510 results on '"Thomas J Walsh"'
Search Results
2. Therapeutic Bacteriophages for Gram-Negative Bacterial Infections in Animals and Humans
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Panagiotis, Zagaliotis, Jordyn, Michalik-Provasek, Jason J, Gill, and Thomas J, Walsh
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Microbiology (medical) ,Infectious Diseases ,Immunology ,Immunology and Allergy ,Molecular Biology - Abstract
Drug-resistant Gram-negative bacterial pathogens are an increasingly serious health threat causing worldwide nosocomial infections with high morbidity and mortality. Of these, the most prevalent and severe are Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, and Salmonella typhimurium. The extended use of antibiotics has led to the emergence of multidrug resistance in these bacteria. Drug-inactivating enzymes produced by these bacteria, as well as other resistance mechanisms, render drugs ineffective and make treatment of such infections more difficult and complicated. This makes the development of novel antimicrobial agents an urgent necessity. Bacteriophages, which are bacteria-killing viruses first discovered in 1915, have been used as therapeutic antimicrobials in the past, but their use was abandoned due to the widespread availability of antibiotics in the 20th century. The emergence, however, of drug-resistant pathogens has re-affirmed the need for bacteriophages as therapeutic strategies. This review describes the use of bacteriophages as novel agents to combat this rapidly emerging public health crisis by comprehensively enumerating and discussing the innovative use of bacteriophages in both animal models and in patients infected by Gram-negative bacteria.
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- 2022
3. New Developments in Pediatric Antifungal Pharmacology
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Andreas H, Groll, Emmanuel, Roilides, and Thomas J, Walsh
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Microbiology (medical) ,Echinocandins ,Antifungal Agents ,Infectious Diseases ,Mycoses ,Pediatrics, Perinatology and Child Health ,Humans ,Child - Published
- 2022
4. Pharmacokinetic modelling of caspofungin to develop an extended dosing regimen in paediatric patients
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Silke Gastine, Georg Hempel, Michael N Neely, Thomas J Walsh, and Andreas H Groll
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Pharmacology ,Microbiology (medical) ,Echinocandins ,Antifungal Agents ,Infectious Diseases ,Caspofungin ,Humans ,Pharmacology (medical) ,Child ,Monte Carlo Method ,Invasive Fungal Infections - Abstract
Background Echinocandins are commonly used in treatment and prophylaxis of invasive fungal diseases. Intravenous daily dosing for prophylaxis in the outpatient setting can however become a hurdle for adequate compliance in the paediatric population. Objectives Simulations were performed to assess extended twice-weekly dosing for antifungal prophylaxis using caspofungin. Methods A population pharmacokinetic model was developed based on previously published data from children aged 3 months to 17 years. Using the final model, Monte Carlo simulations were performed to assess the dose needed for adequate exposure in a twice-weekly setting. Mean weekly AUC0–24 h/MIC together with reported AUC0–24 h from previously reported paediatric trials were used to guide adequate exposure. Results and Conclusions A two-compartment model with linear elimination and allometric scaling using fixed exponents was found most adequate to describe the given paediatric populations. Simulations showed that a 200 mg/m2 twice-weekly regimen with maximal 200 mg total dose should result in exposures matching registered daily dosing as well as commonly used pharmacokinetic/pharmacodynamic targets.
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- 2022
5. Impact of a Rapid Molecular Test for Klebsiella pneumoniae Carbapenemase and Ceftazidime-Avibactam Use on Outcomes After Bacteremia Caused by Carbapenem-Resistant Enterobacterales
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Michael J, Satlin, Liang, Chen, Angela, Gomez-Simmonds, Jamie, Marino, Gregory, Weston, Tanaya, Bhowmick, Susan K, Seo, Steven J, Sperber, Angela C, Kim, Brandon, Eilertson, Sierra, Derti, Stephen G, Jenkins, Michael H, Levi, Melvin P, Weinstein, Yi-Wei, Tang, Tao, Hong, Stefan, Juretschko, Katherine L, Hoffman, Thomas J, Walsh, Lars F, Westblade, Anne-Catrin, Uhlemann, and Barry N, Kreiswirth
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Microbiology (medical) ,Infectious Diseases - Abstract
Background Patients with bacteremia due to carbapenem-resistant Enterobacterales (CRE) experience delays until appropriate therapy and high mortality rates. Rapid molecular diagnostics for carbapenemases and new β-lactam/β-lactamase inhibitors may improve outcomes. Methods We conducted an observational study of patients with CRE bacteremia from 2016 to 2018 at 8 New York and New Jersey medical centers and assessed center-specific clinical microbiology practices. We compared time to receipt of active antimicrobial therapy and mortality between patients whose positive blood cultures underwent rapid molecular testing for the Klebsiella pneumoniae carbapenemase (KPC) gene (blaKPC) and patients whose cultures did not undergo this test. CRE isolates underwent antimicrobial susceptibility testing by broth microdilution and carbapenemase profiling by whole-genome sequencing. We also assessed outcomes when ceftazidime-avibactam and polymyxins were used as targeted therapies. Results Of 137 patients with CRE bacteremia, 89 (65%) had a KPC-producing organism. Patients whose blood cultures underwent blaKPC PCR testing (n = 51) had shorter time until receipt of active therapy (median: 24 vs 50 hours; P = .009) compared with other patients (n = 86) and decreased 14-day (16% vs 37%; P = .007) and 30-day (24% vs 47%; P = .007) mortality. blaKPC PCR testing was associated with decreased 30-day mortality (adjusted odds ratio: .37; 95% CI: .16–.84) in an adjusted model. The 30-day mortality rate was 10% with ceftazidime-avibactam monotherapy and 31% with polymyxin monotherapy (P = .08). Conclusions In a KPC-endemic area, blaKPC PCR testing of positive blood cultures was associated with decreased time until appropriate therapy and decreased mortality for CRE bacteremia, and ceftazidime-avibactam is a reasonable first-line therapy for these infections.
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- 2022
6. Food and Drug Administration Public Workshop Summary—Development Considerations of Antifungal Drugs to Address Unmet Medical Need
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Yuliya Yasinskaya, Shukal Bala, Ursula Waack, Cheryl Dixon, Karen Higgins, Jason N Moore, Caroline J Jjingo, Elizabeth O'Shaughnessy, Philip Colangelo, Radu Botgros, Sumathi Nambiar, David Angulo, Aaron Dane, Tom Chiller, Michael R Hodges, Taylor Sandison, William Hope, Thomas J Walsh, Peter Pappas, Aspasia Katragkou, Laura Kovanda, John H Rex, Kieren A Marr, Luis Ostrosky-Zeichner, Shohko Sekine, Monika Deshpande, Sunita J Shukla, and John Farley
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Microbiology (medical) ,Infectious Diseases - Abstract
Pressing challenges in the treatment of invasive fungal infections (IFIs) include emerging and rare pathogens, resistant/refractory infections, and antifungal armamentarium limited by toxicity, drug-drug interactions, and lack of oral formulations. Development of new antifungal drugs is hampered by the limitations of the available diagnostics, clinical trial endpoints, prolonged trial duration, difficulties in patient recruitment, including subpopulations (eg, pediatrics), and heterogeneity of the IFIs. On 4 August 2020, the US Food and Drug Administration convened a workshop that included IFI experts from academia, industry, and other government agencies to discuss the IFI landscape, unmet need, and potential strategies to facilitate the development of antifungal drugs for treatment and prophylaxis. This article summarizes the key topics presented and discussed during the workshop, such as incentives and research support for drug developers, nonclinical development, clinical trial design challenges, lessons learned from industry, and potential collaborations to facilitate antifungal drug development.
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- 2023
7. Mechanistic Insights to Combating NDM- and CTX-M-Coproducing Klebsiella pneumoniae by Targeting Cell Wall Synthesis and Outer Membrane Integrity
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Nicholas M. Smith, Katie Rose Boissonneault, Liang Chen, Vidmantas Petraitis, Ruta Petraitiene, Xun Tao, Jieqiang Zhou, Yinzhi Lang, Povilas Kavaliauskas, Zackery P. Bulman, Patricia N. Holden, Raymond Cha, Jürgen B. Bulitta, Barry N. Kreiswirth, Thomas J. Walsh, and Brian T. Tsuji
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Pharmacology ,Microbial Sensitivity Tests ,Clinical Therapeutics ,Ceftazidime ,beta-Lactamases ,Anti-Bacterial Agents ,Aztreonam ,Drug Combinations ,Klebsiella pneumoniae ,Infectious Diseases ,Cell Wall ,Klebsiella ,Animals ,Pharmacology (medical) ,Rabbits ,Azabicyclo Compounds ,Polymyxin B - Abstract
Metallo-β-lactamase (MBL)-producing Gram-negative bacteria cause infections associated with high rates of morbidity and mortality. Currently, a leading regimen to treat infections caused by MBL-producing bacteria is aztreonam combined with ceftazidime-avibactam. The purpose of the present study was to evaluate and rationally optimize the combination of aztreonam and ceftazidime-avibactam with and without polymyxin B against a clinical Klebsiella pneumoniae isolate producing NDM-1 and CTX-M by use of the hollow fiber infection model (HFIM). A novel de-escalation approach to polymyxin B dosing was also explored, whereby a standard 0-h loading dose was followed by maintenance doses that were 50% of the typical clinical regimen. In the HFIM, the addition of polymyxin B to aztreonam plus ceftazidime-avibactam significantly improved bacterial killing, leading to eradication, including for the novel de-escalation dosing strategy. Serial samples from the growth control and monotherapies were explored in a Galleria mellonella virulence model to assess virulence changes. Weibull regression showed that low-level ceftazidime resistance and treatment with monotherapy resulted in increased G. mellonella mortality (P
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- 2023
8. Candida auris Pan-Drug-Resistant to Four Classes of Antifungal Agents
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Samantha E. Jacobs, Jonathan L. Jacobs, Emily K. Dennis, Sarah Taimur, Meenakshi Rana, Dhruv Patel, Melissa Gitman, Gopi Patel, Sarah Schaefer, Kishore Iyer, Jang Moon, Victoria Adams, Polina Lerner, Thomas J. Walsh, YanChun Zhu, Mohammed Rokebul Anower, Mayuri M. Vaidya, Sudha Chaturvedi, and Vishnu Chaturvedi
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Pharmacology ,Infectious Diseases ,Antifungal Agents ,Drug Resistance, Fungal ,Mechanisms of Resistance ,Humans ,Pharmacology (medical) ,Microbial Sensitivity Tests ,Candida auris ,Phylogeny - Abstract
Candida auris is an urgent antimicrobial resistance threat due to its global emergence, high mortality, and persistent transmissions. Nearly half of C. auris clinical and surveillance cases in the United States are from the New York and New Jersey Metropolitan area. We performed genome, and drug-resistance analysis of C. auris isolates from a patient who underwent multi-visceral transplantation. Whole-genome comparisons of 19 isolates, collected over 72 days, revealed closed similarity (Average Nucleotide Identity > 0.9996; Aligned Percentage > 0.9764) and a distinct subcluster of NY C. auris South Asia Clade I. All isolates had azole-linked resistance in ERG11(K143R) and CDR1(V704L). Echinocandin resistance first appeared with FKS1(S639Y) mutation and then a unique FKS1(F635C) mutation. Flucytosine-resistant isolates had mutations in FCY1, FUR1, and ADE17. Two pan-drug-resistant C. auris isolates had uracil phosphoribosyltransferase deletion (FUR1[1Δ33]) and the elimination of FUR1 expression, confirmed by a qPCR test developed in this study. Besides ERG11 mutations, four amphotericin B-resistant isolates showed no distinct nonsynonymous variants suggesting unknown genetic elements driving the resistance. Pan-drug-resistant C. auris isolates were not susceptible to two-drug antifungal combinations tested by checkerboard, Etest, and time-kill methods. The fungal population pattern, discerned from SNP phylogenetic analysis, was consistent with in-hospital or inpatient evolution of C. auris isolates circulating locally and not indicative of a recent introduction from elsewhere. The emergence of pan-drug-resistance to four major classes of antifungals in C. auris is alarming. Patients at high risk for drug-resistant C. auris might require novel therapeutic strategies and targeted pre-and/or posttransplant surveillance.
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- 2022
9. Osteoarticular Mycoses
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Maria N. Gamaletsou, Blandine Rammaert, Barry Brause, Marimelle A. Bueno, Sanjeet S. Dadwal, Michael W. Henry, Aspasia Katragkou, Dimitrios P. Kontoyiannis, Matthew W. McCarthy, Andy O. Miller, Brad Moriyama, Zoi Dorothea Pana, Ruta Petraitiene, Vidmantas Petraitis, Emmanuel Roilides, Jean-Pierre Sarkis, Maria Simitsopoulou, Nikolaos V. Sipsas, Saad J. Taj-Aldeen, Valérie Zeller, Olivier Lortholary, Thomas J. Walsh, Laiko General Hospital, University of Athens School of Medicine, Pharmacologie des anti-infectieux et antibiorésistance (PHAR2), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université de Poitiers - Faculté de Médecine et de Pharmacie, Université de Poitiers, Hospital for Special Surgery, Far Eastern Federal University (FEFU), City of Hope National Medical Center, Nationwide Children's Hospital, The Ohio State University School of Medicine, The University of Texas M.D. Anderson Cancer Center [Houston], Weill Medical College of Cornell University [New York], New York Presbyterian Hospital, NIH Clinical Center, Bethesda, Maryland, Hippokration General Hospital, Aristotle University of Thessaloniki, Hamad Medical Corporation [Doha, Qatar], Groupe Hospitalier Diaconesses Croix Saint-Simon, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génomique évolutive, modélisation et santé (GEMS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Center for Innovative Therapeutics and Diagnostics, Richmond, Virginia
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Microbiology (medical) ,cryptococcosis ,phaeohyphomycosis ,General Immunology and Microbiology ,histoplasmosis ,Epidemiology ,coccidioidomycosis ,Public Health, Environmental and Occupational Health ,osteomyelitis ,candidiasis ,mucormycosis ,antifungal therapy ,Infectious Diseases ,aspergillosis ,mycoses ,[SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology - Abstract
Osteoarticular mycoses are chronic debilitating infections that require extended courses of antifungal therapy and may warrant expert surgical intervention. As there has been no comprehensive review of these diseases, the International Consortium for Osteoarticular Mycoses prepared a definitive treatise for this important class of infections. Among the etiologies of osteoarticular mycoses are Candida spp., Aspergillus spp., Mucorales, dematiaceous fungi, non-Aspergillus hyaline molds, and endemic mycoses, including those caused by Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides species. This review analyzes the history, epidemiology, pathogenesis, clinical manifestations, diagnostic approaches, inflammatory biomarkers, diagnostic imaging modalities, treatments, and outcomes of osteomyelitis and septic arthritis caused by these organisms. Candida osteomyelitis and Candida arthritis are associated with greater events of hematogenous dissemination than those of most other osteoarticular mycoses. Traumatic inoculation is more commonly associated with osteoarticular mycoses caused by Aspergillus and non-Aspergillus molds. Synovial fluid cultures are highly sensitive in the detection of Candida and Aspergillus arthritis. Relapsed infection, particularly in Candida arthritis, may develop in relation to an inadequate duration of therapy. Overall mortality reflects survival from disseminated infection and underlying host factors.
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- 2022
10. Meeting the Challenges of Sepsis in Severe Coronavirus Disease 2019: A Call to Arms
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Thomas J Walsh, Rick A Bright, Aparna Ahuja, Matthew W McCarthy, Richard A Marfuggi, and Steven Q Simpson
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Infectious Diseases ,Oncology - Abstract
Sepsis is a life-threatening organ dysfunction that is caused by a dysregulated host response to infection. Sepsis may be caused by bacterial, fungal, or viral pathogens. The clinical manifestations exhibited by patients with severe coronavirus disease 2019 (COVID-19)-related sepsis overlap with those exhibited by patients with sepsis from secondary bacterial or fungal infections and can include an altered mental status, dyspnea, reduced urine output, tachycardia, and hypotension. Critically ill patients hospitalized with severe acute respiratory syndrome coronavirus 2 infections have increased risk for secondary bacterial and fungal infections. The same risk factors that may predispose to sepsis and poor outcome from bloodstream infections (BSIs) converge in patients with severe COVID-19. Current diagnostic standards for distinguishing between (1) patients who are critically ill, septic, and have COVID-19 and (2) patients with sepsis from other causes leave healthcare providers with 2 suboptimal choices. The first choice is to empirically administer broad-spectrum, antimicrobial therapy for what may or may not be sepsis. Such treatment may not only be ineffective and inappropriate, but it also has the potential to cause harm. The development of better methods to identify and characterize antimicrobial susceptibility will guide more accurate therapeutic interventions and reduce the evolution of new antibiotic-resistant strains. The ideal diagnostic test should (1) be rapid and reliable, (2) have a lower limit of detection than blood culture, and (3) be able to detect a specific organism and drug sensitivity directly from a clinical specimen. Rapid direct detection of antimicrobial-resistant pathogens would allow targeted therapy and result in improved outcomes in patients with severe COVID-19 and sepsis.
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- 2022
11. Focused multivector ultraviolet (FMUV) technology rapidly eradicates SARS-CoV-2 in-vitro: Implications for hospital disinfection of COVID-19 environments
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Steven Park, David S. Perlin, Sean Fitzgerald, Vidmantas Petraitis, and Thomas J. Walsh
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Disinfection ,Technology ,Infectious Diseases ,SARS-CoV-2 ,Ultraviolet Rays ,Epidemiology ,Health Policy ,Public Health, Environmental and Occupational Health ,COVID-19 ,Humans ,Hospitals - Abstract
Focused Multivector Ultraviolet technology rapidly killed the SARS-CoV-2 coronavirus in-vitro. Plates were inoculated with a mean of greater than 10
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- 2022
12. Efficacy of Cefiderocol in Experimental Stenotrophomonas maltophilia Pneumonia in Persistently Neutropenic Rabbits
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Vidmantas Petraitis, Ruta Petraitiene, Povilas Kavaliauskas, Ethan Naing, Andrew Garcia, Benjamin N. Georgiades, Roger Echols, Robert A. Bonomo, Yoshinori Yamano, Michael J. Satlin, and Thomas J. Walsh
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Pharmacology ,Adult ,Stenotrophomonas maltophilia ,Siderophores ,Pneumonia ,Microbial Sensitivity Tests ,Anti-Bacterial Agents ,Cephalosporins ,Infectious Diseases ,Trimethoprim, Sulfamethoxazole Drug Combination ,Humans ,Animals ,Pharmacology (medical) ,Rabbits ,Gram-Negative Bacterial Infections - Abstract
Stenotrophomonas maltophilia is an important cause of pneumonia in immunocompromised patients. Cefiderocol is a parenteral siderophore cephalosporin with potent in vitro activity against S. maltophilia .
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- 2022
13. Histoplasmosis in an off-trail Hiker receiving ustekinumab: Implications for Preventive and diagnostic strategies for patients receiving anti-IL-12/23 therapy
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Yun-Han Huang, Harjot K. Singh, Thomas J. Walsh, Rema Rao, and Reed Magleby
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0301 basic medicine ,medicine.medical_specialty ,Medicine (General) ,QH301-705.5 ,medicine.medical_treatment ,030106 microbiology ,030231 tropical medicine ,Case Report ,Microbiology ,Inflammatory bowel disease ,Histoplasmosis ,03 medical and health sciences ,0302 clinical medicine ,R5-920 ,Psoriasis ,Histoplasma ,Ustekinumab ,medicine ,Biology (General) ,biology ,business.industry ,Immunosuppression ,medicine.disease ,biology.organism_classification ,Dermatology ,Clinical trial ,Infectious Diseases ,Methotrexate ,business ,medicine.drug - Abstract
Ustekinumab, an IL-12/23 inhibitor, is an important agent in treatment of inflammatory bowel disease and psoriasis. Clinical trials have not demonstrated significantly increased infection risk with ustekinumab. We report a case of disseminated histoplasmosis in the setting of ustekinumab and methotrexate following a hike in the Catskill Mountains, a region not commonly associated with Histoplasma encapsulatum. To our knowledge, this is the first reported case of newly acquired histoplasmosis complicating treatment with ustekinumab., Highlights • Histoplasma is a widely distributed organism present in the environment distant from regions where it may be considered widely endemic. • Immunosuppressive regimens that include ustekinumab may increase risk of histoplasmosis. • Tissue diagnosis is valuable when suspicion is high and antigenic tests are negative.
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- 2021
14. Colonization With Fluoroquinolone-Resistant Enterobacterales Decreases the Effectiveness of Fluoroquinolone Prophylaxis in Hematopoietic Cell Transplant Recipients
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Rianna Malherbe, Michael Hovan, Stephen G. Jenkins, Koen van Besien, Lars F. Westblade, Jingmei Hsu, Alexandra Gomez-Arteaga, Thomas J. Walsh, Claire Douglass, Catherine B. Small, Michael J. Satlin, Sebastian Mayer, Rosemary Soave, Adrienne A. Phillips, Marisa La Spina, Emily Davidson, Liang Chen, and Barry N. Kreiswirth
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0301 basic medicine ,Microbiology (medical) ,medicine.medical_specialty ,medicine.medical_treatment ,030106 microbiology ,Bacteremia ,Levofloxacin ,Hematopoietic stem cell transplantation ,Neutropenia ,03 medical and health sciences ,0302 clinical medicine ,Ciprofloxacin ,Neoplasms ,Internal medicine ,Enterobacterales ,medicine ,Humans ,Colonization ,030212 general & internal medicine ,Retrospective Studies ,Hematopoietic cell ,business.industry ,Broth microdilution ,Hematopoietic Stem Cell Transplantation ,Antibiotic Prophylaxis ,medicine.disease ,Transplant Recipients ,Anti-Bacterial Agents ,Transplantation ,Major Articles and Commentaries ,Infectious Diseases ,business ,Fluoroquinolones ,medicine.drug - Abstract
Background Levofloxacin prophylaxis is recommended to prevent gram-negative bloodstream infections (BSIs) in patients with prolonged chemotherapy-induced neutropenia. However, increasing fluoroquinolone resistance may decrease the effectiveness of this approach. Methods We assessed the prevalence of colonization with fluoroquinolone-resistant Enterobacterales (FQRE) among patients admitted for hematopoietic cell transplantation (HCT) from November 2016 to August 2019 and compared the risk of gram-negative BSI between FQRE-colonized and noncolonized patients. All patients received levofloxacin prophylaxis during neutropenia. Stool samples were collected upon admission for HCT and weekly thereafter until recovery from neutropenia, and underwent selective culture for FQRE. All isolates were identified and underwent antimicrobial susceptibility testing by broth microdilution. FQRE isolates also underwent whole-genome sequencing. Results Fifty-four of 234 (23%) patients were colonized with FQRE prior to HCT, including 30 of 119 (25%) allogeneic and 24 of 115 (21%) autologous HCT recipients. Recent antibacterial use was associated with FQRE colonization (P = .048). Ninety-one percent of colonizing FQRE isolates were Escherichia coli and 29% produced extended-spectrum β-lactamases. Seventeen (31%) FQRE-colonized patients developed gram-negative BSI despite levofloxacin prophylaxis, compared to only 2 of 180 (1.1%) patients who were not colonized with FQRE on admission (P Conclusions Nearly one-third of HCT recipients with pretransplant FQRE colonization developed gram-negative BSI while receiving levofloxacin prophylaxis, and infections were typically caused by their colonizing strains. In contrast, levofloxacin prophylaxis was highly effective in patients not initially colonized with FQRE.
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- 2021
15. Antifungal efficacy of isavuconazole and liposomal amphotericin B in a rabbit model of Exserohilum rostratum meningoencephalitis: A preclinical paradigm for management of CNS phaeohyphomycosis
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Patriss W. Moradi, Aspasia Katragkou, Vidmantas Petraitis, Laura L. Kovanda, Ethan Naing, Bo Bo Win Maung, Malcolm Finkelman, Gittel E Sussman-Straus, Thomas J. Walsh, and Ruta Petraitiene
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rabbits ,Antifungal Agents ,Pyridines ,Triazole ,Microbial Sensitivity Tests ,Pharmacology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Ascomycota ,Central Nervous System Diseases ,In vivo ,Amphotericin B ,Amphotericin B deoxycholate ,Nitriles ,medicine ,Animals ,Humans ,liposomal amphotericin B ,030212 general & internal medicine ,experimental CNS phaeohyphomycosis ,0303 health sciences ,030306 microbiology ,business.industry ,isavuconazole ,Exserohilum rostratum ,Micafungin ,Disease Management ,Meningoencephalitis ,General Medicine ,Triazoles ,medicine.disease ,In vitro ,Disease Models, Animal ,Phaeohyphomycosis ,Infectious Diseases ,chemistry ,AcademicSubjects/SCI00960 ,Original Article ,Drug Therapy, Combination ,Female ,AcademicSubjects/MED00010 ,business ,medicine.drug - Abstract
Treatment options for Exserohilum rostratum meningoencephalitis and other causes of phaeohyphomycosis of the central nervous system (CNS) are limited, while mortality and morbidity remain high. We therefore evaluated isavuconazole, a new antifungal triazole in comparison to liposomal amphotericin B (LAMB), in vitro and in the rabbit model of Exserohilum rostratum meningoencephalitis. We hypothesized that isavuconazole alone or in combination with LAMB or micafungin may be alternative options for treatment of CNS phaeohyphomycosis. We therefore investigated the in vitro antifungal activity of isavuconazole alone or in combination with amphotericin B deoxycholate (DAMB) or micafungin and efficacy of treatment with isavuconazole and LAMB in a rabbit model of experimental E. rostratum meningoencephalitis. Combination checkerboard plates were used to determine the minimum inhibitory concentrations, minimal lethal concentrations, fractional inhibitory concentration indices, and Bliss surface analysis of isavuconazole and amphotericin B deoxycholate (DAMB), either alone or in combination. As there were no in vitro synergistic or antagonistic interactions for either combination of antifungal agents against the E. rostratum isolates, in vivo studies were conducted with isavuconazole and LAMB as monotherapies. Rabbits were divided in following groups: treated with isavuconazole at 60 mg/kg/d (ISAV60), LAMB at 5.0 (LAMB5), 7.5 (LAMB7.5), and 10 mg/kg/d (LAMB10), and untreated controls (UC). In ISAV60-, LAMB5-, LAMB7.5-, and LAMB10-treated rabbits, significant reductions of fungal burden of E. rostratum in cerebral, cerebellar, and spinal cord tissues (P
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- 2020
16. Bloodstream Infections in Hematologic Malignancy Patients With Fever and Neutropenia: Are Empirical Antibiotic Therapies in the United States Still Effective?
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Andrea J Zimmer, Erica Stohs, Jane Meza, Christopher Arnold, John W Baddley, Pranatharthi Chandrasekar, Zeinab El Boghdadly, Carlos A Gomez, Eileen K Maziarz, Jose G Montoya, Steven Pergam, Kenneth V Rolston, Michael J Satlin, Gowri Satyanarayana, Shmuel Shoham, Lynne Strasfeld, Randy Taplitz, Thomas J Walsh, Jo-Anne H Young, Yuning Zhang, and Alison G Freifeld
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Infectious Diseases ,Oncology - Abstract
Background Rising antimicrobial resistance rates may impact the efficacy of empirical antibiotic treatment for febrile neutropenia in high-risk cancer patients. Lacking contemporary data about the epidemiology, antibiotic resistance patterns, and clinical outcomes from bloodstream infections (BSIs) in US cancer patients, it is unclear if current guidelines remain relevant. Methods In a cross-sectional study, 14 US cancer centers prospectively identified BSIs in high-risk febrile neutropenic (FN) patients, including those receiving chemotherapy for hematologic malignancies or hematopoietic stem cell transplantation. Results Among 389 organisms causing BSI in 343 patients, there was an equal distribution of gram-negative (GN) and gram-positive (GP) bacteria, with variability across centers. Cefepime and piperacillin-tazobactam were the most commonly prescribed empirical antibiotics for FN, at 62% and 23%, respectively; a GP-directed agent was empirically included in nearly half of all FN episodes within the first 24 hours. Susceptibility to fluoroquinolones, cefepime, piperacillin-tazobactam, and carbapenems was 49%, 84%, 88%, and 96%, respectively, among GN isolates. Critical illness (CrI), defined as a new requirement for mechanical ventilation, vasopressor, or death within 30 days, occurred in 15% and did not correlate with fluoroquinolone prophylaxis, organism type, initial antibiotics, or adequacy of coverage. Only severity of illness at presentation, signified by a Pitt bacteremia score ≥2, predicted for critical illness within 30 days. Mortality was 4% by day 7 and 10% overall. Conclusions In accordance with US guidelines, cefepime or piperacillin-tazobactam remain effective agents or empirical treatment for high-risk cancer patients with FN who are stable at presentation, maintaining high GN pathogen susceptibility and yielding excellent outcomes.
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- 2022
17. Management of osteoarticular fungal infections in the setting of immunodeficiency
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Savvas Papachristou, Nikolaos V. Sipsas, Thomas J. Walsh, Elias Iosifidis, Maria N. Gamaletsou, and Emmanuel Roilides
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0301 basic medicine ,Microbiology (medical) ,medicine.medical_specialty ,Antifungal Agents ,medicine.medical_treatment ,030106 microbiology ,Antifungal drug ,Arthritis ,Microbiology ,Immunocompromised Host ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Virology ,Osteoarthritis ,Epidemiology ,medicine ,Humans ,030212 general & internal medicine ,Intensive care medicine ,Immunodeficiency ,Arthritis, Infectious ,Surgical approach ,business.industry ,Osteomyelitis ,Immunotherapy ,medicine.disease ,Infectious Diseases ,Mycoses ,business ,Immunosuppressive Agents ,Dimorphic fungus - Abstract
Introduction: Osteoarticular fungal infections (OAFIs) complicate the clinical course of high-risk patients, including immunosuppressed individuals. Their management, however, despite being intricate, is governed by evidence arising from sub-optimal quality research, such as case series. Guidelines are scarce and when present result in recommendations based on low quality evidence. Furthermore, the differences between the management of immunocompromised and immunocompetent patients are not distinct. This is a narrative review after a literature search in PubMed, up to November 2019.Areas covered: The major fungal groups causing osteomyelitis and/or arthritis are Candida spp., Aspergillus spp., non-Aspergillus filamentous fungi, non-Candida yeasts and endemic dimorphic fungi. Their epidemiology is briefly analyzed with emphasis on immunodeficiency and other risk factors. Management of OAFIs includes appropriate antifungal drug therapy (liposomal amphotericin B, triazoles or echinocandins), local surgery and immunotherapy for primary immunodeficiencies. Cessation of immunosuppressive drugs is also mandated.Expert opinion: Management of OAFIs includes affordable and available options and approaches. However, research on therapeutic practices is urgently required to be further improved, due to the rarity of affected patients. Evolution is expected to translate into novel antifungal drugs, less invasive and precise surgical approaches and targeted enhancement of immunoregulatory pathways in defense of challenging fungal pathogens.
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- 2020
18. Comparative evaluation of operating room terminal cleaning by two methods: Focused multivector ultraviolet (FMUV) versus manual-chemical disinfection
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Kristine Goldstein, Donna Armellino, Thomas J. Walsh, Vidmantas Petraitis, and Linti Thomas
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Operating Rooms ,Ultraviolet Rays ,Epidemiology ,Hospital quality ,Microbial contamination ,Patient care ,Chemical disinfection ,Comparative evaluation ,03 medical and health sciences ,0302 clinical medicine ,Humans ,Medicine ,030212 general & internal medicine ,Terminal cleaning ,Process engineering ,Protocol (science) ,Infection Control ,0303 health sciences ,030306 microbiology ,business.industry ,Health Policy ,Public Health, Environmental and Occupational Health ,Parallel process ,Disinfection ,Infectious Diseases ,business ,Disinfectants - Abstract
This non-randomized comparative observational study evaluated the performance of a standard manual-chemical disinfection process with an automated process employing focused multivector ultraviolet (FMUV) light technology during operating room (OR) terminal cleaning.An Association of periOperative Registered Nurses terminal cleaning protocol was modified to incorporate the use of automated FMUV technology that allows workers to occupy the room during operation. This modified protocol was compared with a standard manual-chemical cleaning and disinfection protocol. Equipment surfaces were pre-sampled before and after terminal cleaning. A total of 165 objects were sampled in each process using a 5-point multisided sampling method.The parallel process employing FMUV reduced the active microbial burden by 96.5% from baseline (P.0001), which was over 2.5 times better than the standard process. The standard terminal manual-chemical disinfection process reduced the active microbial burden on sampled objects by 38.4% from baseline (P.0001).The data demonstrates that the performance of standard manual-chemical disinfection alone is variable in a live clinical setting even under the most ideal conditions. By comparison, automated FMUV treatment incorporated in a parallel process consistently produced thorough and significant reductions of microbial contamination levels on all visibly clean patient care equipment.
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- 2020
19. Dalbavancin Reduces Hospital Stay and Improves Productivity for Patients with Acute Bacterial Skin and Skin Structure Infections: The ENHANCE Trial
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Justin J Choi, Thomas J. Walsh, Nicholas Pickell, Patrick Gillard, Ronald Copp, Katelyn R. Keyloun, and Matthew W. McCarthy
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0301 basic medicine ,Microbiology (medical) ,medicine.medical_specialty ,Activities of daily living ,Acute bacterial skin and skin structure infection ,Cost ,medicine.drug_class ,030106 microbiology ,Antibiotics ,lcsh:Infectious and parasitic diseases ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Intensive care ,Long-acting antibiotic ,Medicine ,lcsh:RC109-216 ,In patient ,030212 general & internal medicine ,Original Research ,business.industry ,Dalbavancin ,Pragmatic trial ,Infectious Diseases ,Skin structure ,business ,Hospital stay - Abstract
Introduction Admissions for acute bacterial skin and skin structure infections (ABSSSI) are often prolonged because of intravenous (IV) antibiotics. Use of a long-acting IV antibiotic may reduce length of stay (LOS) on a hospitalist service. The ENHANCE ABSSSI trial sought to determine the impact on LOS and work productivity in patients treated with a long-acting IV antibiotic, dalbavancin, vs. usual care at an urban tertiary-care center. Methods A single-center, pre- vs. post-period pragmatic trial at Weill-Cornell Medical Center assessed usual care for consecutively enrolled admitted ABSSSI patients during an observational period (pre-period). Identification and treatment of eligible admitted ABSSSI patients with dalbavancin were implemented in the post-period. Those with life-threatening infections, requiring multiple antibiotics/intensive care, or with unstable comorbidities were excluded. Outcomes were assessed over a 44-day follow-up period. Results Of 48 and 43 patients enrolled, respectively, in the pre- and post-periods, mean infection-related LOS was reduced in the post-period (3.2 days vs. 4.8 days; P = 0.003). Similar results were found in an adjusted LOS analysis. Work productivity and activity impairment outcomes significantly improved in the post-period (P ≤ 0.01). Complete response rates were similar: 50% (pre-period) and 57% (post-period). Among AEs identified, 17% (n = 7) were found to have possible causal relation to dalbavancin in the post-period. Few AEs were serious (n = 3; 7% post-period versus n = 1; 2% pre-period). Conclusion After implementing the ENHANCE ABSSSI pathway, LOS was significantly reduced by almost 2 days, with potential improvements in work productivity and ability to complete daily activities. Trial Registration ClinicalTrials.gov identifier, NCT03233438. Funding Allergan plc. Electronic supplementary material The online version of this article (10.1007/s40121-019-00275-4) contains supplementary material, which is available to authorized users.
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- 2019
20. Pharmacokinetics, Tissue Distribution, and Efficacy of VIO-001 (Meropenem/Piperacillin/Tazobactam) for Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia in Immunocompetent Rabbits with Chronic Indwelling Vascular Catheters
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Nicholas K. Goldner, Thomas J. Walsh, Ethan Naing, Christina A. Sutherland, Aki Yoneda Kau, Vidmantas Petraitis, Andrew Garcia, Ruta Petraitiene, David P. Nicolau, Christopher Bulow, and Povilas Kavaliauskas
- Subjects
Methicillin-Resistant Staphylococcus aureus ,medicine.medical_specialty ,Bacteremia ,Microbial Sensitivity Tests ,medicine.disease_cause ,Meropenem ,Gastroenterology ,Tazobactam ,Internal medicine ,medicine ,Animals ,Tissue Distribution ,Experimental Therapeutics ,Pharmacology (medical) ,Pharmacology ,business.industry ,Staphylococcal Infections ,medicine.disease ,Methicillin-resistant Staphylococcus aureus ,Anti-Bacterial Agents ,Piperacillin, Tazobactam Drug Combination ,Infectious Diseases ,Pharmacodynamics ,Piperacillin/tazobactam ,Vancomycin ,Rabbits ,business ,Vascular Access Devices ,Piperacillin ,medicine.drug - Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) infections of surgically implanted subcutaneous vascular catheters (SISVCs) cause serious morbidity in patients with chronic illnesses. Previous in vitro and murine models demonstrated the synergistic interaction of equimolar concentrations of meropenem/piperacillin/tazobactam (MPT) (VIO-001) against MRSA infection. We investigated the pharmacokinetics (PK) and efficacy of VIO-001 for the treatment of MRSA bacteremia in immunocompetent rabbits with SISVCs. In PK studies, we determined that optimal dosing to achieve a time above 4× MIC (T(>4×MIC)) of a duration of 3 to 3.30 h required a 1-h infusion with every-4-h (Q4h) dosing. Study groups in efficacy experiments consisted of MPT combinations of 100/150/100 mg/kg of body weight (MPT100), 200/300/200 mg/kg (MPT200), and 400/600/400 mg/kg (MPT400); vancomycin (VAN) at 15 mg/kg; and untreated controls (UC). The inoculum of MRSA isolate USA300-TCH1516 (1 × 10(3) organisms) was administered via the SISCV on day 1 and locked for 24 h. The 8-day therapy started at 24 h postinoculation. There was a significant reduction of MRSA in blood cultures from the SISVCs in all treatment groups, with full clearance on day 4, versus UCs (P
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- 2021
21. Ibrexafungerp, a Novel Triterpenoid Antifungal in Development for the Treatment of Mold Infections
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David A. Angulo, Barbara Alexander, Riina Rautemaa-Richardson, Ana Alastruey-Izquierdo, Martin Hoenigl, Ashraf S. Ibrahim, Mahmoud A. Ghannoum, Thomas R. King, Nkechi E. Azie, Thomas J. Walsh, and NIH - National Institute of Allergy and Infectious Diseases (NIAID) (Estados Unidos)
- Subjects
Microbiology (medical) ,Prevention ,ibrexafungerp ,Evaluation of treatments and therapeutic interventions ,Plant Science ,invasive fungal infection ,molds ,new antifungal agents ,Emerging Infectious Diseases ,Infectious Diseases ,Rare Diseases ,5.1 Pharmaceuticals ,6.1 Pharmaceuticals ,triterpenoid ,Development of treatments and therapeutic interventions ,Infection ,Ecology, Evolution, Behavior and Systematics - Abstract
Molds are ubiquitous in the environment, and immunocompromised patients are at substantial risk of morbidity and mortality due to their underlying disease and the resistance of pathogenic molds to currently recommended antifungal therapies. This combination of weakened-host defense, with limited antifungal treatment options, and the opportunism of environmental molds renders patients at risk and especially vulnerable to invasive mold infections such as Aspergillus and members of the Order Mucorales. Currently, available antifungal drugs such as azoles and echinocandins, as well as combinations of the same, offer some degree of efficacy in the prevention and treatment of invasive mold infections, but their use is often limited by drug resistance mechanisms, toxicity, drug-drug interactions, and the relative paucity of oral treatment options. Clearly, there is a need for agents that are of a new class that provides adequate tissue penetration, can be administered orally, and have broad-spectrum efficacy against fungal infections, including those caused by invasive mold organisms. Ibrexafungerp, an orally bioavailable glucan synthase inhibitor, is the first in a new class of triterpenoid antifungals and shares a similar target to the well-established echinocandins. Ibrexafungerp has a very favorable pharmacokinetic profile for the treatment of fungal infections with excellent tissue penetration in organs targeted by molds, such as the lungs, liver, and skin. Ibrexafungerp has demonstrated in vitro activity against Aspergillus spp. as well as efficacy in animal models of invasive aspergillosis and mucormycosis. Furthermore, ibrexafungerp is approved for use in the USA for the treatment of women with vulvovaginal candidiasis. Ibrexafungerp is currently being evaluated in clinical trials as monotherapy or in combination with other antifungals for treating invasive fungal infections caused by yeasts and molds. Thus, ibrexafungerp offers promise as a new addition to the clinician's armamentarium against these difficult-to-treat infections. Experiments reported in this manuscript were funded by Scynexis and support for mucormycosis research was provided by the NIH/NIAID under Contract No. HHSN272201700039I (Task order A34-HHSN27200003). Sí
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- 2022
22. Safety, Tolerability, and Population Pharmacokinetics of Intravenous and Oral Isavuconazonium Sulfate in Pediatric Patients
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J. Christopher Day, Haydar Frangoul, Christopher Lademacher, Lara Danziger-Isakov, William J Muller, Inci Yildirim, Amit Desai, William J. Steinbach, Mark E. Jones, Julie Chu, Paul K. Sue, Laura L. Kovanda, Tempe K. Chen, Susan R. Rheingold, Dwight E Yin, Michael Neely, Thomas J. Walsh, Antonio Arrieta, Victoria A. Statler, Desiree Leiva Phillips, Kelley Micklus, Grace A. McComsey, and Kamal Hamed
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0301 basic medicine ,Adolescent ,Pyridines ,030106 microbiology ,Administration, Oral ,Population pharmacokinetics ,Clinical Therapeutics ,Pharmacology ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,population pharmacokinetics ,Oral administration ,Nitriles ,medicine ,Humans ,Pharmacology (medical) ,030212 general & internal medicine ,Child ,invasive fungal infections ,business.industry ,isavuconazole ,Infant ,Safety tolerability ,Triazoles ,Prodrug ,Isavuconazonium ,triazole ,pediatric ,Infectious Diseases ,Tolerability ,Child, Preschool ,business ,medicine.drug - Abstract
Isavuconazole, administered as the water-soluble prodrug isavuconazonium sulfate, is a new triazole agent used to treat invasive fungal infections. This phase 1 study evaluated the pharmacokinetics (PK), safety, and tolerability of isavuconazole in 46 immunocompromised pediatric patients, stratified by age (1 to 80% and >76% of simulated pediatric patients following i.v. or oral administration, respectively. Intravenous and oral administration of isavuconazonium sulfate at the studied dosage of 10 mg/kg was well tolerated and resulted in exposure in pediatric patients similar to that in adults. (This study has been registered at ClinicalTrials.gov under identifier NCT03241550).
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- 2021
23. Assessment of focused multivector ultraviolet disinfection withshadowless delivery using 5-point multisided sampling ofpatientcare equipment without manual-chemical disinfection
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Wladyslaw Kowalski, Thomas J. Walsh, Donna Armellino, and Vidmantas Petraitis
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Sampling protocol ,Surface Properties ,Ultraviolet Rays ,Epidemiology ,Colony Count, Microbial ,Chemical disinfection ,Patient care ,03 medical and health sciences ,0302 clinical medicine ,Humans ,Medicine ,Infection control ,030212 general & internal medicine ,Cross Infection ,0303 health sciences ,Waste management ,030306 microbiology ,business.industry ,Health Policy ,Public Health, Environmental and Occupational Health ,Sampling (statistics) ,Ultraviolet germicidal irradiation ,Disinfection ,Treatment Outcome ,Infectious Diseases ,Equipment and Supplies ,business - Abstract
The aim of this study was to evaluate the performance of a focused multivector ultraviolet (FMUV) system employing shadowless delivery with a 90-second disinfection cycle for patient care equipment inside and outside the operating room (OR) suite without manual-chemical disinfection.A 5-point multisided sampling protocol was utilized to measure the microbial burden on objects inside and outside the OR environment in a 3-phase nonrandomized observational study. Surface sampling was performed pre- and postdisinfection in between cases (IBCs) to assess the performance of manual-chemical disinfection. FMUV system performance was separately assessed pre- and postdisinfection before the first case and IBCs. Additionally, visibly clean high-touch objects were sampled outside the OR, and the microbial burden reductions after FMUV disinfection were quantified without manual-chemical disinfection.Manual-chemical disinfection reduced the active microbial burden on sampled objects IBCs by 52.8%-90.9% (P.05). FMUV reduced the active microbial burden by 92%-97.7% (P.0001) before the firstcase and IBCs combined, and 96.3%-99.6% (P.0001) on objects outside the OR without chemical disinfection.Five-point multisided sampling proved effective for assessing disinfection performance on all exterior sides of equipment. FMUV produced significant overall reductions of the microbial burden on patient care equipment in all study phases and independent of manual cleaning and chemical disinfection.
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- 2019
24. 123. Oral Ibrexafungerp Outcomes by Fungal Disease in Patients from an Interim Analysis of a Phase 3 Open-label Study (FURI)
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Peter G Pappas, Oliver Cornely, Philipp Koehler, Todd P McCarty, Barbara D Alexander, Rachel Miller, Jose A Vazquez, John W Sanders, Caryn Morse, Luis Ostrosky-Zeichner, Robert Krause, Jürgen Prattes, Andrej Spec, Riina Rautemaa-Richardson, Rohit Bazaz, Thomas J Walsh, Francisco M Marty, Isabel H Gonzalez-Bocco, Marisa Miceli, Martin Hoenigl, Thomas F Patterson, Nkechi Azie, and David A Angulo
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Infectious Diseases ,AcademicSubjects/MED00290 ,Oncology ,Oral Abstracts ,education ,health care economics and organizations - Abstract
Background Candida species are a major cause of invasive and mucocutaneouls infections. There are limited oral treatment options available for patients with Candida infections who are unresponsive to or who are intolerant of currently available antifungals. Oral ibrexafungerp is an investigational broad-spectrum glucan synthase inhibitor antifungal with activity against Candida and Aspergillus species, including azole- and echinocandin-resistant strains. A Phase 3 open-label, single-arm study of ibrexafungerp (FURI; NCT03059992) is ongoing for the treatment of patients intolerant of or with fungal disease refractory to standard antifungal therapy. We present an analysis of patient outcomes from the FURI study by fungal disease type. Table 1: FURI Outcomes by Fungal Disease Methods FURI patients were eligible for enrollment if they have proven or probable, severe mucocutaneous candidiasis, invasive candidiasis or invasive aspergillosis,other fungal diseases and evidence of failure to, intolerance to, or toxicity related to a currently approved standard-of-care antifungal treatment or can not receive approved oral antifungal options (e.g., susceptibility of the organism) and a continued IV antifungal therapy is clinically undesirable or unfeasible. Results An independent Data Review Committee (DRC) provided an assessment of treatment response for 74 patients enrolled in the FURI study from 22 centers in US, UK and EU treated with ibrexafungerp for mucocutaneous or invasive fungal infections from 2016- 2020. A total of 39 (52.7%) patients had invasive candidiasis, 32 (43.2%) had mucocutaneous candidiasis and 3 (4.5%) patients had invasive aspergillosis. The percent of patients who were determined to have a complete response (CR), partial response (PR), clinical improvement (CI) was 63.5%, stable disease (SD) was 23.0%, patients with progression of disease 6.8% and 4 patients were indeterminate. Additionally, there was 1 death in the FURI study that was not related to fungal disease. Table 1 shows outcomes by fungal disease type as determined by the DRC. Conclusion Analysis of 74 patients from the FURI study indicates that oral ibrexafungerp provides a favorable therapeutic response in patients with challenging fungal disease and limited treatment options. Disclosures Peter G. Pappas, MD, Astellas (Research Grant or Support)Cidara (Research Grant or Support)F2G (Consultant)Matinas (Consultant, Scientific Research Study Investigator)Mayne Pharma (Research Grant or Support)Scynexis (Research Grant or Support) Oliver Cornely, Prof., Actelion (Consultant, Grant/Research Support)Al-Jazeera Pharmaceuticals (Consultant)Allecra Therapeutics (Consultant)Amplyx (Consultant, Grant/Research Support)Astellas (Consultant, Grant/Research Support)Basilea (Consultant, Grant/Research Support)Biocon (Consultant)Biosys (Consultant)Cidara (Consultant, Grant/Research Support)CoRe Consulting (Consultant)Da Volterra (Consultant, Grant/Research Support)DFG (German Research Foundation) (Grant/Research Support)Entasis (Consultant)F2G (Consultant, Grant/Research Support)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Grant/Research Support)Grupo Biotoscana (Consultant)Immunic (Grant/Research Support)IQVIA (Consultant)Janssen (Grant/Research Support)Matinas (Consultant)Medicines Company (Grant/Research Support)MedPace (Consultant, Grant/Research Support)Melinta Therapeutics (Grant/Research Support)Menarini (Consultant)Merck/MSD (Consultant, Grant/Research Support)Molecular Partners (Consultant)MSG-ERC (Consultant)Mylan (Consultant)Nabriva (Consultant)Noxxon (Consultant)Octapharma (Consultant)Paratek (Consultant)Pfizer (Consultant, Grant/Research Support)PSI (Consultant)Roche Diagnostics (Consultant)Scynexis (Consultant, Grant/Research Support)Seres (Consultant)Shionogi (Consultant)Wiley (Blackwell) (Other Financial or Material Support) Philipp Koehler, MD, Ambu GmbH (Consultant, Speaker's Bureau)Astellas Pharma (Speaker's Bureau)Euopean Confederation of Medical Mycology (Speaker's Bureau)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Speaker's Bureau)MSD (Speaker's Bureau)Noxxon N.V. (Consultant)Pfizer (Speaker's Bureau)State of North Rhine-Westphalia, Germany (Grant/Research Support) Todd P. McCarty, MD, Cidara (Grant/Research Support)GenMark (Grant/Research Support, Other Financial or Material Support, Honoraria for Research Presentation)T2 Biosystems (Consultant) Barbara D. Alexander, MD, MHS, SCYNEXIS, Inc. (Consultant) Rachel Miller, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Caryn Morse, MD, Chimerix (Scientific Research Study Investigator)Covis Pharma (Scientific Research Study Investigator)Gilead Sciences Inc. (Scientific Research Study Investigator)Ridgeback Biotherapeutics (Scientific Research Study Investigator)Roche (Scientific Research Study Investigator)SCYNEXIS, Inc. (Scientific Research Study Investigator)Theratechnologies (Advisor or Review Panel member)Viiv (Advisor or Review Panel member) Luis Ostrosky-Zeichner, MD, Amplyx (Consultant)Cidara (Consultant)F2G (Consultant)Gilead (Grant/Research Support, Speaker's Bureau)Pfizer (Scientific Research Study Investigator, Speaker's Bureau)Scynexis (Grant/Research Support, Scientific Research Study Investigator)Viracor (Consultant) Jürgen Prattes, Dr, AbbVie Inc. (Shareholder)Gilead (Speaker's Bureau)MSD (Grant/Research Support)Novo Nordisk (Shareholder)Pfizer (Advisor or Review Panel member)Stryker (Shareholder) Andrej Spec, MD, MSCI, Mayne Pharma (Grant/Research Support) Riina Rautemaa-Richardson, DDS, PhD, FRCPath, SCYNEXIS, Inc. (Scientific Research Study Investigator) Thomas J. Walsh, MD, PhD (hon), Scynexis (Consultant, Grant/Research Support)Shionogi (Consultant, Grant/Research Support) Francisco M. Marty, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Marisa Miceli, MD, SCYNEXIS, Inc. (Advisor or Review Panel member) Martin Hoenigl, MD, Astellas (Grant/Research Support)Gilead (Grant/Research Support)Pfizer (Grant/Research Support) Martin Hoenigl, MD, Astellas (Individual(s) Involved: Self): Grant/Research Support; F2G (Individual(s) Involved: Self): Grant/Research Support; Gilead (Individual(s) Involved: Self): Grant/Research Support; Pfiyer (Individual(s) Involved: Self): Grant/Research Support; Scýnexis (Individual(s) Involved: Self): Grant/Research Support Thomas F. Patterson, MD, SCYNEXIS, Inc. (Advisor or Review Panel member) Nkechi Azie, MD, SCYNEXIS, Inc. (Employee, Shareholder) David A. Angulo, MD, SCYNEXIS, Inc. (Employee, Shareholder)
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- 2021
25. 992. Oral Ibrexafungerp Outcomes in Patients with Oropharyngeal and Esophageal Candidiasis from an Interim Analysis of a Phase 3 Open-label Study (FURI)
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Jose A Vazquez, Oliver Cornely, Philipp Koehler, Riina Rautemaa-Richardson, Rohit Bazaz, G Marshall Lyon, Francisco M Marty, Isabel H Gonzalez-Bocco, Rachel Miller, Thomas J Walsh, Peter Pappas, Todd P McCarty, John W Sanders, Caryn Morse, Luis Ostrosky-Zeichner, Robert Krause, Jürgen Prattes, Andrej Spec, David Andes, Oliver Witzke, Nkechi Azie, and David A Angulo
- Subjects
Infectious Diseases ,Oncology ,education - Abstract
Background Candida albicans is the predominant organism causing esophageal candidiasis (EC) and oropharyngel candidiasis (OPC). These infections may arise from subjects colonized with Candida who are predisposed due to illness, debility or a local reduction in host resistance to an overgrowth of their own indigenous flora. Patients with mucocutaneous Candida infections can be treated in the outpatient setting, yet there are limited oral treatment options available for patients who are unresponsive to or who are intolerant to currently available antifungals. Oral ibrexafungerp is an investigational broad-spectrum glucan synthase inhibitor antifungal with activity against Candida species, including azole- and echinocandin-resistant strains. A Phase 3 open-label, single-arm study of ibrexafungerp (FURI; NCT03059992) is ongoing for the treatment of patients intolerant of or with fungal disease refractory to standard antifungal therapy. Table 1. FURI Outcomes in OPC and EC Methods FURI subjects were eligible for enrollment if they had proven or probable severe mucocutaneous candidiasis, invasive candidiasis, invasive aspergillosis, or other fungal diseases with evidence of treatment failure, intolerance, or toxicity related to a currently approved standard-of-care antifungal treatment or if they were unable to receive an approved oral antifungal option (e.g., susceptibility of the organism) and a continued IV antifungal therapy was clinically undesirable or unfeasible. Results An independent Data Review Committee (DRC) provided an assessment of treatment response for 74 subjects enrolled in the FURI study from 22 centers in US, UK and EU treated with ibrexafungerp for mucocutaneous or invasive fungal infections from 2016- 2020. A total 32 subjects (43.2%) had mucocutaneous candidiasis and 24 subjects were diagnosed with OPC or EC. The percent of patients who were determined to have a complete response (CR) or partial response (PR) was 62.5%, stable disease (SD), 20.8%, and progression of disease, 16.7%. Table 1 shows outcomes by EC and OPC as determined by the DRC. Conclusion Analysis of 24 EC and OPC patients from the FURI study indicates that oral ibrexafungerp provides a favorable therapeutic response in patients with challenging mucocutaneous fungal disease and limited treatment options. Disclosures Oliver Cornely, Prof., Actelion (Consultant, Grant/Research Support)Al-Jazeera Pharmaceuticals (Consultant)Allecra Therapeutics (Consultant)Amplyx (Consultant, Grant/Research Support)Astellas (Consultant, Grant/Research Support)Basilea (Consultant, Grant/Research Support)Biocon (Consultant)Biosys (Consultant)Cidara (Consultant, Grant/Research Support)CoRe Consulting (Consultant)Da Volterra (Consultant, Grant/Research Support)DFG (German Research Foundation) (Grant/Research Support)Entasis (Consultant)F2G (Consultant, Grant/Research Support)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Grant/Research Support)Grupo Biotoscana (Consultant)Immunic (Grant/Research Support)IQVIA (Consultant)Janssen (Grant/Research Support)Matinas (Consultant)Medicines Company (Grant/Research Support)MedPace (Consultant, Grant/Research Support)Melinta Therapeutics (Grant/Research Support)Menarini (Consultant)Merck/MSD (Consultant, Grant/Research Support)Molecular Partners (Consultant)MSG-ERC (Consultant)Mylan (Consultant)Nabriva (Consultant)Noxxon (Consultant)Octapharma (Consultant)Paratek (Consultant)Pfizer (Consultant, Grant/Research Support)PSI (Consultant)Roche Diagnostics (Consultant)Scynexis (Consultant, Grant/Research Support)Seres (Consultant)Shionogi (Consultant)Wiley (Blackwell) (Other Financial or Material Support) Philipp Koehler, MD, Ambu GmbH (Consultant, Speaker’s Bureau)Astellas Pharma (Speaker’s Bureau)Euopean Confederation of Medical Mycology (Speaker’s Bureau)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Speaker’s Bureau)MSD (Speaker’s Bureau)Noxxon N.V. (Consultant)Pfizer (Speaker’s Bureau)State of North Rhine-Westphalia, Germany (Grant/Research Support) Riina Rautemaa-Richardson, DDS, PhD, FRCPath, SCYNEXIS, Inc. (Scientific Research Study Investigator) G. Marshall Lyon, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Francisco M. Marty, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Rachel Miller, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Thomas J. Walsh, MD, PhD (hon), Scynexis (Consultant, Grant/Research Support)Shionogi (Consultant, Grant/Research Support) Peter Pappas, MD, Astellas (Grant/Research Support)Cidara (Grant/Research Support, Advisor or Review Panel member)Mayne (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support)SCYNEXIS, Inc. (Consultant, Grant/Research Support) Todd P. McCarty, MD, Cidara (Grant/Research Support)GenMark (Grant/Research Support, Other Financial or Material Support, Honoraria for Research Presentation)T2 Biosystems (Consultant) Caryn Morse, MD, Chimerix (Scientific Research Study Investigator)Covis Pharma (Scientific Research Study Investigator)Gilead Sciences Inc. (Scientific Research Study Investigator)Ridgeback Biotherapeutics (Scientific Research Study Investigator)Roche (Scientific Research Study Investigator)SCYNEXIS, Inc. (Scientific Research Study Investigator)Theratechnologies (Advisor or Review Panel member)Viiv (Advisor or Review Panel member) Luis Ostrosky-Zeichner, MD, Amplyx (Consultant)Cidara (Consultant)F2G (Consultant)Gilead (Grant/Research Support, Speaker’s Bureau)Pfizer (Scientific Research Study Investigator, Speaker’s Bureau)Scynexis (Grant/Research Support, Scientific Research Study Investigator)Viracor (Consultant) Jürgen Prattes, Dr, AbbVie Inc. (Shareholder)Gilead (Speaker’s Bureau)MSD (Grant/Research Support)Novo Nordisk (Shareholder)Pfizer (Advisor or Review Panel member)Stryker (Shareholder) Andrej Spec, MD, MSCI, SCYNEXIS, Inc. (Consultant, Scientific Research Study Investigator) David Andes, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Oliver Witzke, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Nkechi Azie, MD, SCYNEXIS, Inc. (Employee, Shareholder) David A. Angulo, MD, SCYNEXIS, Inc. (Employee, Shareholder)
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- 2021
26. Efficacy and Pharmacokinetics of Fosmanogepix (APX001) in the Treatment of Candida Endophthalmitis and Hematogenous Meningoencephalitis in Nonneutropenic Rabbits
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Thomas J. Walsh, Robert Mansbach, Ruta Petraitiene, Bo Bo Win Maung, Michael R. Hodges, Karen Joy Shaw, Vidmantas Petraitis, and Malcolm Finkelman
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medicine.medical_specialty ,Antifungal Agents ,Microbial Sensitivity Tests ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Cerebrospinal fluid ,Endophthalmitis ,Pharmacokinetics ,Meningoencephalitis ,In vivo ,Internal medicine ,Candida albicans ,medicine ,Animals ,Experimental Therapeutics ,Pharmacology (medical) ,030212 general & internal medicine ,Candida ,Pharmacology ,0303 health sciences ,biology ,030306 microbiology ,business.industry ,medicine.disease ,Disseminated Candidiasis ,biology.organism_classification ,Corpus albicans ,Infectious Diseases ,Rabbits ,business - Abstract
Candida endophthalmitis is a serious sight-threatening complication of candidemia that may occur before or during antifungal therapy. Hematogenous Candida meningoencephalitis (HCME) is also a serious manifestation of disseminated candidiasis in premature infants, immunosuppressed children, and immunocompromised adults. We evaluated the antifungal efficacy and pharmacokinetics of the prodrug fosmanogepix (APX001) in a rabbit model of endophthalmitis/HCME. Manogepix (APX001A), the active moiety of prodrug fosmanogepix, inhibits the fungal enzyme Gwt1 and is highly active in vitro and in vivo against Candida spp., Aspergillus spp., and other fungal pathogens. Plasma pharmacokinetics of manogepix after oral administration of fosmanogepix on day 6 at 25, 50, and 100 mg/kg resulted in maximum concentration of drug in plasma (C(max)) of 3.96 ± 0.41, 4.14 ± 1.1, and 11.5 ± 1.1 μg/ml, respectively, and area under the concentration-time curve from 0 to 12 h (AUC(0–12)) of 15.8 ± 3.1, 30.8 ± 5.0, 95.9 ± 14 μg·h/ml, respectively. Manogepix penetrated the aqueous humor, vitreous, and choroid with liquid-to-plasma ratios ranging from 0.19 to 0.52, 0.09 to 0.12, and 0.02 to 0.04, respectively. These concentrations correlated with a significant decrease in Candida albicans burden in vitreous (>10(1) to 10(3) log CFU/g) and choroid (>10(1) to 10(3) log CFU/g) (P ≤ 0.05 and P ≤ 0.001, respectively). The aqueous humor had no detectable C. albicans in treatment and control groups. The tissue/plasma concentration ratios of manogepix in meninges, cerebrum, cerebellum, and spinal cord were approximately 1:1, which correlated with a >10(2) to 10(4) decline of C. albicans in tissue versus control (P ≤ 0.05). Serum and cerebrospinal fluid (CSF) (1→3)-β-d-glucan levels demonstrated significant declines in response to fosmanogepix treatment. These findings provide an experimental foundation for fosmanogepix in treatment of Candida endophthalmitis and HCME and derisk the clinical trials of candidemia and invasive candidiasis.
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- 2021
27. Global guideline for the diagnosis and management of rare mould infections: an initiative of the European Confederation of Medical Mycology in cooperation with the International Society for Human and Animal Mycology and the American Society for Microbiology
- Author
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George Dimopoulos, Thomas Lehrnbecher, Sanjay G. Revankar, Chin Fen Neoh, Patrick C. Y. Woo, Retno Wahyuningsih, Sayoki Mfinanga, Rosanne Sprute, Petr Hamal, Abdullah M. S. Al-Hatmi, Birgit Spiess, Anil Kumar, Galia Rahav, Saad J. Taj-Aldeen, Oliver A. Cornely, Jean-Philippe Bouchara, Kerstin Albus, Michaela Lackner, Valentina Arsic-Arsenijevic, Martin Hoenigl, Jacques F. Meis, Philipp Koehler, Malcolm Richardson, Jo Anne H. Young, Tomáš Freiberger, Coleman Rotstein, Jon Salmanton-García, Anuradha Chowdhary, Matteo Bassetti, Rafael F. Duarte, G. Sybren de Hoog, Jannik Stemler, Monica A Slavin, Dorothee Arenz, Juergen Prattes, Marcio Nucci, Adilia Warris, Danila Seidel, Thomas J. Walsh, Thomas R. Rogers, Jeffrey D. Jenks, Thomas F. Patterson, Terrence Rohan Chinniah, Flavio Queiroz-Telles, Fabianne Carlesse, Groupe d'Étude des Interactions Hôte-Pathogène (GEIHP), Université d'Angers (UA), SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques (ICAT), Laboratoire de Parasitologie-Mycologie (CHU d'Angers), Centre Hospitalier Universitaire d'Angers (CHU Angers), and PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)
- Subjects
0301 basic medicine ,medicine.medical_specialty ,food.ingredient ,Medical mycology ,[SDV]Life Sciences [q-bio] ,030106 microbiology ,Mycology ,03 medical and health sciences ,0302 clinical medicine ,food ,All institutes and research themes of the Radboud University Medical Center ,Intensive care ,Epidemiology ,Medicine ,Animals ,Humans ,030212 general & internal medicine ,Disease management (health) ,Intensive care medicine ,ComputingMilieux_MISCELLANEOUS ,Societies, Medical ,biology ,business.industry ,Dematiaceous ,Fungi ,Disease Management ,Guideline ,biology.organism_classification ,3. Good health ,Infectious Diseases ,lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] ,Mycoses ,Scopulariopsis ,Practice Guidelines as Topic ,business ,Rasamsonia - Abstract
With increasing numbers of patients needing intensive care or who are immunosuppressed, infections caused by moulds other than Aspergillus spp or Mucorales are increasing. Although antifungal prophylaxis has shown effectiveness in preventing many invasive fungal infections, selective pressure has caused an increase of breakthrough infections caused by Fusarium, Lomentospora, and Scedosporium species, as well as by dematiaceous moulds, Rasamsonia, Schizophyllum, Scopulariopsis, Paecilomyces, Penicillium, Talaromyces and Purpureocillium species. Guidance on the complex multidisciplinary management of infections caused by these pathogens has the potential to improve prognosis. Management routes depend on the availability of diagnostic and therapeutic options. The present recommendations are part of the One World-One Guideline initiative to incorporate regional differences in the epidemiology and management of rare mould infections. Experts from 24 countries contributed their knowledge and analysed published evidence on the diagnosis and treatment of rare mould infections. This consensus document intends to provide practical guidance in clinical decision making by engaging physicians and scientists involved in various aspects of clinical management. Moreover, we identify areas of uncertainty and constraints in optimising this management.
- Published
- 2021
28. Navigating the Uncertainties of COVID-19-Associated Aspergillosis: A Comparison With Influenza-Associated Aspergillosis
- Author
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Dimitrios P. Kontoyiannis, Thomas J. Walsh, Russell E. Lewis, and Frédéric Lamoth
- Subjects
0301 basic medicine ,Aspergillus fumigates ,SARS-CoV-2 ,acute respiratory distress syndrome ,corticosteroids ,flu ,intensive care unit ,mechanical ventilation ,pneumonia ,Antifungal Agents ,Review ,medicine.disease_cause ,Aspergillosis ,law.invention ,Aspergillus fumigatus ,03 medical and health sciences ,Galactomannan ,chemistry.chemical_compound ,0302 clinical medicine ,law ,Pandemic ,Influenza, Human ,Immunology and Allergy ,Medicine ,Humans ,030212 general & internal medicine ,skin and connective tissue diseases ,Invasive Pulmonary Aspergillosis ,biology ,business.industry ,Incidence (epidemiology) ,COVID-19 ,medicine.disease ,biology.organism_classification ,Intensive care unit ,respiratory tract diseases ,Pneumonia ,030104 developmental biology ,Infectious Diseases ,AcademicSubjects/MED00290 ,chemistry ,Superinfection ,Immunology ,Pulmonary Aspergillosis ,business - Abstract
Invasive pulmonary aspergillosis (IPA) is increasingly recognized as a life-threatening superinfection of severe respiratory viral infections, such as influenza. The pandemic of Coronavirus Disease 2019 (COVID-19) due to emerging SARS-CoV-2 rose concern about the eventuality of IPA complicating COVID-19 in intensive care unit mechanically-ventilated patients. While the association between severe influenza and IPA has been demonstrated, it remains unclear whether SARS-CoV-2 infection represents a specific risk factor for IPA. A variable incidence of such complication has been previously reported, which can be partly attributed to differences in diagnostic strategy and IPA definitions, and possibly local environmental/epidemiological factors. In this article, we discuss the similarities and differences between influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA). Compared to IAPA, the majority of CAPA cases have been classified as putative rather than proven/probable IPA, in the absence of positive serum galactomannan or histopathologic evidence of angio-invasion. Discrimination between Aspergillus airways colonization and CAPA is difficult. Distinct physiopathology and cytokine profiles of influenza and COVID-19 may explain these discrepancies. Whether CAPA represents a distinct entity is still debatable and many questions remain unanswered, such as its actual incidence, the predisposing role of corticosteroids or immunomodulatory drugs, and the indications for antifungal therapy.
- Published
- 2021
29. FDA Public Workshop Summary: Advancing Animal Models for Antibacterial Drug Development
- Author
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Abhay Joshi, Jürgen B. Bulitta, Binh An Diep, John Farley, Alexander J. Lepak, Ursula Waack, James M Byrne, Thomas J. Walsh, Edward A. Weinstein, Andrew J Phipps, Lynn Miesel, Dmitri Iarikov, Matthew B. Lawrenz, Simone M Shurland, Brian Luna, William W. Hope, Tina Guina, Thushi Amini, and William J. Weiss
- Subjects
Acinetobacter baumannii ,medicine.medical_specialty ,medicine.drug_class ,Swine ,Antibiotics ,education ,medicine.disease_cause ,Food and drug administration ,03 medical and health sciences ,Mice ,Drug Development ,medicine ,Animals ,Pharmacology (medical) ,Intensive care medicine ,Antibacterial drug ,Pharmacology ,0303 health sciences ,biology ,030306 microbiology ,Pseudomonas aeruginosa ,business.industry ,United States Food and Drug Administration ,medicine.disease ,biology.organism_classification ,Meeting Review ,United States ,Anti-Bacterial Agents ,Infectious Diseases ,Drug development ,Models, Animal ,Rabbits ,business ,Pneumonia (non-human) - Abstract
The U.S. Food and Drug Administration (FDA) hosted a public workshop entitled “Advancing Animal Models for Antibacterial Drug Development” on 5 March 2020. The workshop mainly focused on models of pneumonia caused by Pseudomonas aeruginosa and Acinetobacter baumannii . The program included discussions from academic investigators, industry, and U.S. government scientists. The potential use of mouse, rabbit, and pig models for antibacterial drug development was presented and discussed.
- Published
- 2020
30. Antifungal Activity of Gepinacin Scaffold Glycosylphosphatidylinositol Anchor Biosynthesis Inhibitors with Improved Metabolic Stability
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Ruta Petraitiene, Thomas J. Walsh, Leah E. Cowen, Ralph Mazitschek, Luke Whitesell, Catherine A. McLellan, Sean D Liston, Povilas Kavaliauskas, and Vidmantas Petraitis
- Subjects
Antifungal ,Scaffold ,Antifungal Agents ,Glycosylphosphatidylinositols ,medicine.drug_class ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Pharmacokinetics ,Biosynthesis ,medicine ,Animals ,Potency ,Structure–activity relationship ,Experimental Therapeutics ,Pharmacology (medical) ,Glycosylphosphatidylinositol anchor ,030304 developmental biology ,Pharmacology ,0303 health sciences ,030306 microbiology ,Chemistry ,In vitro ,3. Good health ,Infectious Diseases ,Biochemistry ,Rabbits - Abstract
The glycosylphosphatidylinositol anchor biosynthesis inhibitor gepinacin demonstrates broad-spectrum antifungal activity and negligible mammalian toxicity in culture but is metabolically labile. The stability and bioactivity of 39 analogs were tested in vitro to identify LCUT-8, a stabilized lead with increased potency and promising single-dose pharmacokinetics. Unfortunately, no antifungal activity was seen at the maximum dosing achievable in a neutropenic rabbit model. Nevertheless, structure-activity relationships identified here suggest strategies to further improve compound potency, solubility, and stability.
- Published
- 2020
31. Core Recommendations for Antifungal Stewardship: A Statement of the Mycoses Study Group Education and Research Consortium
- Author
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George Richard Thompson, David R. Andes, Luis Ostrosky-Zeichner, John R. Perfect, Elizabeth Dodds Ashley, Melissa D. Johnson, Oliver A. Cornely, Russell E. Lewis, Peter G. Pappas, Theoklis E. Zaoutis, Thomas J. Walsh, Dimitrios P. Kontoyiannis, Johnson M.D., Lewis R.E., Dodds Ashley E.S., Ostrosky-Zeichner L., Zaoutis T., Thompson G.R., Andes D.R., Walsh T.J., Pappas P.G., Cornely O.A., Perfect J.R., and Kontoyiannis D.P.
- Subjects
0301 basic medicine ,Antifungal Agents ,Psychological intervention ,Drug Resistance ,diagnostic ,Inappropriate Prescribing ,Medical and Health Sciences ,antifungal ,aspergillosis ,candidiasis ,diagnostics ,guidelines ,stewardship ,Antimicrobial Stewardship ,0302 clinical medicine ,Immunology and Allergy ,Antimicrobial stewardship ,aspergillosi ,030212 general & internal medicine ,Evidence-Based Medicine ,Biological Sciences ,Infectious Diseases ,Fungal ,Practice Guidelines as Topic ,Engineering ethics ,Supplement Article ,Clinical Competence ,Drug Monitoring ,Infection ,guideline ,Antifungal ,medicine.medical_specialty ,medicine.drug_class ,Best practice ,030106 microbiology ,candidiasi ,Drug Prescriptions ,Microbiology ,Vaccine Related ,03 medical and health sciences ,Clinical Research ,medicine ,Humans ,Complex field ,Public health ,Group education ,Quality Education ,Emerging Infectious Diseases ,Mycoses ,Stewardship ,Business - 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.
- Published
- 2020
32. Pharmacodynamics of Posaconazole in Experimental Invasive Pulmonary Aspergillosis: Utility of Serum Galactomannan as a Dynamic Endpoint of Antifungal Efficacy
- Author
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Thomas J. Walsh, John Bacher, Vidmantas Petraitis, Andreas H. Groll, Georg Hempel, Ruta Petraitiene, William W. Hope, Diana Mickiene, and Silke Gastine
- Subjects
Posaconazole ,Antifungal Agents ,Population ,Microbial Sensitivity Tests ,Pharmacology ,Clinical Therapeutics ,Aspergillosis ,030226 pharmacology & pharmacy ,Aspergillus fumigatus ,Mannans ,03 medical and health sciences ,Galactomannan ,chemistry.chemical_compound ,0302 clinical medicine ,Pharmacokinetics ,Medicine ,Animals ,Humans ,Pharmacology (medical) ,education ,Invasive Pulmonary Aspergillosis ,0303 health sciences ,education.field_of_study ,biology ,030306 microbiology ,business.industry ,Galactose ,Liter ,Triazoles ,medicine.disease ,biology.organism_classification ,Disease Models, Animal ,Infectious Diseases ,chemistry ,Pharmacodynamics ,Rabbits ,business ,medicine.drug - Abstract
Aspergillus galactomannan antigenemia is an accepted tool for the diagnosis of invasive pulmonary aspergillosis (IPA) in neutropenic patients. Little is known, however, about the utility of this biomarker to assess the efficacy of antifungal therapies. The pharmacokinetics (PK) and pharmacodynamics (PD) of posaconazole in treatment and prophylaxis were investigated in the persistently neutropenic rabbit model of Aspergillus fumigatus IPA at doses between 2 and 20 mg/kg per day. Sparse plasma sampling was used to obtain PK data at steady state, and the serum galactomannan index (GMI), as a dynamic endpoint of antifungal response, was obtained every other day, in addition to conventional outcome parameters including survival and fungal tissue burden. Nonparametric PK/PD model building was performed using the Pmetrics package in R. A one-compartment model with linear elimination best described the PK of posaconazole. The PD effect of posaconazole exposure in plasma on the GMI in serum was best described by dynamic Hill functions reflecting growth and killing of the fungus. Through calculations of the area under the concentration-time curve from 0 to 24 h (AUC(0–24)) at steady state, the exposure-response relationship between posaconazole and the GMI for treatment followed a sigmoidal function with an asymptote forming above an AUC(0–24) of 30 mg · h/liter. All prophylactic doses were able to control the fungal burden. A nonparametric population PK/PD model adequately described the effect of posaconazole in prophylaxis and treatment of experimental IPA. An AUC(0–24) greater than 30 mg · h/liter was associated with adequate resolution of the GMI, which well supports previously suggested exposure-response relationships in humans.
- Published
- 2020
33. Pharmacokinetics and Efficacy of Ceftazidime-Avibactam in the Treatment of Experimental Pneumonia Caused by Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae in Persistently Neutropenic Rabbits
- Author
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Joshua A Hayden, Vilma Zigmantaite, Chase A. Mazur, Ramune Grigaleviciute, Michael J. Satlin, Ruta Petraitiene, Thein Aung, Ethan Naing, Thomas J. Walsh, Vidmantas Petraitis, Audrius Kučinskas, Bo Bo Win Maung, Rimantas Stakauskas, Povilas Kavaliauskas, Benjamin Georgiades, and Farehin Khan
- Subjects
medicine.medical_specialty ,Neutropenia ,Klebsiella pneumoniae ,Avibactam ,Ceftazidime ,Bacteremia ,Microbial Sensitivity Tests ,Loading dose ,Gastroenterology ,beta-Lactamases ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Bacterial Proteins ,Pharmacokinetics ,Drug Resistance, Multiple, Bacterial ,Internal medicine ,Pneumonia, Bacterial ,medicine ,Animals ,Experimental Therapeutics ,Pharmacology (medical) ,030212 general & internal medicine ,Pharmacology ,0303 health sciences ,medicine.diagnostic_test ,biology ,030306 microbiology ,business.industry ,Ceftazidime/avibactam ,biology.organism_classification ,medicine.disease ,Bacterial Load ,Anti-Bacterial Agents ,Klebsiella Infections ,Drug Combinations ,Pneumonia ,Carbapenem-Resistant Enterobacteriaceae ,Infectious Diseases ,Bronchoalveolar lavage ,chemistry ,Female ,Rabbits ,beta-Lactamase Inhibitors ,business ,Azabicyclo Compounds ,medicine.drug - Abstract
Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) is an emerging global public health threat that causes life-threatening pneumonia and bacteremia. Ceftazidime-avibactam (CZA) represents a promising advance for the treatment of serious infections caused by KPC-Kp. We investigated the pharmacokinetics and efficacy of ceftazidime-avibactam in the treatment of experimental KPC-Kp pneumonia in persistently neutropenic rabbits. For single-dose and multidose (administration every 8 h) pharmacokinetics, rabbits received ceftazidime-avibactam intravenous infusions at 60/15, 90/22.5, and 120/30 mg/kg of body weight. Ceftazidime mean area under the concentration-time curves (AUCs) ranged from 287 to 608 μg·h/ml for a single dose and from 300 to 781 μg·h/ml for multiple doses. Avibactam AUCs ranged from 21 to 48 μg·h/ml for a single dose and from 26 to 48 μg·h/ml for multiple doses. KPC-Kp pneumonia was established by direct endotracheal inoculation. Treatments consisted of ceftazidime-avibactam at 120/30 mg/kg every 6 h, a polymyxin B (PMB) loading dose of 2.5 mg/kg followed by 1.5 mg/kg every 12 h q12h, or no treatment (untreated controls [UC]). There were significant reductions in the residual bacterial burden, lung weights, and pulmonary hemorrhage scores in CZA- and PMB-treated rabbits for a 7-day or a 14-day (P ≤ 0.01) course in comparison with those in the UC. These results corresponded to significant decreases in the bacterial burden in bronchoalveolar lavage fluid after a 7-day or a 14-day treatment (P ≤ 0.01). The outcomes demonstrated an improved response at 14 days versus that at 7 days. There was significantly prolonged survival in rabbits treated with CZA for 14 days in comparison with that in the PMB-treated or UC rabbits (P ≤ 0.05). This study demonstrates that ceftazidime-avibactam displays linear dose-proportional exposures simulating those seen from human plasma pharmacokinetic profiles, is active for the treatment of experimental KPC-Kp pneumonia in persistently neutropenic rabbits, and provides an experimental foundation for the treatment of severely immunocompromised patients with this life-threatening infection.
- Published
- 2020
34. Ibrexafungerp:A novel oral triterpenoid antifungal in development for the treatment of candida auris infections
- Author
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Maiken Cavling Arendrup, Thomas S. McCormick, Sudha Chaturvedi, Bansidhar Tarai, Thomas J. Walsh, Shawn R. Lockhart, Elizabeth L. Berkow, Vishnu Chaturvedi, Nkechi Azie, Mahmoud A. Ghannoum, Deven Juneja, and David Angulo
- Subjects
0301 basic medicine ,Microbiology (medical) ,Antifungal ,medicine.drug_class ,030106 microbiology ,Resistance ,ibrexafungerp ,Ibrexafungerp ,Biochemistry ,Microbiology ,resistance ,03 medical and health sciences ,Minimum inhibitory concentration ,0302 clinical medicine ,Triterpenoid ,Medicine ,Pharmacology (medical) ,030212 general & internal medicine ,General Pharmacology, Toxicology and Pharmaceutics ,business.industry ,lcsh:RM1-950 ,Candida auris ,Fungicide ,Infectious Diseases ,lcsh:Therapeutics. Pharmacology ,Candida spp ,business ,Echinocandins ,Fluconazole ,antifungal ,medicine.drug - Abstract
Candida auris is an emerging multidrug-resistant fungal pathogen reported worldwide. Infections due to C. auris are usually nosocomial and associated with high rates of fluconazole resistance and mortality. Echinocandins are utilized as the first-line treatment. However, echinocandins are only available intravenously and are associated with increasingly higher rates of resistance by C. auris. Thus, a need exists for novel treatments that demonstrate potent activity against C. auris. Ibrexafungerp is a first-in-class triterpenoid antifungal agent. Similar to echinocandins, ibrexafungerp inhibits (1→3)-β-D-glucan synthase, a key component of the fungal cell wall, resulting in fungicidal activity against Candida spp. Ibrexafungerp demonstrates broad in vitro activity against various Candida spp. including C. auris and C. auris isolates with fks mutations. Minimum inhibitory concentration (MIC50 and MIC90) values in >400 C. auris isolates were 0.5 μg/mL and 1.0 μg/mL, respectively. Clinical results were reported for two patients with invasive candidiasis or candidemia due to C. auris treated during the CARES (Candidiasis Caused by Candida Auris) trial, an ongoing open-label study. These patients experienced a complete response after treatment with ibrexafungerp. Thus, ibrexafungerp represents a promising new antifungal agent for treating C. auris infections.
- Published
- 2020
35. Combination Therapy with Ibrexafungerp (Formerly SCY-078), a First-in-Class Triterpenoid Inhibitor of (1→3)-β-d-Glucan Synthesis, and Isavuconazole for Treatment of Experimental Invasive Pulmonary Aspergillosis
- Author
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Ethan Naing, Nkechi Azie, Bo Bo Win Maung, Ruta Petraitiene, Thomas J. Walsh, Stephen Barat, Katyna Borroto-Esoda, David Angulo, Povilas Kavaliauskas, Aspasia Katragkou, and Vidmantas Petraitis
- Subjects
Antifungal Agents ,Combination therapy ,Pyridines ,Triazole ,Pharmacology ,03 medical and health sciences ,chemistry.chemical_compound ,Galactomannan ,Pharmacokinetics ,In vivo ,Nitriles ,Medicine ,Animals ,Pharmacology (medical) ,Experimental Therapeutics ,Glycosides ,Glucans ,030304 developmental biology ,Invasive Pulmonary Aspergillosis ,0303 health sciences ,Aspergillus ,Lung ,biology ,030306 microbiology ,business.industry ,Triazoles ,biology.organism_classification ,In vitro ,Triterpenes ,Infectious Diseases ,medicine.anatomical_structure ,chemistry ,Rabbits ,business - Abstract
Ibrexafungerp (formerly SCY-078) is a semisynthetic triterpenoid and potent (1→3)-β-d-glucan synthase inhibitor. We investigated the in vitro activity, pharmacokinetics, and in vivo efficacy of ibrexafungerp (SCY) alone and in combination with antimold triazole isavuconazole (ISA) against invasive pulmonary aspergillosis (IPA). The combination of ibrexafungerp and isavuconazole in in vitro studies resulted in additive and synergistic interactions against Aspergillus spp. Plasma concentration-time curves of ibrexafungerp were compatible with linear dose proportional profile. In vivo efficacy was studied in a well-established persistently neutropenic New Zealand White (NZW) rabbit model of experimental IPA. Treatment groups included untreated control (UC) rabbits and rabbits receiving ibrexafungerp at 2.5 (SCY2.5) and 7.5 (SCY7.5) mg/kg of body weight/day, isavuconazole at 40 (ISA40) mg/kg/day, or combinations of SCY2.5+ISA40 and SCY7.5+ISA40. The combination of SCY+ISA produced an in vitro synergistic interaction. There were significant in vivo reductions of residual fungal burden, lung weights, and pulmonary infarct scores in SCY2.5+ISA40, SCY7.5+ISA40, and ISA40 treatment groups versus those of the SCY2.5-treated, SCY7.5-treated, and UC (P < 0.01) groups. Rabbits treated with SCY2.5+ISA40 and SCY7.5+ISA40 had prolonged survival in comparison to that of the SCY2.5-, SCY7.5-, ISA40-treated, or UC (P < 0.05) groups. Serum galactomannan index (GMI) and (1→3)-β-d-glucan levels significantly declined in animals treated with the combination of SCY7.5+ISA40 in comparison to those of animals treated with SCY7.5 or ISA40 (P < 0.05). Ibrexafungerp and isavuconazole combination demonstrated prolonged survival, decreased pulmonary injury, reduced residual fungal burden, and lower GMI and (1→3)-β-d-glucan levels in comparison to those of single therapy for treatment of IPA. These findings provide an experimental foundation for clinical evaluation of the combination of ibrexafungerp and an antimold triazole for treatment of IPA.
- Published
- 2019
36. Amphotericin B Penetrates into the Central Nervous System through Focal Disruption of the Blood-Brain Barrier in Experimental Hematogenous Candida Meningoencephalitis
- Author
-
Ruta Petraitiene, Brenda A. Klaunberg, Thomas J. Walsh, Algidas Basevičius, Vidmantas Petraitis, Jessica M. Valdez, Darius Kalasauskas, Martin J. Lizak, Vasilios Pyrgos, John Bacher, William W. Hope, and Daniel K. Benjamin
- Subjects
Pathology ,medicine.medical_specialty ,animal diseases ,Central nervous system ,Blood–brain barrier ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cerebrospinal fluid ,In vivo ,Amphotericin B ,medicine ,Pharmacology (medical) ,030212 general & internal medicine ,Evans Blue ,Pharmacology ,0303 health sciences ,030306 microbiology ,business.industry ,Meningoencephalitis ,medicine.disease ,Infectious Diseases ,medicine.anatomical_structure ,chemistry ,Complication ,business ,medicine.drug - Abstract
Hematogenous Candida meningoencephalitis (HCME) is a life-threatening complication of neonates and immunocompromised children. Amphotericin B (AmB) shows poor permeability and low cerebrospinal fluid (CSF) concentrations, but is effective in treatment of HCME. In order to better understand the mechanism of CNS penetration of AmB, we hypothesized that AmB may achieve focally higher concentrations in infected CNS lesions. An in vitro BBB model was serially infected with C. albicans. Liposomal AmB (LAMB) or deoxycholate AmB (DAMB) at 5 μg/ml were then provided, vascular and CNS compartments were sampled 4h later. For in vivo correlation, rabbits with experimental HCME received a single dose of DAMB 1 mg/kg or LAMB 5 mg/kg, and were euthanized after 1, 3, 6 and 24h. Evans blue solution (2%) 2 ml/kg administered IV one hour prior to euthanasia stained infected regions of tissue but not histologically normal areas. AmB concentrations in stained and unstained tissue regions were measured using UPLC. For selected rabbits, MRI scans performed on days 1-7 postinoculation were acquired before and after IV bolus Gd-DTPA at 15min intervals through 2h post-injection. The greatest degree of penetration of DAMB and LAMB through the in vitro BBB occurred after 24h of exposure (P=0.0022). In vivo the concentrations of LAMB and DAMB in brain abscesses were 4.35±0.59 and 3.14±0.89-times higher vs. normal tissue (P≤0.019). MRI scans demonstrated that Gd-DTPA accumulated in infected areas with disrupted BBB. Localized BBB disruption in HCME allows high concentrations of AmB within infected tissues, despite the presence of low CSF concentrations.
- Published
- 2019
37. Polymyxin B and fosfomycin thwart KPC-producing Klebsiella pneumoniae in the hollow-fibre infection model
- Author
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Michael J. Satlin, Liang Chen, Miao Zhao, Thomas J. Walsh, Zackery P Bulman, Brian T. Tsuji, Jian Li, Barry N. Kreiswirth, and Roger L. Nation
- Subjects
0301 basic medicine ,Microbiology (medical) ,medicine.drug_class ,Klebsiella pneumoniae ,030106 microbiology ,Antibiotics ,Population ,Microbial Sensitivity Tests ,Fosfomycin ,beta-Lactamases ,Article ,Microbiology ,03 medical and health sciences ,Bacterial Proteins ,Pharmacokinetics ,Drug Resistance, Multiple, Bacterial ,medicine ,Humans ,Pharmacology (medical) ,education ,Polymyxin B ,Antiinfective agent ,education.field_of_study ,biology ,Chemistry ,General Medicine ,biochemical phenomena, metabolism, and nutrition ,biology.organism_classification ,Anti-Bacterial Agents ,Klebsiella Infections ,Infectious Diseases ,Pharmacodynamics ,Drug Therapy, Combination ,medicine.drug - Abstract
Polymyxin B and fosfomycin are two ‘old’ antibiotics that consistently maintain activity against Klebsiella pneumoniae carbapenemase (KPC)-producing organisms based on in vitro susceptibility testing. However, each antibiotic’s use in monotherapy has been associated with high rates of treatment failure. Therefore, our objective was to investigate the combinatorial pharmacodynamics of polymyxin B and fosfomycin against KPC-producing K. pneumoniae. Polymyxin B front-loading (3.33 mg/kg for 1 dose followed by 1.43 mg/kg q12h starting 12h later) and burst (5.53 mg/kg for 1 dose followed by no subsequent doses) simulated dosing regimens were explored in combination with fosfomycin (4g q8h) against KPC-2-producing K. pneumoniae ST258 in a hollow fibre infection model over 120h. Population analysis profiles were used to track the temporal polymyxin B and fosfomycin resistance profiles. Against isolate KPC-Kp 9A (polymyxin B MIC: 0.5mg/L, fosfomycin MIC: ≤8mg/L), monotherapies resulted in >3 log(10)CFU/mL killing within 3h, but regrowth and proliferation of resistant subpopulations within 48h. Polymyxin B combinations with fosfomycin demonstrated rapid bacterial killing (>6 log(10)CFU/mL reductions) while preventing propagation of polymyxin and fosfomycin resistance. Against isolate KPC-Kp 24A with a higher fosfomycin MIC (polymyxin B MIC: 0.5mg/L, fosfomycin MIC: 32g/L), a polymyxin B burst and fosfomycin combination caused a >6 log(10)CFU/mL reduction within 1 hour, although bacterial regrowth occurred with the amplification of fosfomycin-resistant subpopulations. Polymyxin B in combination with fosfomycin may provide a practicable treatment strategy against KPC-producing K. pneumoniae and warrants further investigation.
- Published
- 2018
38. The rise of hospitalists: an opportunity for infectious diseases investigators
- Author
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Matthew W. McCarthy and Thomas J. Walsh
- Subjects
Microbiology (medical) ,medicine.medical_specialty ,Biomedical Research ,030204 cardiovascular system & hematology ,Communicable Diseases ,Microbiology ,03 medical and health sciences ,0302 clinical medicine ,Anti-Infective Agents ,Physicians ,Virology ,Specialization (functional) ,medicine ,Humans ,In patient ,030212 general & internal medicine ,Cooperative Behavior ,Quality of Health Care ,Public health ,Field (Bourdieu) ,Infectious Diseases ,Hospitalists ,Family medicine ,Stewardship ,Cooperative behavior ,Business ,Delivery of Health Care ,Cost containment ,Specialization - Abstract
Despite the essential role played by infectious diseases specialists in patient care, public health, cost-containment, and biomedical research, the field has a substantially higher percentage of vacant positions than other medicine sub-specialties. While much has been written about what this disturbing trend means for patient care, comparatively little attention has been focused on the dire implications for clinical research and the development of novel anti-infective therapy. Areas covered: We examine the ways that hospitalists and infectious disease specialists might collaborate to study emerging diagnostic platforms, novel antimicrobial agents, and strengthen antimicrobial stewardship programs to improve the delivery of high-quality health care. Through the use of PubMed, the manuscript reviews existing collaborations as well as those that might develop in the years to come. Expert commentary: In this paper, we propose potential strategies to confront this emerging problem, focusing on novel collaborations with the hospitalist - the specialist in inpatient medicine - to bolster the pipeline of funding for clinical infectious diseases investigators.
- Published
- 2018
39. Pharmacology of Liposomal Amphotericin B: An Introduction to Preclinical and Clinical Advances for Treatment of Life-threatening Invasive Fungal Infections
- Author
-
Thomas J. Walsh, Russell E. Lewis, Jill Adler-Moore, Walsh T.J., Lewis R.E., and Adler-Moore J.
- Subjects
Microbiology (medical) ,Infectious Diseases ,Systemic mycosis ,business.industry ,fungal infection ,LAmB ,Medicine ,Amphotericin B liposomal ,Liposomal amphotericin ,Supplement Articles ,liposomal amphotericin B ,Pharmacology ,business - Abstract
nessuna
- Published
- 2019
40. Containment strategies to address the expanding threat of multidrug-resistant Candida auris
- Author
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Matthew W. McCarthy and Thomas J. Walsh
- Subjects
0301 basic medicine ,Microbiology (medical) ,Antifungal Agents ,030106 microbiology ,Biology ,Microbiology ,03 medical and health sciences ,Virology ,medicine ,Humans ,Pathogen ,Fungemia ,Organism ,Candida ,business.industry ,Nosocomial transmission ,Environmental resource management ,High mortality ,Candidiasis ,Biofilm ,food and beverages ,medicine.disease ,Drug Resistance, Multiple ,Multiple drug resistance ,Infectious Diseases ,Candida auris ,business - Abstract
Candida auris is an emerging multidrug resistant human yeast pathogen associated with nosocomial transmission and high mortality. The organism can be a challenge to diagnose, may be even more difficult to treat, and continues to pose an expanding threat to patients. Areas covered: Our medical center and others in the surrounding area have seen a concerning rise in confirmed cases of C. auris infection and substantial resources have been dedicated to containment measures. We draw on our in vitro and in vivo work with this organism to examine the most effective ways to curb the current outbreak. Expert commentary: We explore novel strategies to halt the spread C. auris, including enhanced molecular diagnostics, novel therapeutics, and epidemiologic studies to determine risk factors for infection and transmission.
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- 2017
41. 751. Karius Cell-Free DNA Metagenomic Assay of Plasma Detects Pulmonary and Disseminated Trichosporon Infections in Patients with Hematological Malignancies
- Author
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Scott D. Solomon, Tempe Chen, Melissa Sanacore, Lawrence E. Morris, Samuel Webster, Benjamin Briggs, Melhem Solh, Asim A. Ahmed, Bill Pomputius, Joshua Wolf, Asad Bashey, H. Kent Holland, Julie Chu, Thomas J. Walsh, and Kathryn Goggin
- Subjects
Lung ,biology ,medicine.diagnostic_test ,business.industry ,biology.organism_classification ,Trichosporonosis ,medicine.disease ,Candida parapsilosis ,Microbiology ,Infectious Diseases ,medicine.anatomical_structure ,AcademicSubjects/MED00290 ,Oncology ,Cell-free fetal DNA ,Amphotericin B ,Trichosporon ,Biopsy ,Poster Abstracts ,medicine ,Blood culture ,business ,medicine.drug - Abstract
Background Trichosporon species are uncommon but emerging pathogens that cause life-threatening infections that are resistant to amphotericin B and echinocandins. Diagnosis of deeply invasive trichosporonosis is often elusive to conventional culture methods until locally advanced or disseminated disease has advanced. CT scans Pulmonary Trichosporonosis Lung Bx of Trichosporon detected by Karius Cell-Free DNA Metagenomic Assay of Plasma Methods Review of cases of next-generation sequencing of microbial cell-free DNA from plasma using the Karius-based technology for establishing a diagnosis of invasive trichosporonosis Results We found that next-generation sequencing of microbial cell-free DNA from plasma using the Karius-based technology established a diagnosis in six pediatric and adult patients. The median age was 17 yrs (8-72 yrs) all patients had underlying acute leukemia myelogenous leukemia. Six patients had pulmonary nodules and two also had multiple cutaneous lesions with negative blood cultures. Biopsies of one pulmonary nodule and of two cutaneous lesions revealed yeast-like cells. Culture of cutaneous lesions in two patients grew Trichosporon sp. Karius assays performed on plasma and analyzed against a database of more than 300 species of fungi identified Trichosporon asahii in two cases, Trichosporon spp. in three, Trichosporon faecale in one. In all cases, the metagenomic results defined therapy for treatment of invasive trichosporonosis, which is based in antifungal triazoles. In one patient with pulmonary nodules, lung biopsy revealed mixed septate and non-septate hyphal elements that later grew Trichosporon asahii, Rhizomucor pusillus, and Candida parapsilosis, all of which were identified by Karius assay. Conclusion Invasive Trichosporon spp. are uncommon polyene and triazole-resistant pathogens that cause life-threatening invasive fungal disease resistant in immunocompromised patient with hematological malignancies; next-generation sequencing of fungal cell-free DNA by Karius-based technology identified all six cases of pulmonary and disseminated trichosporonosis, contributing to early detection and pathogen-directed antifungal therapy. Disclosures Asim A. Ahmed, MD, Karius (Employee) Joshua Wolf, MBBS, PhD, FRACP, Karius inc (Grant/Research Support)
- Published
- 2020
42. Drug development challenges and strategies to address emerging and resistant fungal pathogens
- Author
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Thomas J. Walsh and Matthew W. McCarthy
- Subjects
0301 basic medicine ,Microbiology (medical) ,Antifungal ,medicine.medical_specialty ,Antifungal Agents ,Echinocandin ,Pyridines ,medicine.drug_class ,030106 microbiology ,Antifungal drug ,Microbial Sensitivity Tests ,Biology ,Microbiology ,Echinocandins ,03 medical and health sciences ,0302 clinical medicine ,Drug Resistance, Fungal ,Virology ,Nitriles ,medicine ,Humans ,Glycosides ,030212 general & internal medicine ,Intensive care medicine ,Candida ,Clinical Trials as Topic ,business.industry ,Public health ,Candidiasis ,Triazoles ,Triterpenes ,Biotechnology ,Infectious Diseases ,Drug development ,Candida auris ,Drug Design ,business ,Biomarkers ,Invasive Fungal Infections ,medicine.drug - Abstract
Introduction: Invasive fungal infections represent an expanding threat to public health. The recent emergence of Candida auris, which is often resistant to existing antifungal agents and is associated with a high mortality rate, underscores the urgent need for novel drug development strategies.Areas covered: In this paper, we examine both challenges and opportunities associated with antifungal drug development and explore potential avenues to accelerate the development pipeline, including data sharing, surrogate endpoints, and the role of historical controls in clinical trials.Expert commentary: We review important lessons learned from the study of other rare diseases, including mitochondrial storage diseases and certain forms of cancer that may inform strategies to develop new antifungal agents while highlighting promising new compounds such as SCY-078 for the treatment of invasive fungal infections.
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- 2017
43. Diabetes mellitus as the major risk factor for mucormycosis in Mexico: Epidemiology, diagnosis, and outcomes of reported cases
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Luis David Chora-Hernandez, Dora E Corzo-Leon, Thomas J. Walsh, and Ana P Rodríguez-Zulueta
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Antifungal Agents ,Adolescent ,030106 microbiology ,Diabetes Complications ,Young Adult ,03 medical and health sciences ,Amphotericin B deoxycholate ,Diabetes mellitus ,Internal medicine ,Epidemiology ,Prevalence ,medicine ,Humans ,Mucormycosis ,Risk factor ,Child ,Intensive care medicine ,Sinusitis ,Mexico ,Aged ,Aged, 80 and over ,Surgical team ,business.industry ,Mortality rate ,Infant, Newborn ,Disease Management ,Infant ,General Medicine ,Length of Stay ,Middle Aged ,medicine.disease ,Survival Analysis ,Hospitalization ,Treatment Outcome ,Infectious Diseases ,Debridement ,Child, Preschool ,Mucorales ,Female ,business - Abstract
Mucormycosis is an emerging infectious disease with high rates of associated mortality and morbidity. Little is known about the characteristics of mucormycosis or entomophthoromycosis occurring in Mexico. A search strategy was performed of literature published in journals found in available databases and theses published online at Universidad Nacional Autónoma de México (UNAM) library website reporting clinical cases or clinical case series of mucormycosis and entomophthoromycosis occurring in Mexico between 1982 and 2016. Among the 418 cases identified, 72% were diabetic patients, and sinusitis accounted for 75% of the reported cases. Diabetes mellitus was not a risk factor for entomophthoromycosis. Mortality rate was 51% (125/244). Rhizopus species were the most frequent isolates (59%, 148/250). Amphotericin B deoxycholate was used in 89% of cases (204/227), while surgery and antifungal management as combined treatment was used in 90% (172/191). In diabetic individuals, this combined treatment approach was associated with a higher probability of survival (95% vs 66%, OR = 0.1, 95% CI, 0.02-0.43' P = .002). The most common complications were associated with nephrotoxicity and prolonged hospitalization due to IV antifungal therapy. An algorithm is proposed to establish an early diagnosis of rhino-orbital cerebral (ROC) mucormycosis based on standardized identification of warning signs and symptoms and performing an early direct microbiological exam and histopathological identification through a multidisciplinary medical and surgical team. In summary, diabetes mellitus was the most common risk factor for mucormycosis in Mexico; combined antifungal therapy and surgery in ROC mucormycosis significantly improved survival.
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- 2017
44. Evaluation of a Multiplex PCR Assay To Rapidly Detect Enterobacteriaceae with a Broad Range of β-Lactamases Directly from Perianal Swabs
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Michael J. Satlin, Claudia Manca, Kalyan D. Chavda, Thomas J. Walsh, Barry N. Kreiswirth, Stephen G. Jenkins, and Liang Chen
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0301 basic medicine ,food.ingredient ,030106 microbiology ,Pcr assay ,Anal Canal ,beta-Lactamases ,Specimen Handling ,Epidemiology and Surveillance ,Microbiology ,03 medical and health sciences ,0302 clinical medicine ,food ,Bacterial Proteins ,Enterobacteriaceae ,Molecular beacon ,Multiplex polymerase chain reaction ,Humans ,Agar ,Pharmacology (medical) ,030212 general & internal medicine ,Pharmacology ,biology ,Chromogenic ,Escherichia coli Proteins ,β lactamases ,Hematopoietic Stem Cell Transplantation ,biology.organism_classification ,Virology ,Highly sensitive ,Infectious Diseases ,Multiplex Polymerase Chain Reaction - Abstract
We developed and evaluated multiplexed molecular beacon probes in a real-time PCR assay to identify prominent extended-spectrum-β-lactamase, plasmid-mediated AmpC β-lactamase (pAmpC) and carbapenemase genes directly from perianal swab specimens within 6 h. We evaluated this assay on 158 perianal swabs collected from hematopoietic stem cell transplant recipients and found that this assay was highly sensitive and specific for detection of CTX-M-, pAmpC-, and KPC-producing Enterobacteriaceae compared to culture on chromogenic agar.
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- 2016
45. Impact of a Multiplexed Polymerase Chain Reaction Panel on Identifying Diarrheal Pathogens in Hematopoietic Cell Transplant Recipients
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Thomas J. Walsh, Tsiporah B. Shore, Carl V. Crawford, Wesley Rogers, Harjot K. Singh, Rosemary Soave, Stephen G. Jenkins, Michael J. Satlin, Koen van Besien, Lars F. Westblade, and Catherine B. Small
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0301 basic medicine ,Microbiology (medical) ,Adult ,Diarrhea ,medicine.medical_specialty ,medicine.medical_treatment ,030106 microbiology ,Population ,Hematopoietic stem cell transplantation ,medicine.disease_cause ,Gastroenterology ,law.invention ,03 medical and health sciences ,Feces ,0302 clinical medicine ,law ,Internal medicine ,Medicine ,Humans ,030212 general & internal medicine ,education ,Yersinia enterocolitica ,Polymerase chain reaction ,education.field_of_study ,biology ,business.industry ,Clostridioides difficile ,Hematopoietic Stem Cell Transplantation ,biology.organism_classification ,Transplant Recipients ,Transplantation ,Infectious Diseases ,Cohort ,Norovirus ,medicine.symptom ,business ,Multiplex Polymerase Chain Reaction - Abstract
BackgroundDiarrhea is common and associated with substantial morbidity among hematopoietic cell transplant (HCT) recipients, but the etiology is often not identified. Multiplexed polymerase chain reaction (PCR) assays increase the detection of diarrheal pathogens, but the impact of this technology in this population has not been evaluated.MethodsOur center replaced stool cultures and other conventional microbiologic methods with the FilmArray Gastrointestinal Panel (GI PCR) in June 2016. We reviewed all adult patients who received an HCT from June 2014–May 2015 (pre–GI PCR, n = 163) and from June 2016–May 2017 (post–GI PCR, n = 182) and followed them for 1 year after transplantation. Clostridioides difficile infection was diagnosed by an independent PCR test in both cohorts.ResultsThe proportion of patients with ≥1 identified infectious diarrheal pathogen increased from 25% to 37% after implementation of GI PCR (P = .01). Eight patients (5%) in the pre–GI PCR cohort tested positive for a pathogen other than C. difficile versus 49 patients (27%) in the post–GI PCR cohort (P < .001). The most common non–C. difficile diarrheal pathogens in the post–GI PCR cohort were enteropathogenic Escherichia coli (n = 14, 8%), norovirus (n = 14, 8%), and Yersinia enterocolitica (n = 7, 4%). The percentage of diarrheal episodes with an identified infectious etiology increased from 14% to 23% (P = .001). Median total costs of stool testing per patient did not increase (pre: $473; post: $425; P = .25).ConclusionsInfectious etiologies of diarrhea were identified in a higher proportion of HCT recipients after replacing conventional stool testing with a multiplexed PCR assay, without an increase in testing costs.
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- 2019
46. Mediastinal Mucormycosis: Case report, review of literature and treatment with continuous liposomal amphotericin B irrigation
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Robert Gotoff, Michael A. Foltzer, Thomas J. Walsh, Joseph D. Cooper, and Russell Carter
- Subjects
0301 basic medicine ,Antifungal ,Adult ,medicine.medical_specialty ,Rhizopus microsporus ,Antifungal Agents ,medicine.drug_class ,030106 microbiology ,Dermatology ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Fatal Outcome ,Amphotericin B ,Lethal infection ,Mediastinal Diseases ,Medicine ,Humans ,Mucormycosis ,Therapeutic Irrigation ,biology ,business.industry ,General Medicine ,medicine.disease ,biology.organism_classification ,Mediastinitis ,Surgery ,Infectious Diseases ,Liposomal amphotericin ,Female ,business ,Rhizopus - Abstract
Mediastinal mucormycosis is an uncommon but lethal infection associated with an 83% mortality. We describe a case of fatal Rhizopus microsporus mediastinitis despite three exploratory mediastinal surgeries and complementary systemic and mediastinal irrigation with liposomal amphotericin B. We further review the literature on surgical and antifungal management of mediastinal mucormycosis.
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- 2019
47. Clinical Pharmacokinetics, Pharmacodynamics, Safety and Efficacy of Liposomal Amphotericin B
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Jill Adler-Moore, Roger J. M. Brüggemann, Thomas J. Walsh, Bart J. A. Rijnders, Andreas H. Groll, Russell E. Lewis, Groll A.H., Rijnders B.J.A., Walsh T.J., Adler-Moore J., Lewis R.E., Bruggemann R.J.M., and Internal Medicine
- Subjects
0301 basic medicine ,Microbiology (medical) ,medicine.medical_specialty ,Antifungal Agents ,030106 microbiology ,Supplement Articles ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Amphotericin B ,pharmacodynamics ,medicine ,Animals ,Humans ,liposomal amphotericin B ,030212 general & internal medicine ,Clinical efficacy ,Intensive care medicine ,business.industry ,fungal infection ,Fungi ,clinical trial ,Clinical trial ,pharmacodynamic ,Treatment Outcome ,lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] ,Infectious Diseases ,Clinical research ,Tolerability ,Pharmacodynamics ,Liposomal amphotericin ,business ,pharmacokinetics ,Invasive Fungal Infections ,medicine.drug - Abstract
Contains fulltext : 205145.pdf (Publisher’s version ) (Open Access) Since its introduction in the 1990s, liposomal amphotericin B (LAmB) continues to be an important agent for the treatment of invasive fungal diseases caused by a wide variety of yeasts and molds. This liposomal formulation was developed to improve the tolerability of intravenous amphotericin B, while optimizing its clinical efficacy. Since then, numerous clinical studies have been conducted, collecting a comprehensive body of evidence on its efficacy, safety, and tolerability in the preclinical and clinical setting. Nevertheless, insights into the pharmacokinetics and pharmacodynamics of LAmB continue to evolve and can be utilized to develop strategies that optimize efficacy while maintaining the compound's safety. In this article, we review the clinical pharmacokinetics, pharmacodynamics, safety, and efficacy of LAmB in a wide variety of patient populations and in different indications, and provide an assessment of areas with a need for further clinical research.
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- 2019
48. Preclinical Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Antifungal Activity of Liposomal Amphotericin B
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Bart J. A. Rijnders, Andreas H. Groll, Jill Adler-Moore, Roger J. M. Brüggemann, Thomas J. Walsh, Russell E. Lewis, Medical Microbiology & Infectious Diseases, Adler-Moore J., Lewis R.E., Bruggemann R.J.M., Rijnders B.J.A., Groll A.H., and Walsh T.J.
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0301 basic medicine ,Microbiology (medical) ,Antifungal Agents ,030106 microbiology ,LAmB ,Supplement Articles ,Spleen ,Microbial Sensitivity Tests ,Pharmacology ,Kidney ,03 medical and health sciences ,Minimum inhibitory concentration ,0302 clinical medicine ,Pharmacokinetics ,Amphotericin B ,Amphotericin B deoxycholate ,pharmacodynamics ,medicine ,preclinical ,Animals ,Humans ,030212 general & internal medicine ,liposomal amphotericin B ,pharmacokinetic ,Lung ,Dose-Response Relationship, Drug ,business.industry ,Fungi ,pharmacodynamic ,lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] ,Infectious Diseases ,medicine.anatomical_structure ,Liver ,Pharmacodynamics ,business ,pharmacokinetics ,Invasive Fungal Infections ,medicine.drug - Abstract
Contains fulltext : 205184.pdf (Publisher’s version ) (Open Access) The improved safety profile and antifungal efficacy of liposomal amphotericin B (LAmB) compared to conventional amphotericin B deoxycholate (DAmB) is due to several factors including, its chemical composition, rigorous manufacturing standards, and ability to target and transit through the fungal cell wall. Numerous preclinical studies have shown that LAmB administered intravenously distributes to tissues frequently infected by fungi at levels above the minimum inhibitory concentration (MIC) for many fungi. These concentrations can be maintained from one day to a few weeks, depending upon the tissue. Tissue accumulation is dose-dependent with drug clearance occurring most rapidly from the brain and slowest from the liver and spleen. LAmB localizes in lung epithelial lining fluid, within liver and splenic macrophages and in kidney distal tubules. LAmB has been used successfully in therapeutic and prophylactic animal models to treat many different fungal pathogens, significantly increasing survival and reducing tissue fungal burden.
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- 2019
49. Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium
- Author
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Oliver A. Cornely, Joseph Meletiadis, Joerg J. Vehreschild, Abdullah M. S. Al-Hatmi, Martin Hoenigl, Ban Hock Tan, Malcolm Richardson, Alexandro Bonifaz, Zdenek Racil, Monica A. Slavin, Henrik Jeldtoft Jensen, Janos Sinko, Arunaloke Chakrabarti, Dora E. Corzo-Leon, Souha S. Kanj, Alessandro C. Pasqualotto, Rita O. Oladele, Arnaldo Lopes Colombo, William J. Steinbach, Ronen Ben-Ami, Livio Pagano, Ashraf S. Ibrahim, Georg Maschmeyer, Jacques F. Meis, Zoi D. Pana, Neeraj Sidharthan, Methee Chayakulkeeree, Atul Patel, Nina Singh, Seyedmojtaba Seyedmousavi, Sharon C.-A. Chen, Brad Spellberg, Dong-Gun Lee, Maria J G T Vehreschild, Frédéric Lamoth, Andreas H. Groll, Sevtap Arikan-Akdagli, Marcio Nucci, Andrew J. Ullmann, Katrien Lagrou, Rajeev Soman, Danila Seidel, Thomas J. Walsh, Roger Wahba, Nikolay Klimko, Fanny Lanternier, Badre E. Lmimouni, Sibylle C. Mellinghoff, P. Lewis White, Stéphane Bretagne, Murat Akova, Emmanuel Roilides, Ana Alastruey-Izquierdo, Alexandre Alanio, Cornelia Lass-Floerl, Markus Ruhnke, Anna Skiada, Mihai Mares, Eric Dannaoui, Mervyn Mer, Hamid Badali, Bruno Hochhegger, Thomas Lehrnbecher, Dorothee Arenz, C. Orla Morrissey, Elio Castagnola, Jesús Guinea, Lubos Drgona, Russell E. Lewis, Nathan P. Wiederhold, Michaela Lackner, Claus Peter Heussel, Theoklis E. Zaoutis, Donald C. Sheppard, University Hospital of Cologne [Cologne], Instituto de Salud Carlos III [Madrid] (ISC), The University of Sydney, Unité de Parasitologie-Mycologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Cité (UPCité), University of California [San Diego] (UC San Diego), University of California (UC), Medical University Graz, University Hospitals Leuven [Leuven], University of the Witwatersrand [Johannesburg] (WITS), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases - CECAD [Cologne, Germany] (Institute for Genetics), University of Cologne, German Centre for Infection Research (DZIF), McGill University = Université McGill [Montréal, Canada], Hacettepe University School of Medicine, Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Parasitologie-Mycologie [CHU Saint Louis, Paris], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris] (IP), Radboud University Medical Center [Nijmegen], Ankara University School of Medicine [Turkey], Department of Infectious Diseases and Tropical Medicine [Paris], Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Medical Microbiology & Infectious Diseases, Cornely O.A., Alastruey-Izquierdo A., Arenz D., Chen S.C.A., Dannaoui E., Hochhegger B., Hoenigl M., Jensen H.E., Lagrou K., Lewis R.E., Mellinghoff S.C., Mer M., Pana Z.D., Seidel D., Sheppard D.C., Wahba R., Akova M., Alanio A., Al-Hatmi A.M.S., Arikan-Akdagli S., Badali H., Ben-Ami R., Bonifaz A., Bretagne S., Castagnola E., Chayakulkeeree M., Colombo A.L., Corzo-Leon D.E., Drgona L., Groll A.H., Guinea J., Heussel C.-P., Ibrahim A.S., Kanj S.S., Klimko N., Lackner M., Lamoth F., Lanternier F., Lass-Floerl C., Lee D.-G., Lehrnbecher T., Lmimouni B.E., Mares M., Maschmeyer G., Meis J.F., Meletiadis J., Morrissey C.O., Nucci M., Oladele R., Pagano L., Pasqualotto A., Patel A., Racil Z., Richardson M., Roilides E., Ruhnke M., Seyedmousavi S., Sidharthan N., Singh N., Sinko J., Skiada A., Slavin M., Soman R., Spellberg B., Steinbach W., Tan B.H., Ullmann A.J., Vehreschild J.J., Vehreschild M.J.G.T., Walsh T.J., White P.L., Wiederhold N.P., Zaoutis T., and Chakrabarti A.
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Posaconazole ,[SDV]Life Sciences [q-bio] ,030106 microbiology ,MEDLINE ,Disease ,mucormycosis, guideline, diagnosis, treatment ,mucormycosis ,Article ,03 medical and health sciences ,0302 clinical medicine ,Amphotericin B deoxycholate ,Medicine ,Humans ,030212 general & internal medicine ,Disease management (health) ,Intensive care medicine ,business.industry ,Mucormycosis ,Disease Management ,Guideline ,medicine.disease ,Settore MED/15 - MALATTIE DEL SANGUE ,Infectious Diseases ,business ,medicine.drug ,Rare disease - Abstract
BackgroundMucormycosis is a difficult to diagnose rare disease with high morbidity and mortality. Diagnosis is often delayed, and disease tends to progress rapidly. Urgent surgical and medical intervention is lifesaving. Guidance on the complex multidisciplinary management has potential to improve prognosis, but approaches differ between health care settings.MethodsFrom January 2018, authors from 33 countries in all United Nations regions analysed the published evidence on mucormycosis management and provided consensus recommendations addressing differences between the regions of the world as part of the “One World One Guideline” initiative of the European Confederation of Medical Mycology (ECMM). The author group based in 17 time zones, relied on electronic media including video tutorial on methodology, and central document repository with several daily updates.FindingsSigns and symptoms of mucormycosis depend on organ patterns and underlying conditions. Diagnostic management does not differ greatly between world regions. Upon suspicion of mucormycosis appropriate imaging is strongly recommended to document extent of disease and is followed by strongly recommended surgical intervention. First-line treatment with high-dose liposomal amphotericin B is strongly recommended, while intravenous isavuconazole and intravenous or delayed release tablet posaconazole are recommended with moderate strength. Both triazoles are strongly recommended salvage treatments. Amphotericin B deoxycholate is recommended against, because of substantial toxicity, but may be the only option in resource limited settings.InterpretationManagement of mucormycosis depends on recognising disease patterns and on early diagnosis. Limited availability of contemporary treatments burdens patients in low and middle income settings. Areas of uncertainty were identified and future research directions specified.
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- 2019
50. A non-randomized trial to assess the safety, tolerability, and pharmacokinetics of posaconazole oral suspension in immunocompromised children with neutropenia
- Author
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Amita Joshi, Thomas J. Walsh, Eric Mangin, Andreas H. Groll, Lillian Sung, Patricia Carmelitano, C. Michel Zwaan, Hetty Waskin, Nicholas A. Kartsonis, Davis Gates, John S. Bradley, Amanda Paschke, Antonio Arrieta, Thomas Lehrnbecher, Ngo, Doan TM, Ngo, Doan T. M., and Pediatrics
- Subjects
0301 basic medicine ,Male ,Posaconazole ,Antifungal Agents ,Administration, Oral ,Pediatrics ,law.invention ,White Blood Cells ,0302 clinical medicine ,Randomized controlled trial ,Animal Cells ,law ,Neoplasms ,Medicine and Health Sciences ,030212 general & internal medicine ,Prospective Studies ,Prospective cohort study ,Child ,Pediatric ,Multidisciplinary ,Pharmaceutics ,Age Factors ,Adjustment of Dosage at Steady State ,Infectious Diseases ,Tolerability ,Research Design ,Child, Preschool ,Area Under Curve ,6.1 Pharmaceuticals ,Administration ,Medicine ,Female ,Cellular Types ,Drug ,Pediatric Infections ,Research Article ,medicine.drug ,Oral ,medicine.medical_specialty ,Neutropenia ,Adolescent ,Clinical Research Design ,General Science & Technology ,Immune Cells ,Science ,Immunology ,030106 microbiology ,Clinical Trials and Supportive Activities ,Antineoplastic Agents ,Research and Analysis Methods ,Drug Administration Schedule ,Beverages ,Dose-Response Relationship ,03 medical and health sciences ,Immunocompromised Host ,Dose Prediction Methods ,Drug Therapy ,Pharmacokinetics ,Clinical Research ,Internal medicine ,medicine ,Humans ,ddc:610 ,Adverse effect ,Preschool ,Nutrition ,Blood Cells ,Tea ,Dose-Response Relationship, Drug ,business.industry ,Biology and Life Sciences ,Infant ,Evaluation of treatments and therapeutic interventions ,Cell Biology ,Triazoles ,medicine.disease ,Diet ,Clinical trial ,Age Groups ,People and Places ,Population Groupings ,Adverse Events ,business ,Invasive Fungal Infections - Abstract
Author(s): Arrieta, Antonio C; Sung, Lillian; Bradley, John S; Zwaan, C Michel; Gates, Davis; Waskin, Hetty; Carmelitano, Patricia; Groll, Andreas H; Lehrnbecher, Thomas; Mangin, Eric; Joshi, Amita; Kartsonis, Nicholas A; Walsh, Thomas J; Paschke, Amanda | Abstract: BACKGROUND:Posaconazole (POS) is a potent triazole antifungal agent approved in adults for treatment and prophylaxis of invasive fungal infections (IFIs). The objectives of this study were to evaluate the pharmacokinetics (PK), safety, and tolerability of POS oral suspension in pediatric subjects with neutropenia. METHODS:This was a prospective, multicenter, sequential dose-escalation study. Enrolled subjects were divided into 3 age groups: AG1, 7 to l18 years; AG2, 2 to l7 years; and AG3, 3 months to l2 years. AG1 and AG2 were divided into 3 dosage cohorts: DC1, 12 mg/kg/day divided twice daily (BID); DC2, 18 mg/kg/day BID; and DC3, 18 mg/kg/day divided thrice daily (TID). AG3 was also divided into DC1 and DC2; however, no subjects were enrolled in DC2. Subjects received 7-28 days of POS oral suspension. PK samples were collected at predefined time points. The POS PK target was predefined as ~90% of subjects with Cavg (AUC /dosing interval) between 500 and 2500 ng/mL, with an anticipated mean steady state Cavg exposure of ~1200 ng/mL. RESULTS:The percentage of subjects meeting the PK target was l90% across all age groups and dosage cohorts (range: 31% to 80%). The percentage of subjects that achieved the Cavg target of 500 to 2500 ng/mL on Day 7 ranged from 31% to 80%, with the lowest proportion in subjects 2 to l7 years receiving 12 mg/kg/day BID (AG2/DC1) and the highest proportion in subjects 7 to l18 years receiving 18 mg/kg/day TID (AG1/DC3). At all three dose levels (12 mg/kg/day BID, 18 mg/kg/day BID and 18 mg/kg/day TID), subjects in AG1 (7 to l18 years old) had higher mean PK exposures at steady state than those in AG2. High variability in exposures was observed in all groups. POS oral suspension was generally well tolerated and most of the reported adverse events were related to the subjects' underlying diseases. CONCLUSION:The POS PK target of 90% of subjects with Cavg between 500 and 2500 ng/mL was not achieved in any of the age groups across the different dosage cohorts. New formulations of the molecule with a greater potential to achieve the established PK target are currently under investigation. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT01716234.
- Published
- 2019
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