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1. Antifungal Drug Usage in European Neonatal Units: A Multicenter Weekly Point Prevalence Study

Author

Chorafa, Elisavet, Iosifidis, Elias, Oletto, Andrea, Warris, Adilia, Castagnola, Elio, Bruggemann, Roger, Groll, Andreas H., Lehrnbecher, Thomas, Ferreras Antolin, Laura, Mesini, Alessio, Agakidou, Eleni, Controzzi, Tiziana, De Luca, Maia, Dimitriou, Gabriel, Emonts, Marieke, Esposito, Susanna, Fernàndez-Polo, Aurora, Ghimenton-Walters, Elisabetta, Gkentzi, Despoina, Grasa, Carlos, Hatzidaki, Eleftheria, Jõgi, Piia, Kildonaviciute, Kornelija, Kontou, Angeliki, Leibold-Aguinarte, Alessa, Manzanares, Angela, Mendoza-Palomar, Natalia, Metsvaht, Tuuli, Noni, Maria, Paulus, Stéphane, Perrone, Serafina, Rincón-López, Elena, Romani, Lorenza, Sánchez, Laura, Cetin, Benhur Sirvan, Spoulou, Vana, Strenger, Volker, Vergadi, Eleni, Villaverde, Serena, Vuerich, Marco, Zamora-Flores, Elena, Roilides, Emmanuel, Fainardi, Valentina, Ramundo, Greta, Alkhaaldi, Aisha Abdalla, Tedford, Kara, Butler, Karina, Solopova, Galina, Zsigmond, Borbala, Szekeres, Klaudia, Sarafidis, Kosmas, Sdougka, Maria, Papakonstantinou, Eugenia, Papadimitriou, Eleni, Tsikopoulos, George, Gijón, Manuel, Arias, Ana, Rojo, Pablo, González Guerrero, Alba, Herrera-Castillo, Laura, Chamorro-de-Vega, Esther, Grasa, Carlos D., Moreno-Ramos, Francisco, Baquero-Artigao, Fernando, Soler-Palacin, Pere, Melendo, Susana, Martín-Gómez, Maria Teresa, Keldorfer, Markus, Morris, Nicholas M., Perwein, Thomas, Gordon, Kathrin, Ebrahimi-Fakhari, Daniel, Masjosthusmann, Katja, Rascon, Jelena, and Kairiene, Igne

Published
2024
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2. Multinational Observational Cohort Study of COVID-19-Associated Pulmonary Aspergillosis

Author

Janssen, Nico A.F., Nyga, Remy, Vanderbeke, Lore, Jacobs, Cato, Ergun, Mehmet, Buil, Jochem B., van Dijk, Karin, Altenburg, Josje, Bouman, Catherine S.C., van der Spoel, Hans I., Rijnders, Bart J.A., Dunbar, Albert, Schouten, Jeroen A., Lagrou, Katrien, Bourgeois, Marc, Reynders, Marijke, van Regenmortel, Niels, Rutsaert, Lynn, Lormans, Piet, Feys, Simon, Debavaye, Yves, Tamion, Fabienne, Costa, Damien, Maizel, Julien, Dupont, Herve, Chouaki, Taieb, Nseir, Saad, Sendid, Boualem, Bruggemann, Roger J.M., van de Veerdonk, Frank L., Wauters, Joost, and Verweij, Paul E.

Subjects
Pulmonary aspergillosis -- Statistics -- Risk factors -- Patient outcomes, Intensive care units -- Statistics, Hospital patients -- Statistics, Health
Abstract

Incidence of coronavirus disease (COVID-19)associated pulmonary aspergillosis (CAPA) in hospital intensive care units (ICUs) is 3.8%-33.3% (1-9). Variations might be explained by differences in patient populations and CAPA definitions used, [...]

Published
2021
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4. 595. Olorofim (OLO) for treatment of invasive mould infections in patients with limited or no treatment options: PK data from a Phase 2b open-label study (NCT03583164, Study 32)

Author

Cornelissen, Karen, primary, Wright, James G, additional, Cristinacce, Andrew, additional, Galbraith, Hal, additional, Bruggemann, Roger, additional, Maertens, Johan A, additional, Thompson, George R, additional, Chen, Sharon C, additional, and Rex, John H, additional

Published
2022
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5. Implementation of a centralized pharmacovigilance system in academic pan‐European clinical trials : experience from EU‐Response and conect4children consortia

Author

Terzić, Vida, Levoyer, Léa, Figarella, Mélanie, Bigagli, Elisabetta, Mercier, Noémie, De Gastines, Lucie, Gibowski, Séverine, Trøseid, Marius, Demotes, Jacques, Olsen, Inge Christoffer, Hites, Maya, Ader, Florence, Lopez, José Ramón Arribas, Mentré, France, Espérou, Hélène, Costagliola, Dominique, Røttingen, John‐Arne, Poissy, Julien, Rozé, Jean‐Christophe, Warris, Adilia, O'Leary, Jackie, Fernandes, Ricardo M., Assoumou, Lambert, Hankard, Regis, Turner, Mark, Yazdanpanah, Yazdan, Diallo, Alpha, Holten, Aleksander Rygh, Barratt‐Due, Andreas, Westerheim, Elin, Colban, Martha, Tonby, Kristian, Peiffer‐Smadja, Nathan, Eustace, Joe, Keane, Ruben E., Arribàs, José R., Garcia, Irene, Mazzaferri, Fulvia, Grimaldi, David, Reuter, Jean, Staub, Therese, Berchem, Guy, Delmas, Christelle, Saillard, Juliette, Fougerou‐Leurent, Claire, Ferrane, Assia, Beniguel, Lydie, Baldé, Aliou, Belhadi, Drifa, Dechanet, Aline, Andrejak, Claire, Del Alamo, Marta, Luz, Filipa, Greil, Richard, Keuschnig, Alexandra, Hajdu, Edit, Halanova, Monika, Troníčková, Radka, Trojanek, Milan, Nerušilová, Katerina, Piekarska, Anna, Wiesner, Agnieszka, Bano, Jesus, Tsiodras, Sotirios, Ladenstein, Ruth, Vande Walle, Johan, Degraeuwe, Eva, Kvamme, Anne Mathilde H., Rajasaar, Héli, Kallio, Jaana, Papazisis, Georgios, László, Bálint, O'cleary, Jackie, Ryszard, Sot, Sousa, Catarina, Rodríguez‐Tenreiro, Carmen, Kindblom, Jenny, Ruegger, Christoph, Möller, Alexander, Hawcutt, Daniel, van der Geest, Tessa, Bruggemann, Roger, Neubert, Antje, Drouard, Anne, Dumousseaux, Marina, Moal, Anaelle, Michon, Amelie, Bouazza, Naim, Ursino, Moreno, Hervé, Magali, Boussaha, Inesse, Lozano, Helene, Gueyffier, Francois, Dilo, Ana, Negrini, Anna, Di Maggio, Lucia, Rocchi, Francesca, Polikar, Betty, Cook, Heather, EU‐Response safety group, [missing], and c4c safety group, [missing]

Subjects
Pharmacology, paediatrics, clinical trials, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], drug safety, pharmacovigilance, public health, Medicine and Health Sciences, Pharmacology (medical)
Abstract

Contains fulltext : 292812.pdf (Publisher’s version ) (Open Access) Setting-up a high quality, compliant and efficient pharmacovigilance (PV) system in multi-country clinical trials can be more challenging for academic sponsors than for companies. To ensure the safety of all participants in academic studies and that the PV system fulfils all regulations, we set up a centralized PV system that allows sponsors to delegate work on PV. This initiative was put in practice by our Inserm-ANRS MIE PV department in two distinct multinational European consortia with 19 participating countries: conect4children (c4c) for paediatrics research and EU-Response for Covid-19 platform trials. The centralized PV system consists of some key procedures to harmonize the complex safety processes, creation of a local safety officer (LSO) network and centralization of all safety activities. The key procedures described the safety management plan for each trial and how tasks were shared and delegated between all stakeholders. Processing of serious adverse events (SAEs) in a unique database guaranteed the full control of the safety data and continuous evaluation of the risk-benefit ratio. The LSO network participated in efficient regulatory compliance across multiple countries. In total, there were 1312 SAEs in EU-Response and 83 SAEs in c4c in the four trials. We present here the lessons learnt from our experience in four clinical trials. We managed heterogeneous European local requirements and implemented efficient communication with all trial teams. Our approach builds capacity for PV that can be used by multiple academic sponsors.

Published
2023

6. 1162. Antifungal Use in Immunocompromised Children in Europe: a 12-week Multicenter Modified Point prevalence Study (CALYPSO)

Author

Chorafa, Elisavet, primary, Iosifidis, Elias, additional, Oletto, Andrea, additional, Warris, Adilia, additional, Castagnola, Elio, additional, Bruggemann, Roger, additional, Groll, Andreas, additional, Lehrnbecher, Thomas, additional, Ferreras-Antolin, Laura, additional, Mesini, Alessio, additional, and Roilides, Emmanuel, additional

Published
2021
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7. Taskforce report on the diagnosis and clinical management of COVID-19 associated pulmonary aspergillosis

Author

Verweij, Paul E., Bruggemann, Roger J. M., Azoulay, Elie, Bassetti, Matteo, Blot, Stijn, Buil, Jochem B., Calandra, Thierry, Chiller, Tom, Clancy, Cornelius J., Cornely, Oliver A., Depuydt, Pieter, Koehler, Philipp, Lagrou, Katrien, de Lange, Dylan, Lass-Florl, Cornelia, Lewis, Russell E., Lortholary, Olivier, Liu, Peter-Wei Lun, Maertens, Johan, Nguyen, M. Hong, Patterson, Thomas F., Rijnders, Bart J. A., Rodriguez, Alejandro, Rogers, Thomas R., Schouten, Jeroen A., Wauters, Joost, van de Veerdonk, Frank L., Martin-Loeches, Ignacio, Verweij, Paul E., Bruggemann, Roger J. M., Azoulay, Elie, Bassetti, Matteo, Blot, Stijn, Buil, Jochem B., Calandra, Thierry, Chiller, Tom, Clancy, Cornelius J., Cornely, Oliver A., Depuydt, Pieter, Koehler, Philipp, Lagrou, Katrien, de Lange, Dylan, Lass-Florl, Cornelia, Lewis, Russell E., Lortholary, Olivier, Liu, Peter-Wei Lun, Maertens, Johan, Nguyen, M. Hong, Patterson, Thomas F., Rijnders, Bart J. A., Rodriguez, Alejandro, Rogers, Thomas R., Schouten, Jeroen A., Wauters, Joost, van de Veerdonk, Frank L., and Martin-Loeches, Ignacio

Abstract

Purpose Invasive pulmonary aspergillosis (IPA) is increasingly reported in patients with severe coronavirus disease 2019 (COVID-19) admitted to the intensive care unit (ICU). Diagnosis and management of COVID-19 associated pulmonary aspergillosis (CAPA) are challenging and our aim was to develop practical guidance. Methods A group of 28 international experts reviewed current insights in the epidemiology, diagnosis and management of CAPA and developed recommendations using GRADE methodology. Results The prevalence of CAPA varied between 0 and 33%, which may be partly due to variable case definitions, but likely represents true variation. Bronchoscopy and bronchoalveolar lavage (BAL) remain the cornerstone of CAPA diagnosis, allowing for diagnosis of invasive Aspergillus tracheobronchitis and collection of the best validated specimen for Aspergillus diagnostics. Most patients diagnosed with CAPA lack traditional host factors, but pre-existing structural lung disease and immunomodulating therapy may predispose to CAPA risk. Computed tomography seems to be of limited value to rule CAPA in or out, and serum biomarkers are negative in 85% of patients. As the mortality of CAPA is around 50%, antifungal therapy is recommended for BAL positive patients, but the decision to treat depends on the patients' clinical condition and the institutional incidence of CAPA. We recommend against routinely stopping concomitant corticosteroid or IL-6 blocking therapy in CAPA patients. Conclusion CAPA is a complex disease involving a continuum of respiratory colonization, tissue invasion and angioinvasive disease. Knowledge gaps including true epidemiology, optimal diagnostic work-up, management strategies and role of host-directed therapy require further study.

Published
2021

8. Concomitant use of isavuconazole and CYP3A4/5 inducers : Where pharmacogenetics meets pharmacokinetics

Author

Van Daele, Ruth, Debaveye, Yves, Vos, Robin, Van Bleyenbergh, Pascal, Bruggemann, Roger J., Dreesen, Erwin, Elkayal, Omar, Guchelaar, Henk-Jan, Vermeersch, Pieter, Lagrou, Katrien, Spriet, Isabel, Van Daele, Ruth, Debaveye, Yves, Vos, Robin, Van Bleyenbergh, Pascal, Bruggemann, Roger J., Dreesen, Erwin, Elkayal, Omar, Guchelaar, Henk-Jan, Vermeersch, Pieter, Lagrou, Katrien, and Spriet, Isabel

Abstract

Background Isavuconazole is a triazole antifungal drug, approved for the treatment of invasive aspergillosis and mucormycosis. Isavuconazole is metabolised by CYP3A4 and CYP3A5, and it has been shown that the CYP3A inducer rifampin reduces isavuconazole exposure. By extrapolation, the concomitant use of isavuconazole with moderate and strong CYP450 inducers is contraindicated, although it is known that some CYP450 inducers are less potent in comparison with rifampin. Objectives We aim to document exposure to isavuconazole in patients concomitantly treated with a CYP450 inducer that is less potent compared to rifampin. Moreover, although it is well known that CYP3A enzymes are important for the metabolism of isavuconazole, this induction effect has never been studied in combination with the patient's CYP3A genotype. Patients We report three patients treated with both isavuconazole and a CYP3A inducer that is less potent compared to rifampin (rifabutin or phenobarbital), in whom we determined isavuconazole concentrations. Results These cases suggest that the CYP3A4/5 genotype is an important determinant for isavuconazole exposure and that it might also influence the CYP450 induction interaction. Conclusions CYP3A inducers that are less potent compared to rifampin, may be combined with isavuconazole in patients with loss of CYP3A5 activity (CYP3A5*3/*3). Therapeutic drug monitoring is recommended during this combination. However, low-isavuconazole exposure was observed in the extensive metaboliser with CYP3A4*1/*1 and CYP3A5*1/*3 alleles.

Published
2021
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9. Taskforce report on the diagnosis and clinical management of COVID-19 associated pulmonary aspergillosis

Author

Universitat Rovira i Virgili, Verweij, Paul E.; Bruggemann, Roger J. M.; Azoulay, Elie; Bassetti, Matteo; Blot, Stijn; Buil, Jochem B.; Calandra, Thierry; Chiller, Tom; Clancy, Cornelius J.; Cornely, Oliver A.; Depuydt, Pieter; Koehler, Philipp; Lagrou, Katrien; de Lange, Dylan; Lass-Florl, Cornelia; Lewis, Russell E.; Lortholary, Olivier; Liu, Peter-Wei Lun; Maertens, Johan; Nguyen, M. Hong; Patterson, Thomas F.; Rijnders, Bart J. A.; Rodriguez, Alejandro; Rogers, Thomas R.; Schouten, Jeroen A.; Wauters, Joost; van de Veerdonk, Frank L.; Martin-Loeches, Ignacio, Universitat Rovira i Virgili, and Verweij, Paul E.; Bruggemann, Roger J. M.; Azoulay, Elie; Bassetti, Matteo; Blot, Stijn; Buil, Jochem B.; Calandra, Thierry; Chiller, Tom; Clancy, Cornelius J.; Cornely, Oliver A.; Depuydt, Pieter; Koehler, Philipp; Lagrou, Katrien; de Lange, Dylan; Lass-Florl, Cornelia; Lewis, Russell E.; Lortholary, Olivier; Liu, Peter-Wei Lun; Maertens, Johan; Nguyen, M. Hong; Patterson, Thomas F.; Rijnders, Bart J. A.; Rodriguez, Alejandro; Rogers, Thomas R.; Schouten, Jeroen A.; Wauters, Joost; van de Veerdonk, Frank L.; Martin-Loeches, Ignacio

Published
2021

10. Clinical relevance of the pharmacokinetic interactions of azole antifungal drugs with other coadministered agents

Author

Bruggemann, Roger J.M., Alffenaar, Jan-Willem C., Blijlevens, Nicole M.A., Billaud, Eliane M., Kosterink, Jos G.W., Verweij, Paul E., and Burger, David M.

Subjects
Drug interactions -- Research, Antifungal agents -- Dosage and administration, Antifungal agents -- Physiological aspects, Antifungal agents -- Research, Pharmacokinetics -- Research, Health, Health care industry
Published
2009

11. Single-dose fluconazole versus standard 2-week therapy for oropharyngeal candidiasis in HIV-infected patients: a randomized, double-blind, double-dummy trial

Author

Hamza, Omar J.M., Matee, Mecky I.N., Bruggemann, Roger J.M., Moshi, Mainen J., Simon, Elison N.M., Mugusi, Ferdinand, Mikx, Frans H.M., van der Lee, Henrich A.L., Verweij, Paul E., and van der Ven, Andre J.A.

Subjects
Fluconazole -- Dosage and administration, Fluconazole -- Research, Drug therapy -- Patient outcomes, Drug therapy -- Research, Thrush (Mouth disease) -- Drug therapy, Health, Health care industry
Published
2008

12. Review of influenza-associated pulmonary aspergillosis in ICU patients and proposal for a case definition: an expert opinion

Author

Verweij, Paul E., Rijnders, Bart J. A., Bruggemann, Roger J. M., Azoulay, Elie, Bassetti, Matteo, Blot, Stijn, Calandra, Thierry, Clancy, Cornelius J., Cornely, Oliver A., Chiller, Tom, Depuydt, Pieter, Giacobbe, Daniele Roberto, Janssen, Nico A. F., Kullberg, Bart-Jan, Lagrou, Katrien, Lass-Florl, Cornelia, Lewis, Russell E., Liu, Peter Wei-Lun, Lortholary, Olivier, Maertens, Johan, Martin-Loeches, Ignacio, Nguyen, M. Hong, Patterson, Thomas F., Rogers, Thomas R., Schouten, Jeroen A., Spriet, Isabel, Vanderbeke, Lore, Wauters, Joost, van de Veerdonk, Frank L., Verweij, Paul E., Rijnders, Bart J. A., Bruggemann, Roger J. M., Azoulay, Elie, Bassetti, Matteo, Blot, Stijn, Calandra, Thierry, Clancy, Cornelius J., Cornely, Oliver A., Chiller, Tom, Depuydt, Pieter, Giacobbe, Daniele Roberto, Janssen, Nico A. F., Kullberg, Bart-Jan, Lagrou, Katrien, Lass-Florl, Cornelia, Lewis, Russell E., Liu, Peter Wei-Lun, Lortholary, Olivier, Maertens, Johan, Martin-Loeches, Ignacio, Nguyen, M. Hong, Patterson, Thomas F., Rogers, Thomas R., Schouten, Jeroen A., Spriet, Isabel, Vanderbeke, Lore, Wauters, Joost, and van de Veerdonk, Frank L.

Abstract

Purpose Invasive pulmonary aspergillosis is increasingly reported in patients with influenza admitted to the intensive care unit (ICU). Classification of patients with influenza-associated pulmonary aspergillosis (IAPA) using the current definitions for invasive fungal diseases has proven difficult, and our aim was to develop case definitions for IAPA that can facilitate clinical studies. Methods A group of 29 international experts reviewed current insights into the epidemiology, diagnosis and management of IAPA and proposed a case definition of IAPA through a process of informal consensus. Results Since IAPA may develop in a wide range of hosts, an entry criterion was proposed and not host factors. The entry criterion was defined as a patient requiring ICU admission for respiratory distress with a positive influenza test temporally related to ICU admission. In addition, proven IAPA required histological evidence of invasive septate hyphae and mycological evidence forAspergillus. Probable IAPA required the detection of galactomannan or positiveAspergillusculture in bronchoalveolar lavage (BAL) or serum with pulmonary infiltrates or a positive culture in upper respiratory samples with bronchoscopic evidence for tracheobronchitis or cavitating pulmonary infiltrates of recent onset. The IAPA case definitions may be useful to classify patients with COVID-19-associated pulmonary aspergillosis (CAPA), while awaiting further studies that provide more insight into the interaction betweenAspergillusand the SARS-CoV-2-infected lung. Conclusion A consensus case definition of IAPA is proposed, which will facilitate research into the epidemiology, diagnosis and management of this emerging acute and severeAspergillusdisease, and may be of use to study CAPA.

Published
2020

14. Mechanism of oxime reactivation of acetylcholinesterase analyzed by chirality and mutagenesis

Author

Wong, Lilly, Radic, Zoran, Bruggemann, Roger J.M., Hosea, Natilie, Berman, Harvey A., and Taylor, Palmer

Subjects
Biochemistry -- Research, Acetylcholinesterase -- Analysis, Chirality -- Analysis, Mutagenesis -- Analysis, Enantiomers -- Analysis, Biological sciences, Chemistry
Abstract

Research has been conducted on the organophosphates. The resolved enantiomeric methylphosphonate acetylcholinesterase conjugate reactivation has been examined.

Published
2000

16. Pneumocystis jirovecii pneumonia: still a concern in patients with haematological malignancies and stem cell transplant recipients

Author

Cordonnier, Catherine, Cesaro, Simone, Maschmeyer, Georg, Einsele, Hermann, Peter Donnelly, J., Alanio, Alexandre, Hauser, Philippe M., Lagrou, Katrien, Melchers, Willem J. G., Helweg-Larsen, Jannik, Matos, Olga, Bretagne, Stephane, Maertens, Johan, Agrawal, Samir, Kibbler, Christopher, Pagliuca, Antonio, Ward, Katherine, Akova, Murat, Herbrecht, Raoul, Mallet, Vincent, Ribaud, Patricia, Aljurf, Mahmoud, Averbuch, Dina, Engelhard, Dan, Berg, Thomas, Cornely, Oliver, Penack, Olaf, van Boemmel, Florian, von Lilienfeld-Toal, Marie, Blennow, Ola, Ljungman, Per, Bruggemann, Roger, Donnelly, Peter, Kullberg, Bart-Jan, Melchers, Willem, Calandra, Thierry, Hirsch, Hans, Marchetti, Oscar, Orasch, Christina, Tissot, Frederic, Castagnola, Elio, Girmenia, Corrado, Mikulska, Malgorzata, Pagano, Livio, Viscoli, Claudio, De La Camara, Rafael, Duarte, Rafael, Munoz, Patricia, Drgona, Lubos, Hargreaves, Ruth, Hubacek, Petr, Kouba, Michal, Racil, Zdenek, Klyasova, Galina, Pettrikos, George, Roilides, Emmanuel, Skiada, Anna, Rizzi-Puechal, Valã©rie, Sinko, Janos, Slavin, Monica, Styczynski, Jan, Tweddle, Lorraine, Wood, Craig, Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Department of Haematology, Oncoematologia Pediatrica, Policlinico G. B. Rossi, Medizinische Klinik, Hämatologie und Onkologie, Klinikum Ernst von Bergmann, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Radboud university [Nijmegen], Université Sorbonne Paris Cité (USPC), 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), Mycologie moléculaire, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Lausanne University Hospital, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Instituto de Higiene e Medicina Tropical (IHMT), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), Department of Hematology, University Hospital Gasthuisberg, The ECIL-5 meeting was supported by unrestricted educational grants from Astellas Pharma, Gilead Sciences, Merck, and Pfizer. The ECIL-6 meeting was supported by unrestricted educational grants from Basilea, Gilead Sciences, Merck, and Pfizer, on behalf of the Fifth European Conference on Infections in Leukemia (ECIL-5†), a joint venture of The European Group for Blood and Marrow Transplantation (EBMT), The European Organization for Research and Treatment of Cancer (EORTC), the Immunocompromised Host Society (ICHS) and The European Leukemia Net (ELN) (61 collabrators), Radboud University [Nijmegen], University Hospital Gasthuisberg [Leuven], Julius-Maximilians-Universität Würzburg (JMU), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Microbiology (medical), medicine.medical_specialty, Antifungal Agents, [SDV]Life Sciences [q-bio], medicine.medical_treatment, 030106 microbiology, Disease, Hematopoietic stem cell transplantation, Pneumocystis carinii, Chemoprevention, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Immunocompromised Host, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Pneumocystis jirovecii, Pharmacology (medical), Intensive care medicine, Hematologic Neoplasms, Pneumonia, Pneumocystis, Stem Cell Transplantation, Transplant Recipients, Pharmacology, Infectious Diseases, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Hematology, biology, Pneumocystis, business.industry, Mortality rate, Pneumonia, biology.organism_classification, medicine.disease, Penumocytis pneumonia, 3. Good health, Leukemia, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], 030220 oncology & carcinogenesis, immunocomrpomised host, Pnemocystis jirovecii, Stem cell, immunocomrpomised host, Penumocytis pneumonia, Pnemocystis jirovecii, business, Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5]
Abstract

Contains fulltext : 171209.pdf (Publisher’s version ) (Closed access) Pneumocystis jirovecii can cause life-threatening pneumonia following treatment for haematological malignancies or after HSCT. The mortality rate of P. jirovecii pneumonia (PCP) in these patients is 30%-60%, especially after HSCT. The clinical presentation of PCP in haematology differs from that associated with HIV infection, with the disease being acute and more often severe, having a lower fungal burden and being more frequently linked to treatment with corticosteroids. Most cases occur in patients not receiving adequate prophylaxis. The development of new therapies, including targeted treatments and monoclonal antibodies in various haematological diseases, justifies constant vigilance in order to identify new at-risk populations and give prophylaxis accordingly. The fifth and sixth European Conferences on Infections in Leukaemia (ECIL-5 and ECIL-6) aimed to review risk factors for PCP in haematology patients and to establish evidence-based recommendations for PCP diagnosis, prophylaxis and treatment. This article focuses on the magnitude of the problem, the main differences in clinical presentation between haematology patients and other immunocompromised populations, especially HIV-infected patients, and the main risk factors.

Published
2016

17. Development and validation of an analytical method using UPLC-MS/MS to quantify everolimus in dried blood spots in the oncology setting

Author

Knapen, Lotte M., Knapen, Lotte M., de Beer, Yvo, Bruggemann, Roger J. M., Stolk, Leo M., de Vries, Frank, Tjan-Heijnen, Vivianne C. G., van Erp, Nielka P., Croes, Sander, Knapen, Lotte M., Knapen, Lotte M., de Beer, Yvo, Bruggemann, Roger J. M., Stolk, Leo M., de Vries, Frank, Tjan-Heijnen, Vivianne C. G., van Erp, Nielka P., and Croes, Sander

Abstract

While the therapeutic drug monitoring (TDM) of everolimus has been routinely performed for over 10 years in solid organ transplantation medicine, in order to optimize the balance between effectiveness and toxicity, it is yet uncommon in the treatment of malignancies. The aim of this study was to develop and validate a bioanalytical method to quantify everolimus in dried blood spots (DBS) to facilitate TDM for the oncology outpatient setting. The hematocrit effect of everolimus was investigated. An 7.5 mm disk from the central part of the DBS was punched, followed by the extraction of everolimus from the DBS by methanol/acetonitrile (80/20%) spiked with deuterium-labelled everolimus as internal standard. Subsequently, everolimus was separated and analyzed using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The UPLC-MS/MS method was validated according to the European Medicine Agency (EMA) guideline. Everolimus concentrations could be quantified over the range of 3-75 mu g/L. The intra- and inter-assay precision and accuracy of the method were shown to be acceptable (coefficient of variation <= 10.7% and relative error <= 4.4%, respectively). The matrix effects appeared to be influenced by the hematocrit effect. The hematocrit effect was tested in a range of 0.20-0.50 L/L, at which hematocrit accuracy and precision were satisfactory at values >= 0.25 L/L. However, at 0.20 L/L hematocrit in combination with high everolimus concentrations of 20 and 40 mu g/L, the precision was adequate (<= 7.4%), but the accuracy was >15% of the nominal concentration. Everolimus was stable in DBS for at least 80 days at 2-8 degrees C. Given these results, the everolimus DBS method has been successfully developed and validated. Special attention is necessary for cancer patients with both a 0.20 L/L hematocrit in combination with everolimus concentrations >= 20 mu g/L. A clinical validation for the use of everolimus DBS in cancer patients

Published
2018

18. European guidelines for primary antifungal prophylaxis in adult haematology patients: summary of the updated recommendations from the European Conference on Infections in Leukaemia

Author

Maertens, Johan A., Girmenia, Corrado, Bruggemann, Roger J., Duarte, Rafael F., Kibbler, Christopher C., Ljungman, Per, Racil, Zdenek, Ribaud, Patricia, Slavin, Monica A., Cornely, Oliver A., Donnelly, J. Peter, Cordonnier, Catherine, Maertens, Johan A., Girmenia, Corrado, Bruggemann, Roger J., Duarte, Rafael F., Kibbler, Christopher C., Ljungman, Per, Racil, Zdenek, Ribaud, Patricia, Slavin, Monica A., Cornely, Oliver A., Donnelly, J. Peter, and Cordonnier, Catherine

Abstract

The European Conference on Infections in Leukaemia (ECIL) updated its guidelines on antifungal prophylaxis for adults using the grading system of IDSA. The guidelines were extended to provide recommendations for other haematological diseases besides AML and recipients of an allogeneic haematopoietic stem cell transplantation (HSCT). Posaconazole remains the drug of choice when the incidence of invasive mould diseases exceeds 8%. For patients undergoing remission-induction chemotherapy for AML and myelodysplastic syndrome (MDS), fluconazole can still offer an alternative provided it forms part of an integrated care strategy that includes screening with biomarkers and imaging. Similarly, aerosolized liposomal amphotericin B combined with fluconazole can be considered for patients at high risk of invasive mould diseases but other formulations of the polyene are discouraged. Fluconazole is still recommended as primary prophylaxis for patients at low risk of invasive mould diseases during the pre-engraftment phase of allogeneic HSCT whereas only a moderate recommendation could be made for itraconazole, posaconazole and voriconazole for patients at high risk. Posaconazole is strongly recommended for preventing invasive mould disease post-engraftment but only when graft-versus-host disease (GvHD) was accompanied by other risk factors such as its severity, use of an alternative donor or when unresponsive to standard corticosteroid therapy. The need for primary prophylaxis for other patient groups was less clear and should be defined by the estimated risk of invasive fungal disease (IFD).

Published
2018

19. still a concern in patients with haematological malignancies and stem cell transplant recipients-authors' response

Author

Cordonnier, Catherine, Alanio, Alexandre, Cesaro, Simone, Maschmeyer, Georg, Einsele, Hermann, Donnelly, J. Peter, Hauser, Philippe M., Lagrou, Katrien, Melchers, Willem J.G., Helweg-Larsen, Jannik, Matos, Olga, Bretagne, Stephane, Maertens, Johan, Agrawal, Samir, Akova, Murat, Aljurf, Mahmoud, Averbuch, Dina, Berg, Thomas, Blennow, Ola, Bruggemann, Roger, Calandra, Thierry, Castagnola, Elio, Cornely, Oliver, De La Camara, Rafael, Drgona, Lubos, Duarte, Rafael, Engelhard, Dan, Girmenia, Corrado, Hargreaves, Ruth, Herbrecht, Raoul, Hirsch, Hans, Hubacek, Petr, Kibbler, Christopher, Klyasova, Galina, Kouba, Michal, Kullberg, Bart Jan, Ljungman, Per, Mallet, Vincent, Marchetti, Oscar, Mikulska, Malgorzata, Munoz, Patricia, Orasch, Christina, Pagano, Livio, Pagliuca, Antonio, Penack, Olaf, Pettrikos, George, Racil, Zdenek, Ribaud, Patricia, Rizzi-Puechal, Valerie, Roilides, Emmanuel, on behalf of the Fifth European Conference on Infections in Leukemia (ECIL-5), The European Group for Blood and Marrow Transplantation (EBMT), The European Organization for Research and Treatment of Cancer (EORTC), Immunocompromised Host Society (ICHS) and The European LeukemiaNet (ELN), Instituto de Higiene e Medicina Tropical (IHMT), Global Health and Tropical Medicine (GHTM), and TB, HIV and opportunistic diseases and pathogens (THOP)

Subjects
Carinii-pneumonia, Aids, Infectious Diseases, ECIL guidelines, SDG 3 - Good Health and Well-being, Outbreaks, Infection, Infants, Management
Abstract

Made available in DSpace on 2021-09-24T00:56:32Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-04-01 publishersversion published

Published
2017

20. Pharmacokinetics/Pharmacodynamics of Antiviral Agents Used to Treat SARS-CoV-2 and Their Potential Interaction with Drugs and Other Supportive Measures: A Comprehensive Review by the PK/PD of Anti-Infectives Study Group of the European Society of Antimicrobial Agents

Author

Zeitlinger, Markus, Koch, Birgit C. P., Bruggemann, Roger, De Cock, Pieter, Felton, Timothy, Hites, Maya, Le, Jennifer, Luque, Sonia, MacGowan, Alasdair P., Marriott, Deborah J. E., Muller, Anouk E., Nadrah, Kristina, Paterson, David L., Standing, Joseph F., Telles, João P., Wölfl-Duchek, Michael, Thy, Michael, and Roberts, Jason A.

Subjects
ANTIVIRAL agents, SARS-CoV-2, ANTI-infective agents, MIDDLE East respiratory syndrome, DRUG interactions, PHARMACODYNAMICS
Abstract

There is an urgent need to identify optimal antiviral therapies for COVID-19 caused by SARS-CoV-2. We have conducted a rapid and comprehensive review of relevant pharmacological evidence, focusing on (1) the pharmacokinetics (PK) of potential antiviral therapies; (2) coronavirus-specific pharmacodynamics (PD); (3) PK and PD interactions between proposed combination therapies; (4) pharmacology of major supportive therapies; and (5) anticipated drug–drug interactions (DDIs). We found promising in vitro evidence for remdesivir, (hydroxy)chloroquine and favipiravir against SARS-CoV-2; potential clinical benefit in SARS-CoV-2 with remdesivir, the combination of lopinavir/ritonavir (LPV/r) plus ribavirin; and strong evidence for LPV/r plus ribavirin against Middle East Respiratory Syndrome (MERS) for post-exposure prophylaxis in healthcare workers. Despite these emerging data, robust controlled clinical trials assessing patient-centred outcomes remain imperative and clinical data have already reduced expectations with regard to some drugs. Any therapy should be used with caution in the light of potential drug interactions and the uncertainty of optimal doses for treating mild versus serious infections. [ABSTRACT FROM AUTHOR]

Published
2020
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21. ECIL guidelines for preventing Pneumocystis jirovecii pneumonia in patients with haematological malignancies and stem cell transplant recipients

Author

Maertens, Johan, Cesaro, Simone, Maschmeyer, Georg, Einsele, Hermann, Donnelly, J. Peter, Alanio, Alexandre, Hauser, Philippe M., Lagrou, Katrien, Melchers, Willem J. G., Helweg-Larsen, Jannik, Matos, Olga, Bretagne, Stã©phane, Cordonnier, Catherine, Agrawal, Samir, Kibbler, Christopher, Pagliuca, SIMONE ANTONIO, Ward, Katherine, Akova, Murat, Herbrecht, Raoul, Mallet, Vincent, Ribaud, Patricia, Aljurf, Mahmoud, Averbuch, Dina, Engelhard, Dan, Berg, Thomas, Cornely, Oliver, Penack, Olaf, van Boemmel, Florian, von Lilienfeld-Toal, Marie, Blennow, Ola, Ljungman, Per, Bruggemann, Roger, Donnelly, Peter, Kullberg, Bart-Jan, Melchers, Willem, Calandra, Thierry, Hirsch, Hans, Marchetti, Oscar, Orasch, Christina, Tissot, Frederic, Castagnola, Elio, Girmenia, Corrado, Mikulska, Malgorzata, Pagano, Livio, Viscoli, Claudio, De La Camara, Rafael, Duarte, Rafael, Munoz, Patricia, Drgona, Lubos, Hargreaves, Ruth, Hubacek, Petr, Kouba, Michal, Racil, Zdenek, Klyasova, Galina, Pettrikos, George, Roilides, Emmanuel, Skiada, Anna, Rizzi-Puechal, Valã©rie, Sinko, Janos, Slavin, Monica, Styczynski, Jan, Tweddle, Lorraine, Wood, Craig, Department of Hematology, University Hospital Gasthuisberg, G.B. Rossi Hospital, Verona University, Medizinische Klinik, Hämatologie und Onkologie, Klinikum Ernst von Bergmann, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Radboud university [Nijmegen], 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), Mycologie moléculaire, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Lausanne University Hospital, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Instituto de Higiene e Medicina Tropical (IHMT), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), Centre National de Référence Mycologie et Antifongiques-Mycologie Moléculaire (CNRMA), Institut Pasteur [Paris], Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), The ECIL-5 meeting was supported by unrestricted educational grants from Astellas Pharma, Gilead Sciences, Merck, and Pfizer., University Hospital Gasthuisberg [Leuven], Università degli studi di Verona = University of Verona (UNIVR), Radboud University [Nijmegen], Julius-Maximilians-Universität Würzburg (JMU), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)

Subjects
0301 basic medicine, Microbiology (medical), Antifungal Agents, [SDV]Life Sciences [q-bio], 030106 microbiology, Pneumocitis jirovecii, Chemoprevention, Trimethoprim, Immunocompromised Host, 03 medical and health sciences, 0302 clinical medicine, Trimethoprim, Sulfamethoxazole Drug Combination, Humans, Pharmacology (medical), Pharmacology, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Sulfamethoxazole Drug Combination, Pneumocystis, Hematologic Neoplasms, Pneumonia, Pneumocystis, Stem Cell Transplantation, Transplant Recipients, Infectious Diseases, immunocomrpomised host, pneumonia, Pneumocitis jirovecii, Pneumonia, 3. Good health, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], 030220 oncology & carcinogenesis, immunocomrpomised host, Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5], [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Contains fulltext : 172373.pdf (Publisher’s version ) (Closed access) The 5th European Conference on Infections in Leukaemia (ECIL-5) meeting aimed to establish evidence-based recommendations for the prophylaxis of Pneumocystis jirovecii pneumonia (PCP) in non-HIV-infected patients with an underlying haematological condition, including allogeneic HSCT recipients. Recommendations were based on the grading system of the IDSA. Trimethoprim/sulfamethoxazole given 2-3 times weekly is the drug of choice for the primary prophylaxis of PCP in adults ( A-II: ) and children ( A-I: ) and should be given during the entire period at risk. Recent data indicate that children may benefit equally from a once-weekly regimen ( B-II: ). All other drugs, including pentamidine, atovaquone and dapsone, are considered second-line alternatives when trimethoprim/sulfamethoxazole is poorly tolerated or contraindicated. The main indications of PCP prophylaxis are ALL, allogeneic HSCT, treatment with alemtuzumab, fludarabine/cyclophosphamide/rituximab combinations, >4 weeks of treatment with corticosteroids and well-defined primary immune deficiencies in children. Additional indications are proposed depending on the treatment regimen.

Published
2016

22. ECIL guidelines for the diagnosis of Pneumocystis jirovecii pneumonia in patients with haematological malignancies and stem cell transplant recipients

Author

Alanio, Alexandre, Hauser, Philippe M., Lagrou, Katrien, Melchers, Willem J. G., Helweg Larsen, Jannik, Matos, Olga, Cesaro, Simone, Maschmeyer, Georg, Einsele, Hermann, Donnelly, J. Peter, Cordonnier, Catherine, Maertens, Johan, Bretagne, Stã©phane, Agrawal, Samir, Kibbler, Christopher, Pagliuca, Antonio, Ward, Katherine, Akova, Murat, Herbrecht, Raoul, Mallet, Vincent, Ribaud, Patricia, Aljurf, Mahmoud, Averbuch, Dina, Engelhard, Dan, Berg, Thomas, Cornely, Oliver, Penack, Olaf, van Boemmel, Florian, von Lilienfeld Toal, Marie, Blennow, Ola, Ljungman, Per, Bruggemann, Roger, Donnelly, Peter, Kullberg, Bart Jan, Melchers, Willem, Calandra, Thierry, Hirsch, Hans, Marchetti, Oscar, Orasch, Christina, Tissot, Frederic, Castagnola, Elio, Girmenia, Corrado, Mikulska, MALGORZATA KAROLINA, Pagano, Livio, Viscoli, Claudio, De La Camara, Rafael, Duarte, Rafael, Munoz, Patricia, Drgona, Lubos, Hargreaves, Ruth, Hubacek, Petr, Kouba, Michal, Racil, Zdenek, Klyasova, Galina, Pettrikos, George, Roilides, Emmanuel, Skiada, Anna, Rizzi Puechal, Valã©rie, Sinko, Janos, Slavin, Monica, Styczynski, Jan, Tweddle, Lorraine, Wood, Craig, Centre National de Référence des Mycoses invasives et antifongiques - Mycologie moléculaire (CNRMA), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7), 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), Mycologie moléculaire, Université de Lausanne = University of Lausanne (UNIL), Université Catholique de Louvain = Catholic University of Louvain (UCL), Radboud University [Nijmegen], Rigshospitalet [Copenhagen], Copenhagen University Hospital, Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), Università degli studi di Verona = University of Verona (UNIVR), Medizinische Klinik, Hämatologie und Onkologie, Klinikum Ernst von Bergmann, Julius Maximilians University Wurzburg, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Department of Hematology, University Hospital Gasthuisberg [Leuven], The ECIL-5 meeting was supported by unrestricted educational grants from Astellas Pharma, Gilead Sciences, Merck, and Pfizer, Université de Lausanne (UNIL), Radboud university [Nijmegen], G.B. Rossi Hospital, Verona University, University Hospital Gasthuisberg, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Julius-Maximilians-Universität Würzburg (JMU)

Subjects
0301 basic medicine, Microbiology (medical), medicine.medical_specialty, [SDV]Life Sciences [q-bio], 030106 microbiology, Dapsone, Pneumocystis carinii, 03 medical and health sciences, Immunocompromised Host, 0302 clinical medicine, Diagnostic Tests, Internal medicine, medicine, Pneumocistis jirovecii, Humans, Routine, Pharmacology (medical), 030212 general & internal medicine, Intensive care medicine, Pharmacology, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], business.industry, Diagnostic Tests, Routine, Pneumocystis, Pneumonia, Pneumocystis, Pneumonia, medicine.disease, Trimethoprim, Transplant Recipients, 3. Good health, Fludarabine, Regimen, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Infectious Diseases, Hematologic Neoplasms, Alemtuzumab, Rituximab, business, Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5], [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Pentamidine, medicine.drug, immunocompromised host, pneumonia, Pneumocistis jirovecii, Stem Cell Transplantation
Abstract

Item does not contain fulltext The Fifth European Conference on Infections in Leukaemia (ECIL-5) convened a meeting to establish evidence-based recommendations for using tests to diagnose Pneumocystis jirovecii pneumonia (PCP) in adult patients with haematological malignancies. Immunofluorescence assays are recommended as the most sensitive microscopic method (recommendation A-II: ). Real-time PCR is recommended for the routine diagnosis of PCP ( A-II: ). Bronchoalveolar lavage (BAL) fluid is recommended as the best specimen as it yields good negative predictive value ( A-II: ). Non-invasive specimens can be suitable alternatives ( B-II: ), acknowledging that PCP cannot be ruled out in case of a negative PCR result ( A-II: ). Detecting beta-d-glucan in serum can contribute to the diagnosis but not the follow-up of PCP ( A-II: ). A negative serum beta-d-glucan result can exclude PCP in a patient at risk ( A-II: ), whereas a positive test result may indicate other fungal infections. Genotyping using multilocus sequence markers can be used to investigate suspected outbreaks ( A-II: ). The routine detection of dihydropteroate synthase mutations in cases of treatment failure is not recommended ( B-II: ) since these mutations do not affect response to high-dose co-trimoxazole. The clinical utility of these diagnostic tests for the early management of PCP should be further assessed in prospective, randomized interventional studies.

Published
2016

24. International expert opinion on the management of infection caused by azole-resistant Aspergillus fumigatus

Author

Verweij, Paul E., Ananda-Rajah, Michelle, Andes, David, Arendrup, Maiken C., Bruggemann, Roger J., Chowdhary, Anuradha, Cornely, Oliver A., Denning, David W., Groll, Andreas H., Izumikawa, Koichi, Kullberg, Bart Jan, Lagrou, Katrien, Maertens, Johan, Meis, Jacques F., Newton, Pippa, Page, Iain, Seyedmousavi, Seyedmojtaba, Sheppard, Donald C., Viscoli, Claudio, Warris, Adilia, Donnelly, J. Peter, Verweij, Paul E., Ananda-Rajah, Michelle, Andes, David, Arendrup, Maiken C., Bruggemann, Roger J., Chowdhary, Anuradha, Cornely, Oliver A., Denning, David W., Groll, Andreas H., Izumikawa, Koichi, Kullberg, Bart Jan, Lagrou, Katrien, Maertens, Johan, Meis, Jacques F., Newton, Pippa, Page, Iain, Seyedmousavi, Seyedmojtaba, Sheppard, Donald C., Viscoli, Claudio, Warris, Adilia, and Donnelly, J. Peter

Abstract

An international expert panel was convened to deliberate the management of azole-resistant aspergillosis. In culture-positive cases, in vitro susceptibility testing should always be performed if antifungal therapy is intended. Different patterns of resistance are seen, with multi-azole and pan-azole resistance more common than resistance to a single triazole. In confirmed invasive pulmonary aspergillosis due to an azole-resistant Aspergillus, the experts recommended a switch from voriconazole to liposomal amphotericin B (L-AmB; Ambisome (R)). In regions with environmental resistance rates of >= 10%, a voriconazole-echinocandin combination or L-AmB were favoured as initial therapy. All experts recommended L-AmB as core therapy for central nervous system aspergillosis suspected to be due to an azole-resistant Aspergillus, and considered the addition of a second agent with the majority favouring flucytosine. Intravenous therapy with either micafungin or L-AmB given as either intermittent or continuous therapy was recommended for chronic pulmonary aspergillosis due to a pan-azole-resistant Aspergillus. Local and national surveillance with identification of clinical and environmental resistance patterns, rapid diagnostics, better quality clinical outcome data, and a greater understanding of the factors driving or minimising environmental resistance are areas where research is urgently needed, as well as the development of new oral agents outside the azole drug class. (C) 2015 The Authors. Published by Elsevier Ltd.

Published
2015

25. Oseltamivir dosing in children undergoing hemodialysis

Author

Schreuder, Michiel F., van der Flier, Michiel, Knops, Noel B., Koster-Kamphuis, Linda, and Bruggemann, Roger j.

Subjects
Oseltamivir phosphate -- Dosage and administration, Swine influenza -- Drug therapy, Hemodialysis patients -- Drug therapy, Practice guidelines (Medicine), Health, Health care industry
Published
2010

26. Mechanism of oxime reactivation of phosphonylated acetylcholinesterase analyzed by chirality and mutagenesis

Author

Radić, Zoran, Kovarik, Zrinka, Wong, Lilly, Bruggemann, Roger J., Hosea, Natalie, Berman, Harvey A., Taylor, Palmer, and BP Doctor

Subjects
Organophosphates, acetylcholinesterase, pyridinium oximes, chirality, organophosphates, reactivation, oximes
Abstract

Organophosphates inactivate acetylcholinesterase by reacting covalently with the active center serine. We have examined the reactivation of a series of resolved enantiomeric methylphosphonate conjugates of acetylcholinesterase by two oximes, 2-pralidoxime (2-PAM) and 1-(2'-hydroxy iminomethyl-1'-pyridinium)-3-(4' carbamoyl-1-pyridinium) (HI-6). The Sp-enantiomers of the methylphosphonate esters are far more reactive in forming the conjugate with the enzyme, and we find that rates of oxime reactivation also show an Sp versus Rp preference suggesting that a similar orientation of the phosphonyl oxygen towards the oxyanion hole is required for both efficient inactivation and reactivation. A comparison of reactivation rates of Sp- and Rp-cycloheptyl-, 3,3 dimethylbutyl- and isopropyl methylphosphonyl conjugates shows that steric hindrance by the alkoxy group precludes facile access of the oxime to the tetrahedral phosphorus. To facilitate access, we substituted smaller side chains in the acyl pocket of the active center and find that the Phe295Leu substitution enhances the HI-6 elicited reactivation rates of the Sp conjugates up to 14-fold, whereas the Phe297Ile substitution preferentially enhances 2-PAM reactivation by as much as 125-fold. The fractional enhancement of reactivation achieved by these mutations of the acyl pocket is greatest for the conjugated phosphonates of the largest steric bulk. By contrast, little enhancement of reactivation rate is seen with these mutants for the Rp conjugates, where limitations on oxime access to the phosphonate and suboptimal positioning of the phosphonyl oxygen in the oxyanion hole may both slow reactivation. To facilitate access of oximes to RP conjugates from the side of the enzyme choline binding site we substituted Ala for Tyr at position 337. This substitution significantly enhanced reactivation rates of all RP conjugates and two out of three SP conjugates, by both 2PAM and HI-6. Maximal rates of reactivation were primarily increased reflecting an improved geometry of the pentacoordinate transition state with the oxime moiety attacking from choline binding site. Combined substitutions of acyl pocket and choline binding site residues at positions 295 and 337, 297 and 337, and ternary residue substitution at positions 295,297,337 further enhanced reactivation rates only in a few cases. The majority of combined mutations, however, reactivated at similar rates as wildtype acetylcholinesterase or slower, thus approaching reactivation rates of wildtype butyrylcholinesterase. The active center gorge of butyrylcholinesterase is devoid of six aromatic residues, found in acetylcholinesterase, three of which are at positions homologous to 295,297 and 337. Taken together, the above findings suggest that impaction of the conjugated organophosphate within the constraints of the active center gorge is a major factor in influencing oxime access and reactivation rates. While opening of the gorge can greatly enhance oxime efficacy, a gorge devoid of critical aromatic residues as seen in butyrylcholinesterase yields an environment not conductive to efficient reactivation. Moreover, the individual oximes differ in attacking orientation leading to the presumed pentavalent transition state. Hence, efficacies of oximes as reactivating agents are dependent not only on oxime structure, but also the steric bulk of the intervening groups surrounding the tetrahedral phosphorus and the attacking oxime molecule. An efficient cholinesterase-oxime binary combination would convert plasma cholinesterase from a stoichiometric to a catalytic scavenger of organophosphate nerve agents. The catalytic turnover and prophylactic efficacy of the combination will depend on the reactivation rate achieved by the oxime. This work was supported by U.S. Army Medical Research and Materiel Command under Grant project Order DAMD17-18014

Published
2000

28. Impact of cyp51AMutations on the Pharmacokinetic and Pharmacodynamic Properties of Voriconazole in a Murine Model of Disseminated Aspergillosis

Author

Mavridou, Eleftheria, Bruggemann, Roger J. M., Melchers, Willem J. G., Verweij, Paul E., and Mouton, Johan W.

Abstract

ABSTRACTThe in vivoefficacy of voriconazole against 4 clinical Aspergillus fumigatusisolates with MICs ranging from 0.125 to 2 mg/liter (CLSI document M38A) was assessed in a nonneutropenic murine model of disseminated aspergillosis. The study involved TR/L98H, M220I, and G54W mutants and a wild-type control isolate. Oral voriconazole therapy was started 24 h after intravenous infection of mice and was given once daily for 14 consecutive days, with doses ranging from 10 to 80 mg/kg of body weight, using survival as the endpoint. Survival for all isolates was dependent on the voriconazole dose level (R2value of 0.5 to 0.6), but a better relationship existed for the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) or the AUC for the free, unbound fraction of the drug divided by the MIC (fAUC/MIC ratio) (R2value of 0.95 to 0.98). The 24-h fAUC/MIC ratio showed a clear relationship to effect, with an exposure index for amount of free drug required for 50% of maximum effectiveness (fEI50) of 11.17 at day 7. Maximum effect was reached at values of around 80 to 100, comparable to that observed for posaconazole and A. fumigatus. Mice infected with an isolate having a MIC of 2 mg/liter required an exposure that was inversely correlated with the increase in MIC compared to that of the wild-type control, but due to nonlinear pharmacokinetics, this required only doubling of the voriconazole dose. The efficacy of voriconazole for isolates with high MICs for other triazoles but voriconazole MICs within the wild-type population range was comparable to that for the wild-type control. Finally, we used a grapefruit juice-free murine model of aspergillosis and concluded that this model is appropriate to study pharmacokinetic/pharmacodynamic relationships of voriconazole.

Published
2010
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