In this subpopulation, mitochondrial transcriptional activity is regulated and this phenotype has been considered as a hallmark of quiescence in stem cells. Based on these findings, we worked to reproduce this phenotype in vitro and then standardize the experimental conditions to consistently generate this dormancy in C. neoformans. We found that incubation of stationary phase yeasts (STAT) in nutriment limited conditions and hypoxia for 8 days (8D-HYPOx) was able to produced cells that mimic the phenotype obtained in vivo. In these conditions, mortality and/or apoptosis occurred in less than 5% of the yeasts compared to 30-40% of apoptotic or dead yeasts upon incubation in normoxia (8D-NORMOx). Yeasts in 8D-HYPOx harbored a lower stress response, delayed growth and less that 1% of culturability on agar plates, suggesting that these yeasts are viable but non culturable cells (VBNC). These VBNC were able to reactivate in the presence of pantothenic acid, a vitamin that is known to be involved in quorum sensing and a precursor of acetyl-CoA. Global metabolism of 8D-HYPOx cells showed some specific requirements and was globally shut down compared to 8D-NORMOx and STAT conditions. Mitochondrial analyses showed that the mitochondrial mass increased with mitochondria mostly depolarized in 8D-HYPOx compared to 8D-NORMox, with increased expression of mitochondrial genes. Proteomic and transcriptomic analyses of 8D-HYPOx revealed that the number of secreted proteins and transcripts detected also decreased compared to 8D-NORMOx and STAT, and the proteome, secretome and transcriptome harbored specific profiles that are engaged as soon as four days of incubation. Importantly, acetyl-CoA and the fatty acid pathway involving mitochondria are required for the generation and viability maintenance of VBNC. Altogether, these data show that we were able to generate for the first time VBNC phenotype in C. neoformans. This VBNC state is associated with a specific metabolism that should be further studied to understand dormancy/quiescence in this yeast., Competing Interests: The authors have declared that no competing interests exist.
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- 2019
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82. Performance of the T2Bacteria Panel for Diagnosing Bloodstream Infections: A Diagnostic Accuracy Study.
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Nguyen MH, Clancy CJ, Pasculle AW, Pappas PG, Alangaden G, Pankey GA, Schmitt BH, Rasool A, Weinstein MP, Widen R, Hernandez DR, Wolk DM, Walsh TJ, Perfect JR, Wilson MN, and Mylonakis E
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- False Positive Reactions, Female, Humans, Male, Middle Aged, Predictive Value of Tests, Prospective Studies, Bacteremia diagnosis, Blood Culture standards
- Abstract
Background: Blood cultures, the gold standard for diagnosing bloodstream infections (BSIs), are insensitive and limited by prolonged time to results. The T2Bacteria Panel (T2 Biosystems) is a direct-from-blood, nonculture test that identifies the most common ESKAPE bacteria (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli)., Objective: To assess performance of the T2Bacteria Panel in diagnosing suspected BSIs in adults., Design: Prospective patient enrollment (8 December 2015 through 4 August 2017)., Setting: Eleven U.S. hospitals., Patients: 1427 patients for whom blood cultures were ordered as standard of care., Intervention: Paired blood culture and T2Bacteria testing., Measurements: Performance of T2Bacteria compared with a single set of blood cultures in diagnosing proven, probable, and possible BSIs caused by T2Bacteria-targeted organisms., Results: Blood culture and T2Bacteria results were positive for targeted bacteria in 3% (39 of 1427) and 13% (181 of 1427) of patients, respectively. Mean times from start of blood culture incubation to positivity and species identification were 38.5 (SD, 32.8) and 71.7 (SD, 39.3) hours, respectively. Mean times to species identification with T2Bacteria were 3.61 (SD, 0.2) to 7.70 (SD, 1.38) hours, depending on the number of samples tested. Per-patient sensitivity and specificity of T2Bacteria for proven BSIs were 90% (95% CI, 76% to 96%) and 90% (CI, 88% to 91%), respectively; the negative predictive value was 99.7% (1242 of 1246). The rate of negative blood cultures with a positive T2Bacteria result was 10% (146 of 1427); 60% (88 of 146) of such results were associated with probable (n = 62) or possible (n = 26) BSIs. If probable BSIs and both probable and possible BSIs were assumed to be true positives missed by blood culture, per-patient specificity of T2Bacteria was 94% and 96%, respectively., Limitation: Low prevalence of positive blood cultures, collection of a single set of culture specimens, and inability of T2Bacteria to detect nontargeted pathogens., Conclusion: The T2Bacteria Panel rapidly and accurately diagnoses BSIs caused by 5 common bacteria., Primary Funding Source: T2 Biosystems.
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- 2019
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83. Real-world implications of QT prolongation in patients receiving voriconazole and amiodarone.
- Author
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Mourad A, Stiber JA, Perfect JR, and Johnson MD
- Subjects
- Aged, Amiodarone administration & dosage, Anti-Arrhythmia Agents administration & dosage, Antifungal Agents administration & dosage, Female, Humans, Male, Middle Aged, Retrospective Studies, Voriconazole administration & dosage, Amiodarone adverse effects, Anti-Arrhythmia Agents adverse effects, Antifungal Agents adverse effects, Drug Interactions, Long QT Syndrome chemically induced, Voriconazole adverse effects
- Abstract
Objectives: Voriconazole, a triazole antifungal, is frequently prescribed in a complex patient population with comorbidities that require concomitant administration of QT interval-prolonging medications. We sought to evaluate QT interval prolongation in patients receiving concomitant therapy with voriconazole and amiodarone and to assess the development of any potentially fatal cardiac arrhythmias as a result., Methods: We conducted a retrospective observational study of patients who had received amiodarone and voriconazole concomitantly between 2005 and 2015, with a prior period of monotherapy, who had ECG data during monotherapy (baseline) and concomitant therapy (follow-up)., Results: We included 46 patients in our final analysis. Overall, the mean change in QT corrected (QTc) from baseline to follow-up was 49.0 ms (P < 0.001). Eighteen (39.1%) patients had a follow-up QTc interval ≥500 ms, with 17 (37.0%) having a change in QTc interval ≥60 ms from baseline to follow-up. Men were more likely to have a follow-up QTc interval of ≥500 ms. In multivariate analysis, only low serum potassium concentration and concomitant 'possible' QT-prolonging drugs were associated with a follow-up QTc interval ≥500 ms and a lower baseline QTc interval was associated with a change in QTc interval of ≥60 ms. Discharge diagnoses of cardiac arrhythmias and events were assessed and none was found to be related to concomitant therapy., Conclusions: Concomitant therapy with amiodarone and voriconazole significantly prolonged the QTc interval to a degree greater than that on monotherapy. However, no clinically significant cardiac events were observed.
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- 2019
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84. Genotypic diversity and clinical outcome of cryptococcosis in renal transplant recipients in Brazil.
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Ponzio V, Chen Y, Rodrigues AM, Tenor JL, Toffaletti DL, Medina-Pestana JO, Colombo AL, and Perfect JR
- Subjects
- Adult, Aged, Brazil, Cryptococcosis drug therapy, Cryptococcosis mortality, Cryptococcus gattii drug effects, Cryptococcus gattii genetics, Cryptococcus neoformans drug effects, Cryptococcus neoformans genetics, Female, Fluconazole therapeutic use, Haplotypes, Humans, Male, Microbial Sensitivity Tests, Middle Aged, Prognosis, Survival Analysis, Young Adult, Cryptococcosis microbiology, Cryptococcus gattii isolation & purification, Cryptococcus neoformans isolation & purification, Fluconazole pharmacology, Genetic Variation, Kidney Transplantation adverse effects
- Abstract
Genotypic diversity and fluconazole susceptibility of 82 Cryptococcus neoformans and Cryptococcus gattii isolates from 60 renal transplant recipients in Brazil were characterized. Clinical characteristics of the patients and prognostic factors were analysed. Seventy-two (87.8%) isolates were C. neoformans and 10 (12.2%) were C. gattii. VNI was the most common molecular type (40 cases; 66.7%), followed by VNII (9 cases; 15%), VGII (6 cases; 10%), VNB (4 cases; 6.7%) and VNI/II (1 case; 1.7%). The isolates showed a high genetic diversity in the haplotype network and six new sequence types were described, most of them for VNB. There was a bias towards skin involvement in the non-VNI population (P = .012). VGII isolates exhibited higher fluconazole minimum inhibitory concentrations compared to C. neoformans isolates (P = 0.008). The 30-day mortality rate was 38.3%, and it was significantly associated with fungemia and absence of headache. Patients infected with VGII had a high mortality rate at 90 days (66.7%). A variety of molecular types produce disease in renal transplant recipients in Brazil and highlighted by VGII and VNB. We report the clinical appearance and impact of the molecular type, fluconazole susceptibility of the isolates, and clinical characteristics on patient outcome in this population.
- Published
- 2019
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85. Phenotypic Variability Correlates with Clinical Outcome in Cryptococcus Isolates Obtained from Botswanan HIV/AIDS Patients.
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Fernandes KE, Brockway A, Haverkamp M, Cuomo CA, van Ogtrop F, Perfect JR, and Carter DA
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- Botswana epidemiology, CD4 Lymphocyte Count, Cryptococcosis complications, Cryptococcus neoformans cytology, Cryptococcus neoformans pathogenicity, Fungal Capsules, Giant Cells, HIV, Humans, Meningitis microbiology, Cryptococcosis microbiology, Cryptococcus neoformans isolation & purification, Genetic Variation, HIV Infections microbiology, Phenotype
- Abstract
Pathogenic species of Cryptococcus cause hundreds of thousands of deaths annually. Considerable phenotypic variation is exhibited during infection, including increased capsule size, capsule shedding, giant cells (≥15 μm), and micro cells (≤1 μm). We examined 70 clinical isolates of Cryptococcus neoformans and Cryptococcus tetragattii from HIV/AIDS patients in Botswana to determine whether the capacity to produce morphological variants was associated with clinical parameters. Isolates were cultured under conditions designed to simulate in vivo stresses. Substantial variation was seen across morphological and clinical data. Giant cells were more common in C. tetragattii, while micro cells and shed capsule occurred in C. neoformans only. Phenotypic variables fell into two groups associated with differing symptoms. The production of "large" phenotypes (greater cell and capsule size and giant cells) was associated with higher CD4 count and was negatively correlated with intracranial pressure indicators, suggesting that these are induced in early stage infection. "Small" phenotypes (micro cells and shed capsule) were associated with lower CD4 counts, negatively correlated with meningeal inflammation indicators, and positively correlated with intracranial pressure indicators, suggesting that they are produced later during infection and may contribute to immune suppression and promote proliferation and dissemination. These trends persisted at the species level, indicating that they were not driven by association with particular Cryptococcus species. Isolates possessing giant cells, micro cells, and shed capsule were rare, but strikingly, they were associated with patient death ( P = 0.0165). Our data indicate that pleomorphism is an important driver in Cryptococcus infection. IMPORTANCE Cryptococcosis results in hundreds of thousands of deaths annually, predominantly in sub-Saharan Africa. Cryptococcus is an encapsulated yeast, and during infection, cells have the capacity for substantial morphological changes, including capsule enlargement and shedding and variations in cell shape and size. In this study, we examined 70 Cryptococcus isolates causing meningitis in HIV/AIDS patients in Botswana in order to look for associations between phenotypic variation and clinical symptoms. Four variant phenotypes were seen across strains: giant cells of ≥15 µm, micro cells of ≤1 µm, shed extracellular capsule, and irregularly shaped cells. We found that "large" and "small" phenotypes were associated with differing disease symptoms, indicating that their production may be important during the disease process. Overall, our study indicates that Cryptococcus strains that can switch on cell types under different situations may be more able to sustain infection and resist the host response., (Copyright © 2018 Fernandes et al.)
- Published
- 2018
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86. Genomic characterization of recurrent mold infections in thoracic transplant recipients.
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Messina JA, Wolfe CR, Hemmersbach-Miller M, Milano C, Todd JL, Reynolds J, Alexander BD, Schell WA, Cuomo CA, and Perfect JR
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- Aged, Antifungal Agents therapeutic use, Aspergillus fumigatus isolation & purification, Aspergillus fumigatus pathogenicity, Biopsy, DNA, Fungal genetics, Fatal Outcome, Humans, Invasive Fungal Infections diagnosis, Invasive Fungal Infections drug therapy, Invasive Fungal Infections pathology, Male, Middle Aged, Recurrence, Saccharomycetales isolation & purification, Saccharomycetales pathogenicity, Transplant Recipients, Whole Genome Sequencing, Aspergillus fumigatus genetics, Heart Transplantation adverse effects, Invasive Fungal Infections microbiology, Lung Transplantation adverse effects, Saccharomycetales genetics
- Abstract
Invasive mold disease in thoracic organ transplant recipients is a well-recognized complication, but the long-term persistence of molds within the human body and evasion of host defenses has not been well-described. We present 2 cases of invasive mold disease (Verruconis gallopava and Aspergillus fumigatus) in thoracic transplant recipients who had the same mold cultured years prior to the invasive disease presentation. The paired isolates from the index and recurrent infections in both patients were compared using whole-genome sequencing to determine if the same strain of mold caused both the index and recurrent infections. In Case 1, the isolates were found to be of the same strain indicating that the initial colonizing isolate identified pre-transplant eventually caused invasive mold disease post-transplant while in Case 2, the 2 isolates were not of the same strain. These results demonstrate the distinct possibility of molds both persisting within the human body for years prior to invasive mold disease or the long-term risk of recurrent, persistent infection with more than one strain. Further studies of long-term molecular epidemiology of IMD and risk factors for mold persistence in transplant recipients are encouraged., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2018
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87. Novel Treatment of Cryptococcal Meningitis via Neurapheresis Therapy.
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Smilnak GJ, Charalambous LT, Cutshaw D, Premji AM, Giamberardino CD, Ballard CG, Bartuska AP, Ejikeme TU, Sheng H, Verbick LZ, Hedstrom BA, Pagadala PC, McCabe AR, Perfect JR, and Lad SP
- Subjects
- Animals, Disease Models, Animal, Meningitis, Cryptococcal cerebrospinal fluid, Meningitis, Cryptococcal microbiology, Rabbits, Antigens, Fungal analysis, Blood Component Removal, Cryptococcus neoformans isolation & purification, Fungal Polysaccharides analysis, Meningitis, Cryptococcal therapy
- Abstract
Cryptococcal meningitis (CM) has emerged as the most common life-threatening fungal meningitis worldwide. Current management involves a sequential, longitudinal regimen of antifungals; despite a significant improvement in survival compared with uniform mortality without treatment, this drug paradigm has not led to a consistent cure. Neurapheresis therapy, extracorporeal filtration of yeasts from cerebrospinal fluid (CSF) in infected hosts, is presented here as a novel, one-time therapy for CM. In vitro filtration of CSF through this platform yielded a 5-log reduction in concentration of the yeast and a 1-log reduction in its polysaccharide antigen over 24 hours. Additionally, an analogous closed-loop system achieved 97% clearance of yeasts from the subarachnoid space in a rabbit model over 4-6 hours. This is the first publication demonstrating the direct ability to rapidly clear, both in vitro and in vivo, the otherwise slowly removed fungal pathogen that directly contributes to the morbidity and mortality seen in CM.
- Published
- 2018
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88. Outcomes of cryptococcosis in renal transplant recipients in a less-resourced health care system.
- Author
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Ponzio V, Camargo LF, Medina-Pestana J, Perfect JR, and Colombo AL
- Subjects
- Adult, Aged, Allografts drug effects, Allografts physiopathology, Amphotericin B adverse effects, Brazil epidemiology, Cryptococcosis drug therapy, Cryptococcosis immunology, Cryptococcosis microbiology, Deoxycholic Acid adverse effects, Drug Combinations, Female, Graft Rejection microbiology, Graft Rejection physiopathology, Humans, Invasive Fungal Infections drug therapy, Invasive Fungal Infections immunology, Invasive Fungal Infections microbiology, Kidney drug effects, Kidney physiopathology, Male, Middle Aged, Retrospective Studies, Transplant Recipients, Young Adult, Antifungal Agents adverse effects, Cryptococcosis mortality, Graft Rejection epidemiology, Invasive Fungal Infections mortality, Kidney Transplantation adverse effects
- Abstract
Background: Cryptococcosis is the second most common cause of invasive fungal infections in renal transplant recipients in many countries, and data on graft outcome after treatment for this infection is lacking in less-resourced health care settings., Methods: Data from 47 renal transplant recipients were retrospectively collected at a single institution during a period of 13 years. Graft dysfunction, graft loss, and mortality rates were evaluated. Predictors of mortality and graft loss were estimated., Results: A total of 38 (97.4%) patients treated with amphotericin B deoxycholate (AMBd) showed graft dysfunction after antifungal initiation and 8 (18.2%) had kidney graft loss. Graft loss within 30 days after cryptococcosis onset was significantly associated with disseminated infection, greater baseline creatinine levels, and graft dysfunction concomitant to AMBd therapy and an additional nephrotoxic condition. The 30-day mortality rate was 19.2% and it was significantly associated with disseminated and pulmonary infections, somnolence at admission, high CSF opening pressure, positive CSF India ink, creatinine levels greater than 2.0 mg/dL at admission, graft dysfunction in patients treated with AMBd and an additional nephrotoxic condition and graft loss within 30 days., Conclusion: Graft dysfunction was common in renal transplant recipients with cryptococcosis treated with AMBd. The rate of graft loss rate was high, most frequently in patients with concomitant nephrotoxic conditions. Therefore, the clinical focus should be on the use of less nephrotoxic lipid formulations of amphotericin B in this specific population requiring a polyene induction regimen for treatment of severe cryptococcosis in all health care systems caring for transplantation recipients., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2018
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89. Isavuconazole for treatment of rare invasive fungal diseases.
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Cornely OA, Mullane KM, Ostrosky-Zeichner L, Maher RM, Croos-Dabrera R, Lu Q, Lademacher C, Perfect JR, Oren I, Schmitt-Hoffmann AH, Giladi M, Marty FM, and Rahav G
- Subjects
- Administration, Intravenous, Administration, Oral, Adult, Aged, Aged, 80 and over, Antifungal Agents adverse effects, Drug-Related Side Effects and Adverse Reactions epidemiology, Drug-Related Side Effects and Adverse Reactions pathology, Female, Humans, Male, Middle Aged, Nitriles adverse effects, Pyridines adverse effects, Survival Analysis, Treatment Outcome, Triazoles adverse effects, Young Adult, Antifungal Agents administration & dosage, Invasive Fungal Infections drug therapy, Nitriles administration & dosage, Pyridines administration & dosage, Triazoles administration & dosage
- Abstract
Data regarding treatment of rare invasive fungal diseases (IFDs) are scarce. We documented the efficacy and safety of isavuconazole for treatment of uncommonly diagnosed IFDs. VITAL was a single-arm, international, open-label study evaluating the efficacy and safety of isavuconazole (200 mg orally or intravenously every 8 hours for 48 hours, then once daily). The primary outcome was overall response at Day 42; key secondary outcomes were overall responses at Day 84 and end of treatment (EOT), mortality at Days 42 and 84, and safety. This analysis includes patients with IFD caused by rare or unidentified pathogens. Twenty-six patients with IFDs caused by rare moulds (n = 17), non-Candida yeasts (n = 2), or unidentified moulds (n = 7) were enrolled (median treatment duration [range], 114.5 [1-496]) days. Overall treatment success was observed in 11/26 (42.3%), 10/26 (38.5%), and 15/26 (57.7%) patients at Days 42, 84, and EOT, respectively. All-cause mortality rates were 2/26 patients (7.7%) at Day 42 and 4/26 patients (15.4%) at Day 84; another two patients died after Day 84. All patients had ≥1 treatment-emergent adverse event (TEAE); 15 patients (57.7%) had serious TEAEs, and TEAEs led to discontinuation of isavuconazole in four patients (15.4%). Isavuconazole may be efficacious for treatment of a range of rare IFDs., (© 2018 The Authors. Mycoses Published by Blackwell Verlag GmbH.)
- Published
- 2018
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90. In Vitro and In Vivo Evaluation of APX001A/APX001 and Other Gwt1 Inhibitors against Cryptococcus.
- Author
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Shaw KJ, Schell WA, Covel J, Duboc G, Giamberardino C, Kapoor M, Moloney M, Soltow QA, Tenor JL, Toffaletti DL, Trzoss M, Webb P, and Perfect JR
- Subjects
- Administration, Oral, Amidohydrolases genetics, Amidohydrolases metabolism, Aminopyridines chemical synthesis, Aminopyridines pharmacokinetics, Animals, Antifungal Agents chemical synthesis, Antifungal Agents pharmacokinetics, Brain drug effects, Brain microbiology, Cryptococcus gattii drug effects, Cryptococcus gattii enzymology, Cryptococcus gattii genetics, Cryptococcus gattii growth & development, Cryptococcus neoformans enzymology, Cryptococcus neoformans genetics, Cryptococcus neoformans growth & development, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Combinations, Drug Synergism, Fluconazole pharmacology, Fungal Proteins genetics, Fungal Proteins metabolism, Humans, Injections, Intraperitoneal, Isoxazoles chemical synthesis, Isoxazoles pharmacokinetics, Lung drug effects, Lung microbiology, Male, Meningitis, Cryptococcal microbiology, Mice, Microbial Sensitivity Tests, Organophosphates chemical synthesis, Organophosphates pharmacokinetics, Prodrugs chemical synthesis, Prodrugs pharmacokinetics, Amidohydrolases antagonists & inhibitors, Aminopyridines pharmacology, Antifungal Agents pharmacology, Cryptococcus neoformans drug effects, Fungal Proteins antagonists & inhibitors, Isoxazoles pharmacology, Meningitis, Cryptococcal drug therapy, Organophosphates pharmacology, Prodrugs pharmacology
- Abstract
Cryptococcal meningitis (CM), caused primarily by Cryptococcus neoformans , is uniformly fatal if not treated. Treatment options are limited, especially in resource-poor geographical regions, and mortality rates remain high despite current therapies. Here we evaluated the in vitro and in vivo activity of several compounds, including APX001A and its prodrug, APX001, currently in clinical development for the treatment of invasive fungal infections. These compounds target the conserved Gwt1 enzyme that is required for the localization of glycosylphosphatidylinositol (GPI)-anchored cell wall mannoproteins in fungi. The Gwt1 inhibitors had low MIC values, ranging from 0.004 μg/ml to 0.5 μg/ml, against both C. neoformans and C. gattii APX001A and APX2020 demonstrated in vitro synergy with fluconazole (fractional inhibitory concentration index, 0.37 for both). In a CM model, APX001 and fluconazole each alone reduced the fungal burden in brain tissue (0.78 and 1.04 log
10 CFU/g, respectively), whereas the combination resulted in a reduction of 3.52 log10 CFU/g brain tissue. Efficacy, as measured by a reduction in the brain and lung tissue fungal burden, was also observed for another Gwt1 inhibitor prodrug, APX2096, where dose-dependent reductions in the fungal burden ranged from 5.91 to 1.79 log10 CFU/g lung tissue and from 7.00 and 0.92 log10 CFU/g brain tissue, representing the nearly complete or complete sterilization of lung and brain tissue at the higher doses. These data support the further clinical evaluation of this new class of antifungal agents for the treatment of CM., (Copyright © 2018 Shaw et al.)- Published
- 2018
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91. Pulmonary blastomycosis presenting as primary lung cancer.
- Author
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Hussaini SMQ, Madut D, Tong BC, Pavlisko EN, Schell WA, Perfect JR, and Thielman NM
- Subjects
- Antifungal Agents therapeutic use, Blastomyces isolation & purification, Blastomycosis drug therapy, Blastomycosis microbiology, DNA, Fungal genetics, DNA, Fungal metabolism, Diagnosis, Differential, Humans, Lung pathology, Lung Neoplasms diagnosis, Male, Middle Aged, Positron Emission Tomography Computed Tomography, Tomography, X-Ray Computed, Triazoles therapeutic use, Blastomyces genetics, Blastomycosis diagnosis
- Abstract
Background: Blastomycosis is an endemic mycosis in North America that is caused by the dimorphic fungus Blastomyces dermatitidis. The illness is a systemic disease with a wide variety of pulmonary and extra-pulmonary manifestations. The initial presentation of blastomycosis may easily be mistaken for other infectious or non-infectious etiologies., Case Presentation: We present the case of a 52-year-old African-American male and former smoker that presented to his primary care provider with a 2-week history of non-productive cough, night sweats and weight loss. Initially diagnosed with primary lung malignancy, the patient was subsequently found to have pulmonary blastomycosis mimicking lung cancer. The patient underwent a successful course of treatment with posaconazole., Conclusions: Chronic blastomycosis can present with clinical and radiographic features indistinguishable from thoracic malignancies. There is no clinical syndrome specific for blastomycosis, thus a high degree of suspicion is required for early diagnosis. In this case report, we review recent evidence in radiographic features, diagnostic considerations and treatment of the disease.
- Published
- 2018
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92. Present and Future Therapy of Cryptococcus Infections.
- Author
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Mourad A and Perfect JR
- Abstract
Cryptococcal infections burden the immunocompromised population with unacceptably high morbidity and mortality. This population includes HIV-infected individuals and those undergoing organ transplants, as well as seemingly immunocompetent patients (non-HIV, non-transplant). These groups are difficult to manage with the current therapeutic options and strategies, particularly in resource-limited settings. New trials aimed at providing the best treatment strategies for resource-limited countries that will reduce costs and adverse reactions have focused on decreasing the length of therapy and using more readily accessible antifungal agents such as fluconazole. Furthermore, the emergence of antifungal resistance poses another challenge for successful treatment and may require the development of new agents for improved management. This review will discuss the principles of management, current and future antifungal agents, as well as emerging techniques and future directions of care for this deadly infection.
- Published
- 2018
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93. Isavuconazole for treatment of invasive fungal diseases caused by more than one fungal species.
- Author
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Marty FM, Cornely OA, Mullane KM, Ostrosky-Zeichner L, Maher RM, Croos-Dabrera R, Lu Q, Lademacher C, Oren I, Schmitt-Hoffmann AH, Giladi M, Rahav G, and Perfect JR
- Subjects
- Administration, Intravenous, Adult, Aged, Antifungal Agents administration & dosage, Antifungal Agents adverse effects, Aspergillosis drug therapy, Aspergillus drug effects, Coinfection microbiology, Drug-Related Side Effects and Adverse Reactions, Female, Humans, Invasive Fungal Infections mortality, Male, Middle Aged, Mucorales drug effects, Mucormycosis drug therapy, Nitriles administration & dosage, Nitriles adverse effects, Pyridines administration & dosage, Pyridines adverse effects, Treatment Outcome, Triazoles administration & dosage, Triazoles adverse effects, Antifungal Agents therapeutic use, Coinfection drug therapy, Invasive Fungal Infections drug therapy, Invasive Fungal Infections microbiology, Nitriles therapeutic use, Pyridines therapeutic use, Triazoles therapeutic use
- Abstract
The optimal approach to treat invasive fungal disease (IFD) caused by more than one fungal species is unknown. We documented the efficacy and safety of isavuconazole for treatment of IFDs caused by more than one fungal species. VITAL was a single-arm, international, open-label study evaluating the efficacy and safety of isavuconazole (200 mg orally or intravenously every 8 hours for 48 hours, then once daily) for treatment of rare IFDs. The primary outcome was the overall response at Day 42; key secondary outcomes were overall responses at Day 84 and end of treatment (EOT), mortality at Days 42 and 84, and safety. This analysis includes patients with IFD caused by multiple fungal species. Fifteen patients were included in this analysis (including Aspergillus spp., n = 11; without Aspergillus spp., n = 4); median treatment duration was 97 days [range, 6-544] days). Overall treatment success was observed in 2/15 patients (13.3%) at Days 42 and 84, and 2/14 (14.3%) at EOT. All-cause mortality was 2/15 (13.3%) at Day 42 and 4/15 (26.7%) at Day 84. All patients had ≥1 treatment-emergent adverse event (TEAE); 12 patients (80.0%) had serious TEAEs; TEAEs led to discontinuation of isavuconazole in two patients (13.3%). Isavuconazole may be useful to treat some IFDs caused by multiple fungal species., (© 2018 The Authors. Mycoses Published by Blackwell Verlag GmbH.)
- Published
- 2018
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94. Isavuconazole treatment for rare fungal diseases and for invasive aspergillosis in patients with renal impairment: Challenges and lessons of the VITAL trial.
- Author
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Perfect JR, Cornely OA, Heep M, Ostrosky-Zeichner L, Mullane KM, Maher R, Croos-Dabrera R, Lademacher C, Engelhardt M, Chen C, and Marty FM
- Subjects
- Adult, Antifungal Agents administration & dosage, Antifungal Agents adverse effects, Fungi drug effects, Humans, Immunocompromised Host, Middle Aged, Mucormycosis drug therapy, Mycoses microbiology, Nitriles administration & dosage, Nitriles adverse effects, Pyridines administration & dosage, Pyridines adverse effects, Rare Diseases drug therapy, Rare Diseases microbiology, Renal Insufficiency complications, Triazoles administration & dosage, Triazoles adverse effects, Antifungal Agents therapeutic use, Invasive Fungal Infections drug therapy, Invasive Pulmonary Aspergillosis drug therapy, Mycoses drug therapy, Nitriles therapeutic use, Pyridines therapeutic use, Randomized Controlled Trials as Topic, Renal Insufficiency microbiology, Triazoles therapeutic use
- Abstract
Invasive fungal disease (IFD) confers a substantial risk for morbidity and mortality to immunocompromised patients. Invasive aspergillosis (IA) is the most common IFD caused by moulds but the prevalence of other rare mould diseases, such as mucormycosis, hyalohyphomycosis and phaeohyphomycosis, may be increasing. Treatments are available for IA, but evidence to support efficacy and safety of antifungal agents for rare IFDs, or for IFDs in special patient populations, is limited or lacking. The VITAL trial was conducted to assess the efficacy and safety of isavuconazole for the treatment of patients with IA and renal impairment, or with IFDs caused by rare moulds, yeasts or dimorphic fungi. These patients stand to benefit most from a new treatment option but are unlikely to be included in a randomised, controlled trial. In this article, we review the challenges faced in the design and conduct of the VITAL trial. We also review the findings of VITAL, which included evidence of the efficacy and safety of isavuconazole. Finally, we consider the importance of trials such as VITAL to inform therapeutic decision making for clinicians faced with the challenge of treating patients with rare IFDs and as one paradigm of how to determine efficacy and safety of new drugs for rare and resistant infections without a suitable comparator., (© 2018 The Authors. Mycoses Published by Blackwell Verlag GmbH.)
- Published
- 2018
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95. On-demand release of Candida albicans biofilms from urinary catheters by mechanical surface deformation.
- Author
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Maskarinec SA, Parlak Z, Tu Q, Levering V, Zauscher S, López GP, Fowler VG Jr, and Perfect JR
- Subjects
- Elastic Modulus, Humans, Biofilms, Candida albicans physiology, Urinary Catheters microbiology
- Abstract
Candida albicans is a leading cause of catheter-associated urinary tract infections and elimination of these biofilm-based infections without antifungal agents would constitute a significant medical advance. A novel urinary catheter prototype that utilizes on-demand surface deformation is effective at eliminating bacterial biofilms and here the broader applicability of this prototype to remove fungal biofilms has been demonstrated. C. albicans biofilms were debonded from prototypes by selectively inflating four additional intralumens surrounding the main lumen of the catheters to provide the necessary surface strain to remove the adhered biofilm. Deformable catheters eliminated significantly more biofilm than the controls (>90% eliminated vs 10% control; p < 0.001). Mechanical testing revealed that fungal biofilms have an elastic modulus of 45 ± 6.7 kPa with a fracture energy of 0.4-2 J m
-2 . This study underscores the potential of mechanical disruption as a materials design strategy to combat fungal device-associated infections.- Published
- 2018
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96. Genome-wide analysis of the regulation of Cu metabolism in Cryptococcus neoformans.
- Author
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Garcia-Santamarina S, Festa RA, Smith AD, Yu CH, Probst C, Ding C, Homer CM, Yin J, Noonan JP, Madhani H, Perfect JR, and Thiele DJ
- Subjects
- Animals, Base Sequence, Cryptococcus neoformans pathogenicity, Cryptococcus neoformans physiology, Fungal Proteins genetics, Gene Expression Profiling, Gene Expression Regulation, Fungal genetics, Genome-Wide Association Study, Humans, RNA, Fungal, Transcription Factors genetics, Virulence genetics, Copper metabolism, Cryptococcosis microbiology, Cryptococcus neoformans genetics, Fungal Proteins metabolism, Transcription Factors metabolism
- Abstract
The ability of the human fungal pathogen Cryptococcus neoformans to adapt to variable copper (Cu) environments within the host is key for successful dissemination and colonization. During pulmonary infection, host alveolar macrophages compartmentalize Cu into the phagosome and C. neoformans Cu-detoxifying metallothioneins, MT1 and MT2, are required for survival of the pathogen. In contrast, during brain colonization the C. neoformans Cu
+ importers Ctr1 and Ctr4 are required for virulence. Central for the regulation and expression of both the Cu detoxifying MT1/2 and the Cu acquisition Ctr1/4 proteins is the Cu-metalloregulatory transcription factor Cuf1, an established C. neoformans virulence factor. Due to the importance of the distinct C. neoformans Cu homeostasis mechanisms during host colonization and virulence, and to the central role of Cuf1 in regulating Cu homeostasis, we performed a combination of RNA-Seq and ChIP-Seq experiments to identify differentially transcribed genes between conditions of high and low Cu. We demonstrate that the transcriptional regulation exerted by Cuf1 is intrinsically complex and that Cuf1 also functions as a transcriptional repressor. The Cu- and Cuf1-dependent regulon in C. neoformans reveals new adaptive mechanisms for Cu homeostasis in this pathogenic fungus and identifies potential new pathogen-specific targets for therapeutic intervention in fungal infections., (© 2018 John Wiley & Sons Ltd.)- Published
- 2018
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97. Titan cells formation in Cryptococcus neoformans is finely tuned by environmental conditions and modulated by positive and negative genetic regulators.
- Author
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Hommel B, Mukaremera L, Cordero RJB, Coelho C, Desjardins CA, Sturny-Leclère A, Janbon G, Perfect JR, Fraser JA, Casadevall A, Cuomo CA, Dromer F, Nielsen K, and Alanio A
- Subjects
- Animals, Cryptococcosis microbiology, Cryptococcus neoformans genetics, Disease Models, Animal, Genes, Fungal, Host-Pathogen Interactions genetics, Humans, Hyphae cytology, Hyphae genetics, Hyphae pathogenicity, Lung Diseases, Fungal microbiology, Mice, Mice, Inbred C57BL, Models, Biological, Mutation, Phenotype, Quorum Sensing, Cryptococcus neoformans cytology, Cryptococcus neoformans pathogenicity
- Abstract
The pathogenic fungus Cryptococcus neoformans exhibits morphological changes in cell size during lung infection, producing both typical size 5 to 7 μm cells and large titan cells (> 10 μm and up to 100 μm). We found and optimized in vitro conditions that produce titan cells in order to identify the ancestry of titan cells, the environmental determinants, and the key gene regulators of titan cell formation. Titan cells generated in vitro harbor the main characteristics of titan cells produced in vivo including their large cell size (>10 μm), polyploidy with a single nucleus, large vacuole, dense capsule, and thick cell wall. Here we show titan cells derived from the enlargement of progenitor cells in the population independent of yeast growth rate. Change in the incubation medium, hypoxia, nutrient starvation and low pH were the main factors that trigger titan cell formation, while quorum sensing factors like the initial inoculum concentration, pantothenic acid, and the quorum sensing peptide Qsp1p also impacted titan cell formation. Inhibition of ergosterol, protein and nucleic acid biosynthesis altered titan cell formation, as did serum, phospholipids and anti-capsular antibodies in our settings. We explored genetic factors important for titan cell formation using three approaches. Using H99-derivative strains with natural genetic differences, we showed that titan cell formation was dependent on LMP1 and SGF29 genes. By screening a gene deletion collection, we also confirmed that GPR4/5-RIM101, and CAC1 genes were required to generate titan cells and that the PKR1, TSP2, USV101 genes negatively regulated titan cell formation. Furthermore, analysis of spontaneous Pkr1 loss-of-function clinical isolates confirmed the important role of the Pkr1 protein as a negative regulator of titan cell formation. Through development of a standardized and robust in vitro assay, our results provide new insights into titan cell biogenesis with the identification of multiple important factors/pathways., Competing Interests: The authors have declared that no competing interests exist.
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- 2018
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98. Management of an Outbreak of Exophiala dermatitidis Bloodstream Infections at an Outpatient Oncology Clinic.
- Author
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Vasquez A, Zavasky D, Chow NA, Gade L, Zlatanic E, Elkind S, Litvintseva AP, Pappas PG, Perfect JR, Revankar S, Lockhart SR, Chiller T, Ackelsberg J, and Vallabhaneni S
- Subjects
- Aged, Ambulatory Care Facilities, Antifungal Agents therapeutic use, Asymptomatic Infections, Exophiala drug effects, Exophiala isolation & purification, Female, Fungemia mortality, Humans, Immunocompromised Host, Male, Middle Aged, Oncology Service, Hospital, Outpatients, Phaeohyphomycosis mortality, Rhodotorula drug effects, Rhodotorula isolation & purification, Disease Management, Disease Outbreaks, Drug Contamination, Fungemia drug therapy, Phaeohyphomycosis drug therapy
- Abstract
We report the presentation and management of 17 cases of Exophiala dermatitidis and Rhodotorula mucilaginosa bloodstream infections caused by a compounded parenteral medication at an oncology clinic. Twelve patients were asymptomatic. All central venous catheters were removed and antifungal therapy, primarily voriconazole, was administered to patients. Three patients died.
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- 2018
- Full Text
- View/download PDF
99. Prevalence, healthcare resource utilization and overall burden of fungal meningitis in the United States.
- Author
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Charalambous LT, Premji A, Tybout C, Hunt A, Cutshaw D, Elsamadicy AA, Yang S, Xie J, Giamberardino C, Pagadala P, Perfect JR, and Lad SP
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Candidiasis economics, Candidiasis epidemiology, Candidiasis microbiology, Coccidioidomycosis economics, Coccidioidomycosis epidemiology, Coccidioidomycosis microbiology, Female, Histoplasmosis economics, Histoplasmosis epidemiology, Histoplasmosis microbiology, Humans, Male, Meningitis, Cryptococcal economics, Meningitis, Cryptococcal epidemiology, Meningitis, Cryptococcal microbiology, Meningitis, Fungal diagnosis, Meningitis, Fungal economics, Middle Aged, Prevalence, United States epidemiology, Young Adult, Cost of Illness, Health Resources statistics & numerical data, Meningitis, Fungal epidemiology, Meningitis, Fungal microbiology
- Abstract
Purpose: Previous epidemiological and cost studies of fungal meningitis have largely focused on single pathogens, leading to a poor understanding of the disease in general. We studied the largest and most diverse group of fungal meningitis patients to date, over the longest follow-up period, to examine the broad impact on resource utilization within the United States., Methodology: The Truven Health Analytics MarketScan database was used to identify patients with a fungal meningitis diagnosis in the United States between 2000 and 2012. Patients with a primary diagnosis of cryptococcal, Coccidioides, Histoplasma, or Candida meningitis were included in the analysis. Data concerning healthcare resource utilization, prevalence and length of stay were collected for up to 5 years following the original diagnosis., Results: Cryptococcal meningitis was the most prevalent type of fungal meningitis (70.1 % of cases over the duration of the study), followed by coccidioidomycosis (16.4 %), histoplasmosis (6.0 %) and candidiasis (7.6 %). Cryptococcal meningitis and candidiasis patients accrued the largest average charges ($103 236 and $103 803, respectively) and spent the most time in the hospital on average (70.6 and 79 days). Coccidioidomycosis and histoplasmosis patients also accrued substantial charges and time in the hospital ($82 439, 48.1 days; $78 609, 49.8 days, respectively)., Conclusion: Our study characterizes the largest longitudinal cohort of fungal meningitis in the United States. Importantly, the health economic impact and long-term morbidity from these infections are quantified and reviewed. The healthcare resource utilization of fungal meningitis patients in the United States is substantial.
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- 2018
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100. Tolerability profile of the current antifungal armoury.
- Author
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Mourad A and Perfect JR
- Subjects
- Disease Management, Humans, Invasive Fungal Infections diagnosis, Invasive Fungal Infections drug therapy, Antifungal Agents adverse effects, Drug-Related Side Effects and Adverse Reactions epidemiology, Drug-Related Side Effects and Adverse Reactions pathology
- Abstract
The tolerability of available antifungal agents is essential to the final outcome of the management of invasive mycoses. There are limited classes of antifungal agents for use, and they can have serious direct toxicities and/or drug-drug interactions. In this review, we examine the common toxicities noted for antifungal agents and attempt to both identify the issues around the adverse events and provide clinical context for their occurrence in these fragile patients., (© The Author 2018. 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
- 2018
- Full Text
- View/download PDF
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