44 results on '"Buil JB"'
Search Results
2. [Persistent dermatomycosis due toTrichophyton indotineae].
- Author
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Buil JB, Meijer EFJ, den Reijer M, Zeeuwen-Franssen MEJ, Melchers WJG, and Verweij PE
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- Humans, Trichophyton isolation & purification, Trichophyton drug effects, Dermatomycoses drug therapy, Dermatomycoses diagnosis, Antifungal Agents therapeutic use, Tinea drug therapy, Tinea diagnosis
- Abstract
Trichophyton indotineae is a recently identified dermatophyte that frequently causes extensive and persistent dermatomycosis, particularly tinea corporis, tinea cruris, and tinea faciei. The infection is frequently encountered in countries of the Indian subcontinent and surrounding areas. In Europe, T. indotineae has mainly been detected in patients with an epidemiological link to the aforementioned regions. Unlike dermatomycoses caused by other dermatophyte species, infections caused by T. indotineae often exhibit treatment failure with commonly prescribed antifungal drugs. Reduced susceptibility to terbinafine is often observed in T. indotineae . In addition, reduced susceptibility to itraconazole has also been reported. Due to the extensive and persistent nature of the infection, as well as the reduced susceptibility to antifungal drugs, international experts recommend aggressive treatment of T. indotineae using a combination of oral and topical antifungals. Susceptibility testing may be warranted to guide treatment decisions. Early recognition of T. indotineae infections is crucial to prevent prolonged recurrences.
- Published
- 2024
3. Azole Resistance in Veterinary Clinical Aspergillus fumigatus Isolates in the Netherlands.
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van Dijk MAM, Buil JB, Tehupeiory-Kooreman M, Broekhuizen MJ, Broens EM, Wagenaar JA, and Verweij PE
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- Animals, Netherlands epidemiology, Retrospective Studies, Fungal Proteins genetics, Birds microbiology, Cats, Dogs, Cytochrome P-450 Enzyme System, Aspergillus fumigatus drug effects, Aspergillus fumigatus genetics, Aspergillus fumigatus isolation & purification, Azoles pharmacology, Drug Resistance, Fungal genetics, Aspergillosis microbiology, Aspergillosis veterinary, Antifungal Agents pharmacology, Microbial Sensitivity Tests
- Abstract
Aspergillus fumigatus is a saprophytic fungal pathogen that causes opportunistic infections in animals and humans. Azole resistance has been reported globally in human A. fumigatus isolates, but the prevalence of resistance in isolates from animals is largely unknown. A retrospective resistance surveillance study was performed using a collection of clinical A. fumigatus isolates from various animal species collected between 2015 and 2020. Agar-based azole resistance screening of all isolates was followed by in vitro antifungal susceptibility testing and cyp51A gene sequencing of the azole-resistant isolates. Over the 5 year period 16 (11.3%) of 142 A. fumigatus culture-positive animals harbored an azole-resistant isolate. Resistant isolates were found in birds (15%; 2/13), cats (21%; 6/28), dogs (8%; 6/75) and free-ranging harbor porpoise (33%; 2/6). Azole-resistance was cyp51A mediated in all isolates: 81.3% (T-67G/)TR
34 /L98H, 12.5% TR46 /Y121F/T289A. In one azole-resistant A. fumigatus isolate a combination of C(-70)T/F46Y/C(intron7)T/C(intron66)T/M172V/E427K single-nucleotide polymorphisms in the cyp51A gene was found. Of the animals with an azole-resistant isolate and known azole exposure status 71.4% (10/14) were azole naive. Azole resistance in A. fumigatus isolates from animals in the Netherlands is present and predominantly cyp51A TR-mediated, supporting an environmental route of resistance selection. Our data supports the need to include veterinary isolates in resistance surveillance programs. Veterinarians should consider azole resistance as a reason for therapy failure when treating aspergillosis and consider resistance testing of relevant isolates., (© 2024. The Author(s).)- Published
- 2024
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4. The yeast genus Tardiomyces gen. nov. with one new species and two new combinations.
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Spruijtenburg B, de Souza Lima BJF, Tosar STG, Borman AM, Andersen CT, Nizamuddin S, Ahmad S, de Almeida Junior JN, Vicente VA, Nosanchuk JD, Buil JB, de Hoog S, Meijer EFJ, Meis JF, and de Groot T
- Abstract
Purpose: Rare yeasts species are increasingly reported as causative agents of invasive human infection. Proper identification and antifungal therapy are essential to manage these infections. Candida blankii is one of these emerging pathogens and is known for its reduced susceptibility to multiple antifungals., Methods: To obtain more insight into the characteristics of this species, 26 isolates reported as C. blankii were investigated using genetic and phenotypical approaches., Results: Among the 26 isolates, seven recovered either from blood, sputum, urine, or the oral cavity, displayed substantial genetic and some phenotypical differences compared to the other isolates, which were confirmed as C. blankii. We consider these seven strains to represent a novel species, Tardiomyces depauwii. Phylogenomics assigned C. blankii, C. digboiensis, and the novel species in a distinct branch within the order Dipodascales, for which the novel genus Tardiomyces is erected. The new combinations Tardiomyces blankii and Tardiomyces digboiensis are introduced. Differences with related, strictly environmental genera Sugiyamaella, Crinitomyces, and Diddensiella are enumerated. All three Tardiomyces species share the rare ability to grow up to 42 °C, display slower growth in nutrient-poor media, and show a reduced susceptibility to azoles and echinocandins. Characteristics of T. depauwii include high MIC values with voriconazole and a unique protein pattern., Conclusion: We propose the novel yeast species Tardiomyces depauwii and the transfer of C. blankii and C. digboiensis to the novel Tardiomyces genus., (© 2024. The Author(s).)
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- 2024
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5. Antifungal Resistance in Pulmonary Aspergillosis.
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Verweij PE, Song Y, Buil JB, Zhang J, and Melchers WJG
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- Humans, Antifungal Agents pharmacology, Antifungal Agents therapeutic use, Aspergillus fumigatus genetics, Aspergillus, Chronic Disease, Persistent Infection, Pulmonary Aspergillosis drug therapy, Pulmonary Aspergillosis diagnosis, Pulmonary Aspergillosis microbiology, Aspergillosis, Allergic Bronchopulmonary drug therapy, Cystic Fibrosis drug therapy
- Abstract
Aspergilli may cause various pulmonary diseases in humans, including allergic bronchopulmonary aspergillosis (ABPA), chronic pulmonary aspergillosis (CPA), and acute invasive pulmonary aspergillosis (IPA). In addition, chronic colonization may occur in cystic fibrosis (CF). Aspergillus fumigatus represents the main pathogen, which may employ different morphotypes, for example, conidia, hyphal growth, and asexual sporulation, in the various Aspergillus diseases. These morphotypes determine the ease by which A. fumigatus can adapt to stress by antifungal drug exposure, usually resulting in one or more resistance mutations. Key factors that enable the emergence of resistance include genetic variation and selection. The ability to create genetic variation depends on the reproduction mode, including, sexual, parasexual, and asexual, and the population size. These reproduction cycles may take place in the host and/or in the environment, usually when specific conditions are present. Environmental resistance is commonly characterized by tandem repeat (TR)-mediated mutations, while in-host resistance selection results in single-resistance mutations. Reported cases from the literature indicate that environmental resistance mutations are almost exclusively present in patients with IA indicating that the risk for in-host resistance selection is very low. In aspergilloma, single-point mutations are the dominant resistance genotype, while in other chronic Aspergillus diseases, for example, ABPA, CPA, and CF, both TR-mediated and single-resistance mutations are reported. Insights into the pathogenesis of resistance selection in various Aspergillus diseases may help to improve diagnostic and therapeutic strategies., Competing Interests: None declared., (Thieme. All rights reserved.)
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- 2024
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6. Fungi involved in rhinosinusitis in arid regions: insights from molecular identification and antifungal susceptibility.
- Author
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Zhou S, Ismail MAI, Buil JB, Gabr A, Verweij PE, Mahgoub ES, de Hoog S, Kang Y, and Ahmed SA
- Abstract
Fungal rhinosinusitis (FRS) is a common problem worldwide, with an increasing burden in arid climate regions. Aspergillus species are the most common causative agents involved. In the present study, we investigated the prevalence, molecular characterization, and antifungal susceptibility of opportunists causing FRS in Sudan on the basis of strains collected over a period of 5 years. β-Tubulin and calmodulin sequencing were used for species identification, and antifungal susceptibility profiles were evaluated by the protocol of the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Predominant species belonged to the Aspergillus flavus complex ( n = 244), A. terreus complex ( n = 16), A. fumigatus complex ( n = 7), and other fungi ( n = 17). Molecular identification of 94 strains of Aspergillus revealed the following species: A. flavus ( n = 88), A. terreus ( n = 1), A. citrinoterreus ( n = 2), A. fumigatus ( n = 1), A. caespitosus ( n = 1), and A. sydowii ( n = 1). Several A. flavus and an A. fumigatus isolates showed reduced susceptibility to azoles (minimum inhibitory concentrations above the clinical breakpoints or epidemiological cutoff values). Despite several mutations revealed in cyp51A of these isolates, none could be directly linked to azole resistance. Molecular identification of fungi causing FRS is useful to identify cryptic species and for epidemiologic studies. IMPORTANCE Fungal rhinosinusitis (FRS) is a significant clinical problem in arid regions. This study provides new insights into the prevalence, etiology, and antifungal susceptibility of FRS pathogens in Sudan, where the disease burden is high. Aspergillus species, particularly the A. flavus complex, were identified as the primary FRS pathogens in the region, with some evidence of antifungal resistance. The molecular identification of fungal species causing FRS is useful for detecting antifungal resistance, identifying cryptic species, and characterizing the epidemiology of the disease. The emergence of Azole resistance Aspergilli in Sudan highlights the need for continued surveillance and appropriate use of antifungal agents. These findings have important implications for clinical management, public health policy, and future research on FRS. Publishing this study in Microbiology Spectrum would enable other researchers and clinicians to build on these findings, ultimately improving the diagnosis, treatment, and prevention of FRS.
- Published
- 2023
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7. Clinical Impact of Polymerase Chain Reaction-Based Aspergillus and Azole Resistance Detection in Invasive Aspergillosis: A Prospective Multicenter Study.
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Huygens S, Dunbar A, Buil JB, Klaassen CHW, Verweij PE, van Dijk K, de Jonge N, Janssen JJWM, van der Velden WJFM, Biemond BJ, Bart A, Bruns AHW, Haas PA, Demandt AMP, Oudhuis G, von dem Borne P, van der Beek MT, Klein SK, Godschalk P, Span LFR, Postma DF, Kampinga GA, Maertens J, Lagrou K, Mercier T, Moors I, Boelens J, Selleslag D, Reynders M, Zandijk W, Doorduijn JK, Cornelissen JJ, Schauwvlieghe AFAD, and Rijnders BJA
- Subjects
- Humans, Prospective Studies, Azoles pharmacology, Azoles therapeutic use, Aspergillus, Aspergillus fumigatus, Real-Time Polymerase Chain Reaction methods, Triazoles pharmacology, Triazoles therapeutic use, Antifungal Agents pharmacology, Antifungal Agents therapeutic use, Drug Resistance, Fungal, Invasive Pulmonary Aspergillosis diagnosis, Invasive Pulmonary Aspergillosis drug therapy, Invasive Pulmonary Aspergillosis microbiology, Aspergillosis diagnosis, Aspergillosis drug therapy, Aspergillosis microbiology, Invasive Fungal Infections diagnosis, Invasive Fungal Infections drug therapy
- Abstract
Background: Invasive aspergillosis (IA) by a triazole-resistant Aspergillus fumigatus is associated with high mortality. Real-time resistance detection will result in earlier initiation of appropriate therapy., Methods: In a prospective study, we evaluated the clinical value of the AsperGenius polymerase chain reaction (PCR) assay in hematology patients from 12 centers. This PCR assay detects the most frequent cyp51A mutations in A. fumigatus conferring azole resistance. Patients were included when a computed tomography scan showed a pulmonary infiltrate and bronchoalveolar fluid (BALf) sampling was performed. The primary end point was antifungal treatment failure in patients with azole-resistant IA., Results: Of 323 patients enrolled, complete mycological and radiological information was available for 276 (94%), and probable IA was diagnosed in 99/276 (36%). Sufficient BALf for PCR testing was available for 293/323 (91%). Aspergillus DNA was detected in 116/293 (40%) and A. fumigatus DNA in 89/293 (30%). The resistance PCR was conclusive in 58/89 (65%) and resistance detected in 8/58 (14%). Two had a mixed azole-susceptible/azole-resistant infection. In the 6 remaining patients, treatment failure was observed in 1. Galactomannan positivity was associated with mortality (P = .004) while an isolated positive Aspergillus PCR was not (P = .83)., Conclusions: Real-time PCR-based resistance testing may help to limit the clinical impact of triazole resistance. In contrast, the clinical impact of an isolated positive Aspergillus PCR on BALf seems limited. The interpretation of the EORTC/MSGERC PCR criterion for BALf may need further specification (eg, minimum cycle threshold value and/or PCR positive on >1 BALf sample)., Competing Interests: Potential conflicts of interest J. M. reports grants from Gilead Sciences, Inc; consulting fees, payment for lectures/presentations, and support for meetings/travel expenses from Gilead Sciences, Inc, MSD, Pfizer, Takeda, and F2G; and participation on a data safety monitoring board or advisory board for Gilead Sciences, Inc, MSD, Pfizer, Takeda, F2G, and Cidara. P. G. reports partial support for travel to Trends In Medical Mycology conference. K. L. reports grants from Thermo Fisher Scientific and TECOmedical paid to their institution; consulting fees from Gilead, MSD, and MRM Health, all paid to their institution; and personal fees for lectures/presentations for Pfizer, Gilead, and FUJIFILM Wako. M. R. reports support for travel to Trends In Medical Mycology conference. J. J. reports grants from Novartis and BMS, both paid to their institution; payment for lectures from AbbVie, Novartis, Pfizer, and Incyte; and serving as president of the Apps for Care and Science, a nonprofit organization, supported by AbbVie, Alexion, Amgen, Astellas, BMS, Daiichi-Sankyo, Janssen-Cilag, Olympus, Incyte, Sanofi Genzyme, Servier, Jazz, and Takeda. J. B. reports research grants from Gilead Sciences, Inc, and F2G. P. V. reports research grants from F2G and Gilead, paid to their institution; honoraria for lectures from F2G, Gilead, and Pfizer, all paid to their institution; and participation on a data safety monitoring board for F2G, paid to their institution. S. H. reports support from Gilead for travel to the International Society for Human and Animal Mycology 2022 conference. B. R. reports research grants from Gilead Sciences, Inc; support for meetings/travel expenses from Gilead Sciences, Inc, F2G, and Pfizer; consulting fees from F2G; payment/honoraria for lectures/presentations from Gilead Sciences, Inc; and participation on a data safety monitoring board/advisory board for Exevir. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
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- 2023
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8. Targeting the 16S rRNA Gene by Reverse Complement PCR Next-Generation Sequencing: Specific and Sensitive Detection and Identification of Microbes Directly in Clinical Samples.
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Moorlag SJCFM, Coolen JPM, van den Bosch B, Jin EH, Buil JB, Wertheim HFL, and Melchers WJG
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- Humans, RNA, Ribosomal, 16S genetics, Genes, rRNA, Sequence Analysis, DNA methods, Polymerase Chain Reaction methods, High-Throughput Nucleotide Sequencing methods, DNA, Bacterial genetics, Bacteria, Bacterial Infections microbiology
- Abstract
The detection and accurate identification of bacterial species in clinical samples are crucial for diagnosis and appropriate antibiotic treatment. To date, sequencing of the 16S rRNA gene has been widely used as a complementary molecular approach when identification by culture fails. The accuracy and sensitivity of this method are highly affected by the selection of the 16S rRNA gene region targeted. In this study, we assessed the clinical utility of 16S rRNA reverse complement PCR (16S RC-PCR), a novel method based on next-generation sequencing (NGS), for the identification of bacterial species. We investigated the performance of 16S RC-PCR on 11 bacterial isolates, 2 polymicrobial community samples, and 59 clinical samples from patients suspected of having a bacterial infection. The results were compared to culture results, if available, and to the results of Sanger sequencing of the 16S rRNA gene (16S Sanger sequencing). By 16S RC-PCR, all bacterial isolates were accurately identified to the species level. Furthermore, in culture-negative clinical samples, the rate of identification increased from 17.1% (7/41) to 46.3% (19/41) when comparing 16S Sanger sequencing to 16S RC-PCR. We conclude that the use of 16S RC-PCR in the clinical setting leads to an increased sensitivity of detection of bacterial pathogens, resulting in a higher number of diagnosed bacterial infections, and thereby can improve patient care. IMPORTANCE The identification of the causative infectious pathogen in patients suspected of having a bacterial infection is essential for diagnosis and the start of appropriate treatment. Over the past 2 decades, molecular diagnostics have improved the ability to detect and identify bacteria. However, novel techniques that can accurately detect and identify bacteria in clinical samples and that can be implemented in clinical diagnostics are needed. Here, we demonstrate the clinical utility of bacterial identification in clinical samples by a novel method called 16S RC-PCR. Using 16S RC-PCR, we reveal a significant increase in the number of clinical samples in which a potentially clinically relevant pathogen is identified compared to the commonly used 16S Sanger method. Moreover, RC-PCR allows automation and is well suited for implementation in a diagnostic laboratory. In conclusion, the implementation of this method as a diagnostic tool is expected to result in an increased number of diagnosed bacterial infections, and in combination with adequate treatment, this could improve clinical outcomes for patients., Competing Interests: The authors declare no conflict of interest.
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- 2023
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9. Emergence of invasive infections with Magnusiomyces species in AML patients in a single center: a possible relationship with echinocandin prophylaxis.
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Molendijk EBD, van der Velden WJFM, Aarntzen EHJG, Coolen JPM, Blijlevens NMA, and Buil JB
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- Humans, Antifungal Agents therapeutic use, Microbial Sensitivity Tests, Echinocandins therapeutic use, Leukemia, Myeloid, Acute complications, Leukemia, Myeloid, Acute drug therapy
- Published
- 2023
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10. Retrospective Multicenter Evaluation of the VirClia Galactomannan Antigen Assay for the Diagnosis of Pulmonary Aspergillosis with Bronchoalveolar Lavage Fluid Samples from Patients with Hematological Disease.
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Buil JB, Huygens S, Dunbar A, Schauwvlieghe A, Reynders M, Langerak D, van Dijk K, Bruns A, Haas PJ, Postma DF, Biemond B, Delma FZ, de Kort E, Melchers WJG, Verweij PE, and Rijnders B
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- Humans, Retrospective Studies, Bronchoalveolar Lavage Fluid microbiology, Mannans analysis, Sensitivity and Specificity, Pulmonary Aspergillosis, Invasive Pulmonary Aspergillosis diagnosis, Hematologic Diseases
- Abstract
Galactomannan (GM) testing of bronchoalveolar lavage (BAL) fluid samples has become an essential tool to diagnose invasive pulmonary aspergillosis (IPA) and is part of diagnostic guidelines. Enzyme-linked immunosorbent assays (ELISAs) (enzyme immunoassays [EIAs]) are commonly used, but they have a long turnaround time. In this study, we evaluated the performance of an automated chemiluminescence immunoassay (CLIA) with BAL fluid samples. This was a multicenter retrospective study in the Netherlands and Belgium. BAL fluid samples were collected from patients with underlying hematological diseases with a suspected invasive fungal infection. Diagnosis of IPA was based on the 2020 European Organisation for Research and Treatment of Cancer (EORTC)/Mycoses Study Group Education and Research Consortium (MSGERC) consensus definitions. GM results were reported as optical density index (ODI) values. ODI cutoff values for positive results that were evaluated were 0.5, 0.8, and 1.0 for the EIA and 0.16, 0.18, and 0.20 for the CLIA. Probable IPA cases were compared with two control groups, one with no evidence of IPA and another with no IPA or possible IPA. Qualitative agreement was analyzed using Cohen's κ, and quantitative agreement was analyzed by Spearman's correlation. We analyzed 141 BAL fluid samples from 141 patients; 66 patients (47%) had probable IPA, and 56 cases remained probable IPA when the EIA GM result was excluded as a criterion, because they also had positive culture and/or duplicate positive PCR results. Sixty-three patients (45%) had possible IPA and 12 (8%) had no IPA. The sensitivity and specificity of the two tests were quite comparable, and the overall qualitative agreement between EIA and CLIA results was 81 to 89%. The correlation of the actual CLIA and EIA values was strong at 0.72 (95% confidence interval, 0.63 to 0.80). CLIA has similar performance, compared to the gold-standard EIA, with the benefits of faster turnaround because batching is not required. Therefore, CLIA can be used as an alternative GM assay for BAL fluid samples., Competing Interests: The authors declare a conflict of interest. J.B.B. received research grants from Gilead Sciences and F2G Ltd. E.d.K. received a research grant from Gilead Sciences. B.R. received a research grant from Gilead Sciences. He received consulting fees from F2G Ltd and support for meetings from Pfizer, Gilead Sciences an F2G Ltd. S.H. declares to have received travel support from Gilead Sciences. P.E.V. reports grants received from Gilead Sciences, MSD, Pfizer, Mundipharma and F2G, and non-financial support from OLM and IMMY. B.R. participated in the DSMB by Exevir and received travel support to medical conferences by Gilead Sciences and Pfizer., A.S., P.-J.H., D.L., B.B., N.B. M.R., A.B., D.F.P., A.D., K.v.D., F.Z.D., W.J.G.M. declared to have no conflict of interests.
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- 2023
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11. Resistance profiling of Aspergillus fumigatus to olorofim indicates absence of intrinsic resistance and unveils the molecular mechanisms of acquired olorofim resistance.
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Buil JB, Oliver JD, Law D, Baltussen T, Zoll J, Hokken MWJ, Tehupeiory-Kooreman M, Melchers WJG, Birch M, and Verweij PE
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- Acetamides, Antifungal Agents pharmacology, Fungal Proteins genetics, Microbial Sensitivity Tests, Piperazines, Pyrroles, Aspergillus fumigatus genetics, Pyrimidines pharmacology
- Abstract
Olorofim (F901318) is a new antifungal currently under clinical development that shows both in vitro and in vivo activity against a number of filamentous fungi including Aspergillus fumigatus . In this study, we screened A. fumigatus isolates for intrinsic olorofim-resistant A. fumigatus and evaluated the ability of A. fumigatus to acquire an olorofim-resistant phenotype. No intrinsic resistance was found in 975 clinical A. fumigatus isolates. However, we found that isolates with increased olorofim MICs (> 8 mg/L) could be selected using a high number of conidia and olorofim exposure under laboratory conditions. Assessment of the frequency of acquired olorofim resistance development of A. fumigatus was shown to be higher than for voriconazole but lower than for itraconazole. Sequencing the PyrE gene of isogenic isolates with olorofim MICs of >8 mg/L identified various amino acid substitutions with a hotspot at locus G119. Olorofim was shown to have reduced affinity to mutated target protein dihydroorotate dehydrogenase (DHODH) and the effect of these mutations was proven by introducing the mutations directly in A. fumigatus . We then investigated whether G119 mutations were associated with a fitness cost in A. fumigatus. These experiments showed a small but significant reduction in growth rate for strains with a G119V substitution, while strains with a G119C substitution did not exhibit a reduction in growth rate. These in vitro findings were confirmed in an in vivo pathogenicity model.
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- 2022
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12. Olecranon bursitis caused by Scedosporium apiospermum in a patient treated with CAR-T cells.
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Falkenburg WJJ, Jalink M, Kersten MJ, Buil JB, and van Dijk K
- Abstract
Chimeric antigen receptor (CAR-) T cell therapy is a relatively new form of immunotherapy for hematological malignancies. Although patients are at increased risk of infection following CAR-T cell therapy, reports of fungal infections are scarce. We report a case of Scedosporium apiospermum infection causing bursitis of the elbow in a lymphoma patient after treatment with CAR-T cells. The fungal bursitis relapsed under posaconazole treatment, but was cured after surgical extirpation of the bursa., (© 2022 The Authors.)
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- 2022
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13. Invasive Fungal Disease in Patients with Myeloid Malignancies: A Retrospective Cohort Study of a Diagnostic-Driven Care Pathway Withholding Mould-Active Prophylaxis.
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De Kort EA, Buil JB, Schalekamp S, Schaefer-Prokop C, Verweij PE, Schaap NPM, Blijlevens NMA, and Van der Velden WJFM
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Objectives: Patients receiving remission induction therapy for acute myeloid leukaemia (AML) are at high risk of developing invasive fungal disease (IFD). Newer therapies with targeted antileukemic agents and the emergence of azole resistance pose a challenge to the strategy of primary antifungal prophylaxis. We report the experience of a diagnostic-driven care pathway (DCP) for the management of IFD in these patients, using only culture-directed mould inactive prophylaxis., Methods: Retrospectively, we used a single-centre study of consecutive patients receiving intensive chemotherapy for myeloid malignancies between 2014 and 2021. DCP consisted of serial cultures and serum galactomannan (sGM) screening, CT imaging, and bronchoscopy to direct targeted antifungal treatment. IFD was classified according to the 2020 EORTC/MSGERC criteria., Results: A total of 192 patients with myeloid malignancies received 300 courses of intensive chemotherapy. There were 14 cases of invasive yeast infections and 18 of probable/proven invasive mould disease (IMD). The incidence of probable/proven IMD during the first cycle of remission-induction chemotherapy was 4.6% (n = 9). sGM remained negative in all cases of invasive aspergillosis (IA), with positive mycology findings in bronchoalveolar lavage. All-cause mortality was 9.4% (n = 18) 100 days after starting chemotherapy and was comparable between patients with or without IFD. The fungal-related mortality was 1% (n = 2)., Conclusion: Diagnostic-driven based management without universal mould active prophylaxis is a feasible strategy in the management of IFD and limits unnecessary antimould treatment during intensive chemotherapy. The poor performance of serial serum galactomannan screening in detecting IA warrants further investigation.
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- 2022
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14. Diagnosis, treatment and prognosis of otomastoiditis induced by Fusobacterium necrophorum: A retrospective multicentre cohort study.
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Thevis M, Leow TYS, Bekkers S, Otten J, Waterval JJ, Derks J, Buil JB, Kunst HPM, and Jansen TTG
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- Anti-Bacterial Agents therapeutic use, Child, Child, Preschool, Cohort Studies, Humans, Prognosis, Retrospective Studies, Fusobacterium Infections complications, Fusobacterium Infections diagnosis, Fusobacterium Infections drug therapy, Fusobacterium necrophorum
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Objectives: Otomastoiditis caused by the anaerobic Fusobacterium necrophorum (F. necrophorum) often induces severe complications, such as meningitis and sinus thrombosis. Early diagnosis is difficult, partly because little is known about specific early signs. Comprehensive research about clinically chosen antimicrobial therapy has not been done yet and prognostic information about otomastoiditis caused by F. necrophorum is scarce. More knowledge about this subject is required., Methods: In this retrospective cohort study, we included all cases of otomastoiditis caused by F. necrophorum treated in two university medical centres in the Netherlands during the past 10 years. Data was gathered from patient records and analysed using independent sample T-tests and Chi
2 -tests., Results: This study reveals that otomastoiditis caused by F. necrophorum potentially induces neurological sequelae. Thereby, 80% of all included patients (n = 16) needed readmission within six months due to recurrence or complications of otomastoiditis caused by F. necrophorum. Mean (range) of age, CRP and temperature were 4.5 years (0.9-29.3), 243 mg/L (113-423) and 40 °C (37-41). All patients were hospitalized and treated with antibiotics, mostly metronidazole (n = 13/16) and a β -lactam (n = 15/16). Additional treatment contained low molecular weight heparin (83%, n = 10/12), dexamethasone (78%, n = 7/9) and/or surgery (80%, n = 12/16, whereof 9/12 mastoidectomy)., Conclusions: Patients and/or their parents need to be informed about this potential unfortunate prognosis when otomastoiditis caused by F. necrophorum is diagnosed. To improve early diagnosis, otomastoiditis caused by F. necrophorum should be suspected and therefore immediately cultured when a) young children present with otomastoiditis, with b) high CRP values, and/or c) vomiting and decreased consciousness., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2022
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15. Absence of candidemia in critically ill patients with COVID-19 receiving selective digestive decontamination.
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Buil JB, Schouten JA, Wauters J, van de Hoeven H, and Verweij PE
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- Anti-Bacterial Agents therapeutic use, Critical Illness therapy, Decontamination, Digestive System, Gastrointestinal Tract, Humans, COVID-19, Candidemia drug therapy
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- 2022
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16. A 67-Year-Old Male Patient With COVID-19 With Worsening Respiratory Function and Acute Kidney Failure.
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Melchers M, Festen B, den Dekker BM, Mooren ERM, van Binsbergen AL, van Bree SHW, Heusinkveld M, Schellaars R, Buil JB, Verweij PE, and van Zanten ARH
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- Aged, Amphotericin B therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Atrial Fibrillation complications, Bronchoscopy, Dexamethasone therapeutic use, Diabetes Mellitus, Type 2 complications, Fatal Outcome, Humans, Leukemia, Lymphocytic, Chronic, B-Cell complications, Male, Nitriles therapeutic use, Obesity complications, Oxygen Inhalation Therapy, Pyridines therapeutic use, Respiration, Artificial, SARS-CoV-2, Smoking adverse effects, Tomography, X-Ray Computed, Triazoles therapeutic use, Voriconazole therapeutic use, Acute Kidney Injury virology, Antifungal Agents therapeutic use, COVID-19 complications, Mucormycosis diagnosis, Mucormycosis drug therapy, Pulmonary Aspergillosis diagnosis, Pulmonary Aspergillosis drug therapy
- Abstract
Case Presentation: A 67-year-old obese man (BMI 38.0) with type 2 diabetes mellitus (DM), chronic atrial fibrillation, and chronic lymphocytic leukemia stage II, stable for 8 years after chemotherapy, and a history of smoking presented to the ED with progressive dyspnea and fever due to SARS-CoV-2 infection. He was admitted to a general ward and treated with dexamethasone (6 mg IV once daily) and oxygen. On day 3 of hospital admission, he became progressively hypoxemic and was admitted to the ICU for invasive mechanical ventilation. Dexamethasone treatment was continued, and a single dose of tocilizumab (800 mg) was administered. On day 9 of ICU admission, voriconazole treatment was initiated after tracheal white plaques at bronchoscopy, suggestive of invasive Aspergillus tracheobronchitis, were noticed. However, his medical situation dramatically deteriorated., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2022
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17. [Terbinafine resistance explains treatment failure in a patient with tinea corporis].
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Buil JB, Bronckers IMGJ, Driessen RJB, Do Nguyen Dan T, Melchers WJG, and Verweij PE
- Subjects
- Antifungal Agents therapeutic use, Drug Resistance, Fungal, Humans, Terbinafine therapeutic use, Treatment Failure, Tinea drug therapy, Tinea epidemiology, Tinea microbiology
- Abstract
Background: Tinea corporis is a superficial fungal infection of the limbs, chest or back caused by dermatophytes. Local antifungal treatment is often sufficient to treat tinea corporis. Systemic treatment may be needed in more severe cases, in immunocompromised patients or when treatment failure is documented. Treatment failure is relative common and frequent causes are low compliance, low systemic antifungal drug concentrations, reduced penetration of topical agents or an immunocompromised status. Recently, antifungal resistance has been documented in dermatophytes., Case Description: We describe a patient with terbinafine treatment failure caused by antifungal drug resistance., Conclusion: The frequency of terbinafine resistance in the Netherlands is unknown as no surveillance is performed. Recent reports from both India and European countries indicate that antifungal resistance should be considered in patients with terbinafine treatment failure.
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- 2021
18. Aspergillus Test Profiles and Mortality in Critically Ill COVID-19 Patients.
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Ergün M, Brüggemann RJM, Alanio A, Dellière S, van Arkel A, Bentvelsen RG, Rijpstra T, van der Sar-van der Brugge S, Lagrou K, Janssen NAF, Buil JB, van Dijk K, Melchers WJG, Reijers MHE, Schouten JA, Wauters J, Cordey A, Soni S, White PL, van de Veerdonk FL, and Verweij PE
- Subjects
- Animals, Aspergillus, Case-Control Studies, Critical Illness, Humans, Mannans, SARS-CoV-2, COVID-19, Invasive Pulmonary Aspergillosis diagnosis
- Abstract
The literature regarding COVID-19-associated pulmonary aspergillosis (CAPA) has shown conflicting observations, including survival of CAPA patients not receiving antifungal therapy and discrepancy between CAPA diagnosis and autopsy findings. To gain insight into the pathophysiology of CAPA, we performed a case-control study in which we compared Aspergillus test profiles in CAPA patients and controls in relation to intensive care unit (ICU) mortality. This was a multinational case-control study in which Aspergillus test results, use of antifungal therapy, and mortality were collected from critically ill COVID-19 patients. Patients were classified using the 2020 European Confederation for Medical Mycology and the International Society for Human and Animal Mycology (ECMM/ISHAM) consensus case definitions. We analyzed 219 critically ill COVID-19 cases, including 1 proven, 38 probable, 19 possible CAPA cases, 21 Aspergillus-colonized patients, 7 patients only positive for serum (1,3)-β-d-glucan (BDG), and 133 cases with no evidence of CAPA. Mortality was 53.8% in CAPA patients compared to 24.1% in patients without CAPA ( P = 0.001). Positive serum galactomannan (GM) and BDG were associated with increased mortality compared to serum biomarker-negative CAPA patients (87.5% versus 41.7%, P = 0.046; 90.0% versus 42.1%, P = 0.029, respectively). For each point increase in GM or 10-point BDG serum concentration, the odds of death increased (GM, odds ratio [OR] 10.208, 95% confidence interval [CI], 1.621 to 64.291, P = 0.013; BDG, OR, 1.247, 95% CI, 1.029 to 1.511, P = 0.024). CAPA is a complex disease, probably involving a continuum of respiratory colonization, tissue invasion, and angioinvasion. Serum biomarkers are useful for staging CAPA disease progression and, if positive, indicate angioinvasion and a high probability of mortality. There is need for a biomarker that distinguishes between respiratory tract colonization and tissue-invasive CAPA disease.
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- 2021
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19. Multinational Observational Cohort Study of COVID-19-Associated Pulmonary Aspergillosis 1 .
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Janssen NAF, Nyga R, Vanderbeke L, Jacobs C, Ergün M, Buil JB, van Dijk K, Altenburg J, Bouman CSC, van der Spoel HI, Rijnders BJA, Dunbar A, Schouten JA, Lagrou K, Bourgeois M, Reynders M, van Regenmortel N, Rutsaert L, Lormans P, Feys S, Debavaye Y, Tamion F, Costa D, Maizel J, Dupont H, Chouaki T, Nseir S, Sendid B, Brüggemann RJM, van de Veerdonk FL, Wauters J, and Verweij PE
- Subjects
- Cohort Studies, Humans, SARS-CoV-2, COVID-19, Invasive Pulmonary Aspergillosis, Pulmonary Aspergillosis
- Abstract
We performed an observational study to investigate intensive care unit incidence, risk factors, and outcomes of coronavirus disease-associated pulmonary aspergillosis (CAPA). We found 10%-15% CAPA incidence among 823 patients in 2 cohorts. Several factors were independently associated with CAPA in 1 cohort and mortality rates were 43%-52%.
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- 2021
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20. Molecular Mechanisms of 5-Fluorocytosine Resistance in Yeasts and Filamentous Fungi.
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Delma FZ, Al-Hatmi AMS, Brüggemann RJM, Melchers WJG, de Hoog S, Verweij PE, and Buil JB
- Abstract
Effective management and treatment of fungal diseases is hampered by poor diagnosis, limited options for antifungal therapy, and the emergence of antifungal drug resistance. An understanding of molecular mechanisms contributing to resistance is essential to optimize the efficacy of currently available antifungals. In this perspective, one of the oldest antifungals, 5-fluorocytosine (5-FC), has been the focus of recent studies applying advanced genomic and transcriptomic techniques to decipher the order of events at the molecular level that lead to resistance. These studies have highlighted the complexity of resistance and provided new insights that are reviewed in the present paper.
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- 2021
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21. Taskforce report on the diagnosis and clinical management of COVID-19 associated pulmonary aspergillosis.
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Verweij PE, Brüggemann RJM, Azoulay E, Bassetti M, Blot S, Buil JB, Calandra T, Chiller T, Clancy CJ, Cornely OA, Depuydt P, Koehler P, Lagrou K, de Lange D, Lass-Flörl C, Lewis RE, Lortholary O, Liu PL, Maertens J, Nguyen MH, Patterson TF, Rijnders BJA, Rodriguez A, Rogers TR, Schouten JA, Wauters J, van de Veerdonk FL, and Martin-Loeches I
- Subjects
- Humans, Intensive Care Units, SARS-CoV-2, COVID-19, Invasive Pulmonary Aspergillosis diagnosis, Pulmonary Aspergillosis diagnosis, Pulmonary Aspergillosis drug therapy, Pulmonary Aspergillosis epidemiology
- 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., (© 2021. The Author(s).)
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- 2021
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22. A mould infection in disguise.
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Buil JB, Pickkers P, van der Lee HAL, and Verweij PE
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- Fatal Outcome, Female, Humans, Invasive Fungal Infections diagnosis, Invasive Fungal Infections microbiology, Scedosporium isolation & purification
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- 2021
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23. Case series of four secondary mucormycosis infections in COVID-19 patients, the Netherlands, December 2020 to May 2021.
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Buil JB, van Zanten ARH, Bentvelsen RG, Rijpstra TA, Goorhuis B, van der Voort S, Wammes LJ, Janson JA, Melchers M, Heusinkveld M, Melchers WJG, Kuijper EJ, and Verweij PE
- Subjects
- Female, Humans, Male, Netherlands epidemiology, SARS-CoV-2, COVID-19, Mucorales, Mucormycosis diagnosis
- Abstract
We describe four secondary fungal infections caused by Mucorales species in COVID-19 patients. Three COVID-19 associated mucormycosis (CAM) occurred in ICU, one outside ICU. All were men aged > 50 years, three died. Clinical presentations included pulmonary, rhino-orbital cerebral and disseminated infection. Infections occurred in patients with and without diabetes mellitus. CAM is an emerging disease and our observations underscore the need to be aware of invasive mucormycosis, including in COVID-19 patients without (poorly controlled) diabetes mellitus and outside ICU.
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- 2021
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24. Posaconazole for prevention of invasive pulmonary aspergillosis in critically ill influenza patients (POSA-FLU): a randomised, open-label, proof-of-concept trial.
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Vanderbeke L, Janssen NAF, Bergmans DCJJ, Bourgeois M, Buil JB, Debaveye Y, Depuydt P, Feys S, Hermans G, Hoiting O, van der Hoven B, Jacobs C, Lagrou K, Lemiale V, Lormans P, Maertens J, Meersseman P, Mégarbane B, Nseir S, van Oers JAH, Reynders M, Rijnders BJA, Schouten JA, Spriet I, Thevissen K, Thille AW, Van Daele R, van de Veerdonk FL, Verweij PE, Wilmer A, Brüggemann RJM, and Wauters J
- Subjects
- Adult, Critical Illness, Humans, Intensive Care Units, Triazoles, Influenza, Human complications, Influenza, Human drug therapy, Influenza, Human prevention & control, Invasive Pulmonary Aspergillosis drug therapy, Invasive Pulmonary Aspergillosis prevention & control
- Abstract
Purpose: Influenza-associated pulmonary aspergillosis (IAPA) is a frequent complication in critically ill influenza patients, associated with significant mortality. We investigated whether antifungal prophylaxis reduces the incidence of IAPA., Methods: We compared 7 days of intravenous posaconazole (POS) prophylaxis with no prophylaxis (standard-of-care only, SOC) in a randomised, open-label, proof-of-concept trial in patients admitted to an intensive care unit (ICU) with respiratory failure due to influenza (ClinicalTrials.gov, NCT03378479). Adult patients with PCR-confirmed influenza were block randomised (1:1) within 10 days of symptoms onset and 48 h of ICU admission. The primary endpoint was the incidence of IAPA during ICU stay in patients who did not have IAPA within 48 h of ICU admission (modified intention-to-treat (MITT) population)., Results: Eighty-eight critically ill influenza patients were randomly allocated to POS or SOC. IAPA occurred in 21 cases (24%), the majority of which (71%, 15/21) were diagnosed within 48 h of ICU admission, excluding them from the MITT population. The incidence of IAPA was not significantly reduced in the POS arm (5.4%, 2/37) compared with SOC (11.1%, 4/36; between-group difference 5.7%; 95% CI - 10.8 to 21.7; p = 0.32). ICU mortality of early IAPA was high (53%), despite rapid antifungal treatment., Conclusion: The higher than expected incidence of early IAPA precludes any definite conclusion on POS prophylaxis. High mortality of early IAPA, despite timely antifungal therapy, indicates that alternative management strategies are required. After 48 h, still 11% of patients developed IAPA. As these could benefit from prophylaxis, differentiated strategies are likely needed to manage IAPA in the ICU.
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- 2021
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25. Genetic and Phenotypic Characterization of in-Host Developed Azole-Resistant Aspergillus flavus Isolates.
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Buil JB, Houbraken J, Reijers MH, Zoll J, Sanguinetti M, Meis JF, Verweij PE, and Melchers WJG
- Abstract
Aspergillus flavus is a pathogenic fungal species that can cause pulmonary aspergillosis, and triazole compounds are used for the treatment of these infections. Prolonged exposure to azoles may select for compensatory mutations in the A. flavus genome, resulting in azole resistance. Here, we characterize a series of 11 isogenic A. flavus strains isolated from a patient with pulmonary aspergillosis. Over a period of three months, the initially azole-susceptible strain developed itraconazole and voriconazole resistance. Short tandem repeat analysis and whole-genome sequencing revealed the high genetic relatedness of all isolates, indicating an infection with one single isolate. In contrast, the isolates were macroscopically highly diverse, suggesting an adaptation to the environment due to (epi)genetic changes. The whole-genome sequencing of susceptible and azole-resistant strains showed a number of mutations that might be associated with azole resistance. The majority of resistant strains contain a Y119F mutation in the Cyp51A gene, which corresponds to the Y121F mutation found in A. fumigatus . One azole-resistant strain demonstrated a divergent set of mutations, including a V99A mutation in a major facilitator superfamily (MSF) multidrug transporter (AFLA 083950).
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- 2021
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26. Update on Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry Identification of Filamentous Fungi.
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Wilkendorf LS, Bowles E, Buil JB, van der Lee HAL, Posteraro B, Sanguinetti M, and Verweij PE
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- Humans, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Clinical Laboratory Services, Fungi
- Abstract
Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS)-based species identification has found its place in many clinical routine diagnostic laboratories over the past years, allowing significantly reduced turnaround times and high-precision results. With regard to MALDI-TOF MS for filamentous fungi, here, we discuss different approaches for sample processing and growth conditions before analysis. In particular, we review the performances of different commercially available databases as well as the potential of complementary (self-constructed) in-house databases., (Copyright © 2020 American Society for Microbiology.)
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- 2020
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27. A Multidisciplinary Approach to Fungal Infections: One-Year Experiences of a Center of Expertise in Mycology.
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Janssen NAF, Brüggemann RJM, Reijers MH, Henriet SSV, Ten Oever J, de Mast Q, Berk Y, de Kort EA, Kullberg BJ, Netea MG, Buil JB, Rahamat-Langendoen JC, Bury D, Muilwijk EW, Meis JF, Verweij PE, and van de Veerdonk FL
- Abstract
Invasive fungal diseases (IFDs) often represent complicated infections in complex patient populations. The Center of Expertise in Mycology Radboudumc/CWZ (EMRC) organizes a biweekly multidisciplinary mycology meeting to discuss patients with severe fungal infections and to provide comprehensive advice regarding diagnosis and treatment. Here, we describe the patient population discussed at these meetings during a one-year period with regards to their past medical history, diagnosis, microbiological and other diagnostic test results and antifungal therapy. The majority of patients discussed were adults (83.1%), 62.5% of whom suffered from pulmonary infections or signs/symptoms, 10.9% from otorhinolaryngeal infections and/or oesophagitis, 9.4% from systemic infections and 9.4% from central nervous system infections. Among children, 53.8% had pulmonary infections or signs/symptoms, 23.1% systemic fungal infections and 23.1% other, miscellaneous fungal infections. 52.5% of adult patients with pulmonary infections/symptoms fulfilled diagnostic criteria for chronic pulmonary aspergillosis (CPA). Culture or polymerase chain reaction (PCR) demonstrated fungal pathogens in 81.8% of patients, most commonly Aspergillus . A multidisciplinary mycology meeting can be a useful addition to the care for patients with (I)FDs and can potentially aid in identifying healthcare and research needs regarding the field of fungal infections. The majority of patients discussed at the multidisciplinary meetings suffered from pulmonary infections, predominantly CPA.
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- 2020
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28. In vitro interaction of isavuconazole and anidulafungin against azole-susceptible and azole-resistant Aspergillus fumigatus isolates.
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Buil JB, Brüggemann RJM, Bedin Denardi L, Melchers WJG, and Verweij PE
- Subjects
- Anidulafungin, Antifungal Agents pharmacology, Antifungal Agents therapeutic use, Drug Resistance, Fungal, Fungal Proteins, Humans, Microbial Sensitivity Tests, Nitriles, Pyridines, Triazoles, Aspergillus fumigatus genetics, Azoles pharmacology
- Abstract
Background: The voriconazole and echinocandin combination has been found to be synergistic in vitro and in vivo against most Aspergillus fumigatus isolates, both with a WT azole phenotype and an azole-resistant phenotype. The interaction between isavuconazole and echinocandins is less well studied. This is especially true for azole-resistant isolates., Objectives: We investigated the in vitro interaction between isavuconazole and anidulafungin for 30 A. fumigatus isolates including 18 azole-resistant isolates with various isavuconazole resistance phenotypes., Methods: The isavuconazole/anidulafungin interaction was studied by using an adapted EUCAST-based 2D (12 × 8) chequerboard broth microdilution colorimetric assay using XTT. The interaction was analysed by FIC index (FICi) analysis and Bliss independence (BI) interaction analysis., Results: Both the FICi analysis and the BI analysis showed synergistic interaction between isavuconazole and anidulafungin for the majority of WT and azole-resistant isolates. As we did not see significant beneficial effects of combination therapy in TR46/Y121F/T289A isolates at clinically achievable drug concentrations, it is unlikely that TR46/Y121F/T289A infections would benefit from isavuconazole and anidulafungin combination therapy., Conclusions: In regions with high azole resistance rates this combination may benefit patients with WT disease, azole-resistant invasive aspergillosis and those with mixed azole-susceptible and azole-resistant infection, but may not be beneficial for aspergillosis due to isolates with high isavuconazole resistance, such as TR46/Y121F/T289A isolates., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)
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- 2020
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29. Paradoxal Trends in Azole-Resistant Aspergillus fumigatus in a National Multicenter Surveillance Program, the Netherlands, 2013-2018.
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Lestrade PPA, Buil JB, van der Beek MT, Kuijper EJ, van Dijk K, Kampinga GA, Rijnders BJA, Vonk AG, de Greeff SC, Schoffelen AF, van Dissel J, Meis JF, Melchers WJG, and Verweij PE
- Subjects
- Antifungal Agents pharmacology, Antifungal Agents therapeutic use, Drug Resistance, Fungal, Fungal Proteins genetics, Humans, Microbial Sensitivity Tests, Netherlands epidemiology, Aspergillus fumigatus genetics, Azoles pharmacology
- Abstract
We investigated the prevalence of azole resistance of Aspergillus fumigatus isolates in the Netherlands by screening clinical A. fumigatus isolates for azole resistance during 2013-2018. We analyzed azole-resistant isolates phenotypically by in vitro susceptibility testing and for the presence of resistance mutations in the Cyp51A gene. Over the 6-year period, 508 (11%) of 4,496 culture-positive patients harbored an azole-resistant isolate. Resistance frequency increased from 7.6% (95% CI 5.9%-9.8%) in 2013 (58/760 patients) to 14.7% (95% CI 12.3%-17.4%) in 2018 (112/764 patients) (p = 0.0001). TR
34 /L98H (69%) and TR46 /Y121F/T289A (17%) accounted for 86% of Cyp51A mutations. However, the mean voriconazole MIC of TR34 /L98H isolates decreased from 8 mg/L (2013) to 2 mg/L (2018), and the voriconazole-resistance frequency was 34% lower in 2018 than in 2013 (p = 0.0001). Our survey showed changing azole phenotypes in TR34 /L98H isolates, which hampers the use of current PCR-based resistance tests.- Published
- 2020
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30. Azole-Resistant COVID-19-Associated Pulmonary Aspergillosis in an Immunocompetent Host: A Case Report.
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Meijer EFJ, Dofferhoff ASM, Hoiting O, Buil JB, and Meis JF
- Abstract
COVID-19-associated pulmonary aspergillosis (CAPA) is a recently described disease entity affecting patients with severe pulmonary abnormalities treated in intensive care units. Delays in diagnosis contribute to a delayed start of antifungal therapy. In addition, the emergence of resistance to triazole antifungal agents puts emphasis on early surveillance for azole-resistant Aspergillus species. We present a patient with putative CAPA due to Aspergillus fumigatus with identification of a triazole-resistant isolate during therapy. We underline the challenges faced in the management of these cases, the importance of early diagnosis and need for surveillance given the emergence of triazole resistance.
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- 2020
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31. Burden of serious fungal infections in the Netherlands.
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Buil JB, Meijer EFJ, Denning DW, Verweij PE, and Meis JF
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- Candidiasis epidemiology, Candidiasis, Vulvovaginal epidemiology, Cryptococcosis epidemiology, Female, Humans, Incidence, Invasive Fungal Infections etiology, Invasive Pulmonary Aspergillosis epidemiology, Morbidity, Mucormycosis epidemiology, Netherlands epidemiology, Prevalence, Cost of Illness, Invasive Fungal Infections epidemiology
- Abstract
Background: Fungal diseases have an ever-increasing global disease burden, although regional estimates for specific fungal diseases are often unavailable or dispersed., Objectives: Here, we report the current annual burden of life-threatening and debilitating fungal diseases in the Netherlands., Methods: The most recent available epidemiological data, reported incidence and prevalence of fungal diseases were used for calculations., Results: Overall, we estimate that the annual burden of serious invasive fungal infections in the Netherlands totals 3 185 patients, including extrapulmonary or disseminated cryptococcosis (n = 9), pneumocystis pneumonia (n = 740), invasive aspergillosis (n = 1 283), chronic pulmonary aspergillosis (n = 257), invasive Candida infections (n = 684), mucormycosis (n = 15) and Fusarium keratitis (n = 8). Adding the prevalence of recurrent vulvo-vaginal candidiasis (n = 220 043), allergic bronchopulmonary aspergillosis (n = 13 568) and severe asthma with fungal sensitisation (n = 17 695), the total debilitating burden of fungal disease in the Netherlands is 254 491 patients yearly, approximately 1.5% of the country's population., Conclusion: We estimated the annual burden of serious fungal infections in the Netherlands at 1.5% of the population based on previously reported modelling of fungal rates for specific populations at risk. With emerging new risk groups and increasing reports on antifungal resistance, surveillance programmes are warranted to obtain more accurate estimates of fungal disease epidemiology and associated morbidity and mortality., (© 2020 The Authors. Mycoses published by Blackwell Verlag GmbH.)
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- 2020
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32. Pharmacokinetics and Pharmacodynamics of Posaconazole.
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Chen L, Krekels EHJ, Verweij PE, Buil JB, Knibbe CAJ, and Brüggemann RJM
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- Administration, Oral, Animals, Antifungal Agents administration & dosage, Antifungal Agents adverse effects, Drug Compounding, Humans, Injections, Intravenous, Triazoles administration & dosage, Triazoles adverse effects, Antifungal Agents pharmacokinetics, Aspergillosis drug therapy, Triazoles pharmacokinetics
- Abstract
Posaconazole is typically used for preventing invasive yeast and mold infections such as invasive aspergillosis in high-risk immunocompromised patients. The oral suspension was the first released formulation and many pharmacokinetic and pharmacodynamic studies of this formulation have been published. Erratic absorption profiles associated with this formulation were widely reported. Posaconazole exposure was found to be significantly influenced by food and many gastrointestinal conditions, including pH and motility. As a result, low posaconazole plasma concentrations were obtained in large groups of patients. These issues of erratic absorption urged the development of the subsequently marketed delayed-release tablet, which proved to be associated with higher and more stable exposure profiles. Shortly thereafter, an intravenous formulation was released for patients who are not able to take oral formulations. Both new formulations require a loading dose on day 1 to achieve high posaconazole concentrations more quickly, which was not possible with the oral suspension. So far, there appears to be no evidence of increased toxicity correlated to the higher posaconazole exposure achieved with the regimen for these formulations. The higher systemic availability of posaconazole for the delayed-release tablet and intravenous formulation have resulted in these two formulations being preferable for both prophylaxis and treatment of invasive fungal disease. This review aimed to integrate the current knowledge on posaconazole pharmacokinetics, pharmacodynamics, major toxicity, existing resistance, clinical experience in special populations, and new therapeutic strategies in order to get a clear understanding of the clinical use of this drug.
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- 2020
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33. Comparison of MIC Test Strip and Sensititre YeastOne with the CLSI and EUCAST Broth Microdilution Reference Methods for In Vitro Antifungal Susceptibility Testing of Cryptococcus neoformans.
- Author
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Delma FZ, Al-Hatmi AMS, Buil JB, van der Lee H, Tehupeiory-Kooreman M, de Hoog GS, Meletiadis J, and Verweij PE
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- Cryptococcosis microbiology, Cryptococcus neoformans isolation & purification, Humans, Microbial Sensitivity Tests standards, Time Factors, Antifungal Agents pharmacology, Cryptococcus neoformans drug effects, Microbial Sensitivity Tests methods
- Abstract
We compared MIC test strip (MTS) and Sensititre YeastOne (SYO) methods with EUCAST and CLSI methods for amphotericin B, 5-fluocytosine, fluconazole, voriconazole, and isavuconazole against 106 Cryptococcus neoformans isolates. The overall essential agreement between the EUCAST and CLSI methods was >72% and >94% at ±1 and ±2 dilutions, respectively. The essential agreements between SYO and EUCAST/CLSI for amphotericin B, 5-flucytosine, fluconazole, and voriconazole were >89/>93% and between MTS and EUCAST/CLSI were >57/>75%. Very major error rates were low for amphotericin B and fluconazole (<3%) and a bit higher for the other drugs (<8%)., (Copyright © 2020 American Society for Microbiology.)
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- 2020
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34. High-dose posaconazole for azole-resistant aspergillosis and other difficult-to-treat mould infections.
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Schauwvlieghe AFAD, Buil JB, Verweij PE, Hoek RAS, Cornelissen JJ, Blijlevens NMA, Henriet SSV, Rijnders BJA, and Brüggemann RJM
- Subjects
- Adolescent, Adult, Aged, Antifungal Agents administration & dosage, Antifungal Agents adverse effects, Azoles pharmacology, Cytochrome P-450 Enzyme System genetics, Dose-Response Relationship, Drug, Drug Resistance, Fungal, Fungal Proteins genetics, Humans, Likelihood Functions, Middle Aged, Mutation, Probability, Retrospective Studies, Surveys and Questionnaires, Triazoles administration & dosage, Triazoles adverse effects, Antifungal Agents therapeutic use, Aspergillosis drug therapy, Triazoles therapeutic use
- Abstract
Background: Oral follow-up therapy is problematic in moulds with reduced azole-susceptibility, such as azole-resistant Aspergillus fumigatus infection. Currently, only intravenous liposomal amphotericin B (L-AmB) is advocated by guidelines for the treatment of azole-resistant aspergillosis infections. Preclinical research indicates that high-dose posaconazole (HD-POS) might be a feasible option provided that high drug exposure (ie POS serum through levels >3 mg/L) can be achieved and is safe., Objectives: To describe our experience with the use of oral HD-POS as treatment strategies for patients infected with pathogens with a POS MIC close to the clinical breakpoint., Patients/methods: We review evidence supporting the use of HD-POS and describe our experience on safety and efficacy in 16 patients. In addition, we describe the adverse events (AE) observed in 25 patients with POS concentrations at the higher end of the population distribution during treatment with the licensed dose., Results: Sixteen patients were treated intentionally with HD-POS for voriconazole-resistant invasive aspergillosis (7/16), mucormycosis (4/16), salvage therapy for IA (4/16) and IA at a sanctuary site (spondylodiscitis) in 1. Grade 3-4 AEs were observed in 6, and all of them were considered at least possibly related. Grade 3-4 AEs were observed in 5 of the 25 patients with spontaneous high POS serum through levels considered at least possibly related using Naranjo scale., Conclusions: High-dose posaconazole is a treatment option if strict monitoring for both exposure and for AE is possible., (© 2019 The Authors. Mycoses published by Blackwell Verlag GmbH.)
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- 2020
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35. External Quality Assessment Evaluating the Ability of Dutch Clinical Microbiological Laboratories to Identify Candida auris .
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Buil JB, van der Lee HAL, Curfs-Breuker I, Verweij PE, and Meis JF
- Abstract
Background: Candida auris is a yeast that is causing nosocomial outbreaks in healthcare facilities around the world. There is a risk of the misidentification of C. auris with matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS)-when libraries are used that lack C. auris spectra, or when conventional biochemical methods are used., Methods: We conducted an external quality assessment to evaluate the ability of Dutch clinical microbiological laboratories to identify C. auris , and to raise awareness about the risk of misidentification., Results: 35/47 participating laboratories were able to identify C. auris correctly. Only 2/14 labs that potentially misidentified C. auris with their primary identification methods specified that they would perform additional tests to exclude C. auris when appropriate. 45/47 labs used MALDI-TOF MS systems to identify Candida species., Conclusions: There was a lack of awareness about the potential misidentification of C. auris in many labs that used MALDI-TOF MS with libraries that lacked C. auris spectra, and labs that used Vitek 2. However, as the currently available MALDI-TOF MS libraries in The Netherlands contain several C. auris spectra, we expect that currently almost all participating laboratories are able to identify C. auris correctly, as 45/47 participating laboratories use MALDI-TOF MS as their primary yeast identification method.
- Published
- 2019
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36. The fading boundaries between patient and environmental routes of triazole resistance selection in Aspergillus fumigatus.
- Author
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Buil JB, Hare RK, Zwaan BJ, Arendrup MC, Melchers WJG, and Verweij PE
- Subjects
- Aspergillosis genetics, Aspergillosis microbiology, Aspergillus fumigatus genetics, Aspergillus fumigatus isolation & purification, Humans, Selection, Genetic, Antifungal Agents pharmacology, Aspergillosis epidemiology, Aspergillus fumigatus drug effects, Drug Resistance, Fungal genetics, Environment, Fungal Proteins genetics, Mutation, Triazoles pharmacology
- Abstract
Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2019
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37. Trends in Azole Resistance in Aspergillus fumigatus, the Netherlands, 1994-2016.
- Author
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Buil JB, Snelders E, Denardi LB, Melchers WJG, and Verweij PE
- Subjects
- Aspergillosis microbiology, Humans, Netherlands epidemiology, Antifungal Agents pharmacology, Aspergillosis epidemiology, Aspergillus fumigatus drug effects, Azoles pharmacology, Drug Resistance, Fungal
- Abstract
We investigated azole resistance in Aspergillus fumigatus in a tertiary reference hospital in the Netherlands during 1994-2016. The 5-year patient-adjusted proportion of resistance increased from 0.79% for 1996-2001 to 4.25% for 2002-2006, 7.17% for 2007-2011, and 7.04% for 2012-2016. However, we observed substantial variation between years.
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- 2019
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38. Airway persistence by the emerging multi-azole-resistant Rasamsonia argillacea complex in cystic fibrosis.
- Author
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Abdolrasouli A, Bercusson AC, Rhodes JL, Hagen F, Buil JB, Tang AYY, de Boer LL, Shah A, Milburn AJ, Elborn JS, Jones AL, Meis JF, Fisher MC, Schelenz S, Simmonds NJ, and Armstrong-James D
- Subjects
- Adult, Child, Cohort Studies, Echinocandins pharmacology, Eurotiales classification, Eurotiales drug effects, Eurotiales genetics, Female, Genotype, Genotyping Techniques, Humans, Male, Microbial Sensitivity Tests, Middle Aged, Mycological Typing Techniques, Young Adult, Antifungal Agents pharmacology, Azoles pharmacology, Communicable Diseases, Emerging microbiology, Cystic Fibrosis complications, Drug Resistance, Fungal, Eurotiales isolation & purification, Lung Diseases, Fungal microbiology
- Abstract
Infections caused by Rasamsonia argillacea complex have been reported in various clinical settings. Cystic fibrosis (CF) is one of the main underlying conditions. An observational cohort study of CF patients with Rasamsonia in respiratory samples was conducted. Eight isolates from 6 patients were identified as R. argillacea complex and tested for antifungal susceptibility. All isolates had high MICs to voriconazole and posaconazole and low MECs to echinocandins. Four patients experienced lung function decline in the year preceding first Rasamsonia isolation. This continued in the year following first isolation in 3 out of 4 cases. Antifungal therapy was initiated in 2 patients, to which only one exhibited a clinical response. Three out of 6 patients died within 3 years of isolating Rasamsonia. Genotyping suggests that similar genotypes of Rasamsonia can persist in CF airways. Consistent with other fungi in CF, the clinical impact of airway colonisation by Rasamsonia is variable. In certain patients, Rasamsonia may be able to drive clinical decline. In others, though a clear impact on lung function may be difficult to determine, the appearance of Rasamsonia acts as a marker of disease severity. In others it does not appear to have an obvious clinical impact on disease progression., (© 2018 Blackwell Verlag GmbH.)
- Published
- 2018
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39. Itraconazole, Voriconazole, and Posaconazole CLSI MIC Distributions for Wild-Type and Azole-Resistant Aspergillus fumigatus Isolates.
- Author
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Buil JB, Hagen F, Chowdhary A, Verweij PE, and Meis JF
- Abstract
Azole resistance in Aspergillus fumigatus is most frequently conferred by mutations in the cyp51A gene encoding 14α-sterol demethylases. TR
34 /L98H and TR46 /Y121F/T289A are the two most common mutations associated with environmental resistance selection. We studied the minimal inhibitory concentration (MIC) distribution of clinical A. fumigatus isolates to characterize the Clinical and Laboratory Standards Institute (CLSI) susceptibility profiles of isolates with the wild-type (WT) cyp51A genotype, and isolates with the TR34 /L98H and TR46 /Y121F/T289A cyp51A mutations. Susceptibility testing was performed according to CLSI M38-A2. The MICs of 363 A. fumigatus isolates were used in this study. Based on the CLSI epidemiological cut-off values (ECVs), 141 isolates were phenotypically non-WT and 222 isolates had a phenotypically WT susceptibility. All isolates with the TR34 /L98H mutation had an itraconazole MIC > 1 mg/L which is above the CLSI ECV. Eighty-six of 89 (97%) isolates with the TR34 /L98H mutation had voriconazole and posaconazole MICs above the CLSI ECV, i.e., MICs of 1 and 0.25 mg/L, respectively. The isolates with a TR46 /Y121F/T289A mutation showed a different phenotype. All 37 isolates with a TR46 /Y121F/T289A mutation had a voriconazole MIC above the CLSI ECV, while 28/37 (76%) isolates had an itraconazole MIC > 1 mg/L. Interestingly, only 13 of 37 (35%) isolates had a posaconazole MIC > 0.25 mg/L.- Published
- 2018
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40. Molecular Detection of Azole-Resistant Aspergillus fumigatus in Clinical Samples.
- Author
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Buil JB, Zoll J, Verweij PE, and Melchers WJG
- Abstract
Aspergillus diseases are often caused by Aspergillus fumigatus . Azoles are the mainstay of therapy, but the management of aspergillosis is hampered by the emergence of azole resistance. Rapid detection of azole resistance might benefit treatment outcome by early treatment modifications. However, the yield of fungal culture in invasive aspergillosis is low and susceptibility testing requires several days to be completed. To overcome the low yield of fungal cultures and slow detection of resistance, it is possible to use molecular tools directly on clinical specimens in order to rapidly detect molecular markers of azole resistance. Molecular tools to detect resistant markers in the Cyp51A gene can be expected to be less sensitive compared to molecular tools to detect Aspergillus DNA as the Cyp51A gene is a single copy gene and the target for Aspergillus DNA is often a multi-copy gene. In this mini-review, we summarize the current molecular tools for detection of azole-resistant A. fumigatus directly in clinical material. Several in-house PCR assays have been applied directly on clinical material. Furthermore, two assays are commercial available; the AsperGenius and MycoGENIE. The amplification of resistance markers was successful in 70-100% of samples that were positive for Aspergillus DNA in BAL samples using the AsperGenius assay. Despite using several samples per patient, amplification of resistance markers was only successful in 33-57% of patients with Aspergillus DNA in blood. Furthermore, several sequence based methods have been applied with the benefit of the ability to detect other Cyp51A gene alterations.
- Published
- 2018
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41. Isavuconazole susceptibility of clinical Aspergillus fumigatus isolates and feasibility of isavuconazole dose escalation to treat isolates with elevated MICs.
- Author
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Buil JB, Brüggemann RJM, Wasmann RE, Zoll J, Meis JF, Melchers WJG, Mouton JW, and Verweij PE
- Published
- 2018
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42. Single-Center Evaluation of an Agar-Based Screening for Azole Resistance in Aspergillus fumigatus by Using VIPcheck.
- Author
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Buil JB, van der Lee HAL, Rijs AJMM, Zoll J, Hovestadt JAMF, Melchers WJG, and Verweij PE
- Subjects
- Aspergillus fumigatus isolation & purification, Genotype, Humans, Microbial Sensitivity Tests, Antifungal Agents pharmacology, Aspergillus fumigatus drug effects, Cytochrome P-450 Enzyme System genetics, Drug Resistance, Fungal genetics, Fungal Proteins genetics, Itraconazole pharmacology, Triazoles pharmacology, Voriconazole pharmacology
- Abstract
Antifungal susceptibility testing is an essential tool for guiding therapy, although EUCAST and CLSI reference methods are often available only in specialized centers. We studied the performance of an agar-based screening method for the detection of azole resistance in Aspergillus fumigatus cultures. The VIPcheck consists of four wells containing voriconazole, itraconazole, posaconazole, or a growth control. Ninety-six A. fumigatus isolates were used. Thirty-three isolates harbored a known resistance mechanism: TR
34 /L98H (11 isolates), TR46 /Y121F/T289A (6 isolates), TR53 (2 isolates), and 14 isolates with other cyp51A gene point mutations. Eighteen resistant isolates had no cyp51A -mediated azole resistance. Forty-five isolates had a wild-type (WT) azole phenotype. Four technicians and two inexperienced interns, blinded to the genotype/phenotype, read the plates visually after 24 h and 48 h and documented minimal growth, uninhibited growth, and no growth. The performance was compared to the EUCAST method. After 24 h of incubation, the mean sensitivity and specificity were 0.54 and 1.00, respectively, with uninhibited growth as the threshold. After 48 h of incubation, the performance mean sensitivity and specificity were 0.98 and 0.93, respectively, with minimal growth. The performance was not affected by observer experience in mycology. The interclass correlation coefficient was 0.87 after 24 h and 0.85 after 48 h. VIPcheck enabled the selection of azole-resistant A. fumigatus colonies, with a mean sensitivity and specificity of 0.98 and 0.93, respectively. Uninhibited growth on any azole-containing well after 24 h and minimal growth after 48 h were indicative of resistance. These results indicate that the VIPcheck is an easy-to-use tool for azole resistance screening and the selection of colonies that require MIC testing., (Copyright © 2017 American Society for Microbiology.)- Published
- 2017
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43. In vitro activity of the novel antifungal compound F901318 against difficult-to-treat Aspergillus isolates.
- Author
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Buil JB, Rijs AJMM, Meis JF, Birch M, Law D, Melchers WJG, and Verweij PE
- Subjects
- Aspergillus genetics, Aspergillus fumigatus genetics, Aspergillus fumigatus isolation & purification, Cytochrome P-450 Enzyme System genetics, Drug Resistance, Fungal genetics, Fungal Proteins genetics, Genotype, Humans, Invasive Pulmonary Aspergillosis drug therapy, Itraconazole pharmacology, Microbial Sensitivity Tests, Nitriles pharmacology, Point Mutation, Pyridines pharmacology, Triazoles pharmacology, Voriconazole pharmacology, Acetamides pharmacology, Antifungal Agents pharmacology, Aspergillus drug effects, Aspergillus fumigatus drug effects, Invasive Pulmonary Aspergillosis microbiology, Piperazines pharmacology, Pyrimidines pharmacology, Pyrroles pharmacology
- Abstract
Background: F901318 is a new antifungal agent with a novel mechanism of action with activity against Aspergillus species. We investigated the in vitro activity of F901318 against a collection of Aspergillus isolates., Methods: A total of 213 Aspergillus isolates were used in this study. A total of 143 Aspergillus fumigatus sensu stricto isolates were used, of which 133 were azole resistant [25 TR34/L98H; 25 TR46/Y121F/T289A; 33 A. fumigatus with cyp51A-associated point mutations (25 G54, 1 G432 and 7 M220); and 50 azole-resistant A. fumigatus without known resistance mechanisms]. Ten azole-susceptible A. fumigatus isolates were used as WT controls. The in vitro activity was also determined against Aspergillus calidoustus (25 isolates), Aspergillus flavus (10), Aspergillus nidulans (10) and Aspergillus tubingensis (25). F901318 activity was compared with that of itraconazole, voriconazole, posaconazole, isavuconazole, amphotericin B and anidulafungin. Minimum effective concentrations and MICs were determined using the EUCAST broth microdilution method., Results: F901318 was active against all tested isolates: A. fumigatus WT, MIC90 0.125 mg/L (range 0.031-0.125); TR34/L98H,TR46/Y121F/T289A and azole resistant without known resistance mechanisms, MIC90 0.125 mg/L (range 0.031-0.25); A. fumigatus with cyp51A-associated point mutations, MIC90 0.062 mg/L (range 0.015-0.125); and other species, A. calidoustus MIC90 0.5 mg/L (range 0.125-0.5), A. flavus MIC90 0.062 mg/L (range 0.015-0.62), A. nidulans MIC90 0.125 mg/L (range 0.062-0.25) and A. tubingensis MIC90 0.062 mg/L (range 0.015-0.25)., Conclusions: F901318 showed potent and consistent in vitro activity against difficult-to-treat Aspergillus spp. with intrinsic and acquired antifungal resistance due to known and unknown resistance mechanisms, suggesting no significant implications of azole resistance mechanisms for the mode of action of F901318., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2017
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44. Are the TR46/Y121F/T289A Mutations in Azole-Resistant Aspergillosis Patient Acquired or Environmental?
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Buil JB, Meis JF, Melchers WJ, and Verweij PE
- Subjects
- Aspergillus fumigatus drug effects, Aspergillus fumigatus isolation & purification, Drug Resistance, Fungal genetics, Environment, Fatal Outcome, Fungicides, Industrial, Humans, Mutation, Antifungal Agents pharmacology, Aspergillosis microbiology, Aspergillus fumigatus genetics, Azoles pharmacology, Fungal Proteins genetics
- Published
- 2016
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