119 results on '"Florian P. Maurer"'
Search Results
2. Delineating Mycobacterium abscessus population structure and transmission employing high-resolution core genome multilocus sequence typing
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Margo Diricks, Matthias Merker, Nils Wetzstein, Thomas A. Kohl, Stefan Niemann, and Florian P. Maurer
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Science - Abstract
Mycobacterium abscessus is an emerging infection of increasing public health concern due to outbreaks and intrinsic multidrug-resistance. Here, the authors develop and evaluate a core-genome multilocus sequence typing scheme for this pathogen to facilitate standardised molecular surveillance.
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- 2022
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3. Rapid molecular diagnostics of tuberculosis resistance by targeted stool sequencing
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Doctor B. Sibandze, Alexander Kay, Viola Dreyer, Welile Sikhondze, Qiniso Dlamini, Andrew DiNardo, Godwin Mtetwa, Bhekumusa Lukhele, Debrah Vambe, Christoph Lange, Muyalo Glenn Dlamini, Tara Ness, Rojelio Mejia, Barbara Kalsdorf, Jan Heyckendorf, Martin Kuhns, Florian P. Maurer, Sindisiwe Dlamini, Gugu Maphalala, Stefan Niemann, and Anna Mandalakas
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Tuberculosis ,Drug resistance ,Feces ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background Stool is an important diagnostic specimen for tuberculosis in populations who struggle to provide sputum, such as children or people living with HIV. However, the culture of Mycobacterium tuberculosis (M. tuberculosis) complex strains from stool perform poorly. This limits the opportunity for phenotypic drug resistance testing with this specimen. Therefore, reliable molecular methods are urgently needed for comprehensive drug resistance testing on stool specimens. Methods We evaluated the performance of targeted next-generation sequencing (tNGS, Deeplex® Myc-TB) for the detection of mutations associated with M. tuberculosis complex drug resistance on DNA isolated from stool specimens provided by participants from a prospective cohort of patients treated for tuberculosis in Eswatini (n = 66; 56 with and 10 participants without M. tuberculosis complex DNA detected in stool by real-time quantitative PCR), and an independent German validation cohort of participants with culture-confirmed tuberculosis (n = 21). Results The tNGS assay detected M. tuberculosis complex DNA in 38 of 56 (68%) samples; for 28 of 38 (74%) samples, a full M. tuberculosis complex drug resistance prediction report was obtained. There was a high degree of concordance with sputum phenotypic drug susceptibility results (κ = 0.82). The ability to predict resistance was concentration-dependent and successful in 7/10 (70%), 18/25 (72%), and 3/21 (14%) of samples with stool PCR concentration thresholds of > 100 femtogram per microliter (fg/μl), 1 to 100 fg/μl, and
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- 2022
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4. Molecular Epidemiology of Mycobacterium abscessus Isolates Recovered from German Cystic Fibrosis Patients
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Nils Wetzstein, Margo Diricks, Thomas A. Kohl, Thomas A. Wichelhaus, Sönke Andres, Laura Paulowski, Carsten Schwarz, Astrid Lewin, Jan Kehrmann, Barbara C. Kahl, Karl Dichtl, Christian Hügel, Olaf Eickmeier, Christina Smaczny, Annika Schmidt, Stefan Zimmermann, Lutz Nährlich, Sylvia Hafkemeyer, Stefan Niemann, Florian P. Maurer, and Michael Hogardt
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Mycobacterium abscessus ,cystic fibrosis ,whole-genome sequencing ,dominant circulating clones ,hospital transmission ,German CF registry ,Microbiology ,QR1-502 - Abstract
ABSTRACT Infections due to Mycobacterium abscessus are a major cause of mortality and morbidity in cystic fibrosis (CF) patients. Furthermore, M. abscessus has been suspected to be involved in person-to-person transmissions. In 2016, dominant global clonal complexes (DCCs) that occur worldwide among CF patients have been described. To elucidate the epidemiological situation of M. abscessus among CF patients in Germany and to put these data into a global context, we performed whole-genome sequencing of a set of 154 M. abscessus isolates from 123 German patients treated in 14 CF centers. We used MTBseq pipeline to identify clusters of closely related isolates and correlate those with global findings. Genotypic drug susceptibility for macrolides and aminoglycosides was assessed by characterization of the erm(41), rrl, and rrs genes. By this approach, we could identify representatives of all major DCCs (Absc 1, Absc 2, and Mass 1) in our cohort. Intrapersonal isolates showed higher genetic relatedness than interpersonal isolates (median 3 SNPs versus 16 SNPs; P
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- 2022
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5. Secretome characterization of clinical isolates from the Mycobacterium abscessus complex provides insight into antigenic differences
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Fernanda Cornejo-Granados, Thomas A. Kohl, Flor Vásquez Sotomayor, Sönke Andres, Rogelio Hernández-Pando, Juan Manuel Hurtado-Ramirez, Christian Utpatel, Stefan Niemann, Florian P. Maurer, and Adrian Ochoa-Leyva
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Bioinformatics ,Antigenicity ,M. abscessus subspecies ,In silico analysis ,Vaccinology ,Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background Mycobacterium abscessus (MAB) is a widely disseminated pathogenic non-tuberculous mycobacterium (NTM). Like with the M. tuberculosis complex (MTBC), excreted / secreted (ES) proteins play an essential role for its virulence and survival inside the host. Here, we used a robust bioinformatics pipeline to predict the secretome of the M. abscessus ATCC 19977 reference strain and 15 clinical isolates belonging to all three MAB subspecies, M. abscessus subsp. abscessus, M. abscessus subsp. bolletii, and M. abscessus subsp. massiliense. Results We found that ~ 18% of the proteins encoded in the MAB genomes were predicted as secreted and that the three MAB subspecies shared > 85% of the predicted secretomes. MAB isolates with a rough (R) colony morphotype showed larger predicted secretomes than isolates with a smooth (S) morphotype. Additionally, proteins exclusive to the secretomes of MAB R variants had higher antigenic densities than those exclusive to S variants, independent of the subspecies. For all investigated isolates, ES proteins had a significantly higher antigenic density than non-ES proteins. We identified 337 MAB ES proteins with homologues in previously investigated M. tuberculosis secretomes. Among these, 222 have previous experimental support of secretion, and some proteins showed homology with protein drug targets reported in the DrugBank database. The predicted MAB secretomes showed a higher abundance of proteins related to quorum-sensing and Mce domains as compared to MTBC indicating the importance of these pathways for MAB pathogenicity and virulence. Comparison of the predicted secretome of M. abscessus ATCC 19977 with the list of essential genes revealed that 99 secreted proteins corresponded to essential proteins required for in vitro growth. Conclusions This study represents the first systematic prediction and in silico characterization of the MAB secretome. Our study demonstrates that bioinformatics strategies can help to broadly explore mycobacterial secretomes including those of clinical isolates and to tailor subsequent, complex and time-consuming experimental approaches accordingly. This approach can support systematic investigation exploring candidate proteins for new vaccines and diagnostic markers to distinguish between colonization and infection. All predicted secretomes were deposited in the Secret-AAR web-server ( http://microbiomics.ibt.unam.mx/tools/aar/index.php ).
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- 2021
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6. Sub-Lineage Specific Phenolic Glycolipid Patterns in the Mycobacterium tuberculosis Complex Lineage 1
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Nicolas Gisch, Christian Utpatel, Lisa M. Gronbach, Thomas A. Kohl, Ursula Schombel, Sven Malm, Karen M. Dobos, Danny C. Hesser, Roland Diel, Udo Götsch, Silke Gerdes, Yassir A. Shuaib, Nyanda E. Ntinginya, Celso Khosa, Sofia Viegas, Glennah Kerubo, Solomon Ali, Sahal A. Al-Hajoj, Perpetual W. Ndung’u, Andrea Rachow, Michael Hoelscher, Florian P. Maurer, Dominik Schwudke, Stefan Niemann, Norbert Reiling, and Susanne Homolka
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Mycobacterium tuberculosis complex ,single nucleotide polymorphism (SNPs) ,NMR ,phenolic glycolipids ,genetic diversity ,phylogeny ,Microbiology ,QR1-502 - Abstract
“Ancestral” Mycobacterium tuberculosis complex (MTBC) strains of Lineage 1 (L1, East African Indian) are a prominent tuberculosis (TB) cause in countries around the Indian Ocean. However, the pathobiology of L1 strains is insufficiently characterized. Here, we used whole genome sequencing (WGS) of 312 L1 strains from 43 countries to perform a characterization of the global L1 population structure and correlate this to the analysis of the synthesis of phenolic glycolipids (PGL) – known MTBC polyketide-derived virulence factors. Our results reveal the presence of eight major L1 sub-lineages, whose members have specific mutation signatures in PGL biosynthesis genes, e.g., pks15/1 or glycosyltransferases Rv2962c and/or Rv2958c. Sub-lineage specific PGL production was studied by NMR-based lipid profiling and strains with a completely abolished phenolphthiocerol dimycoserosate biosynthesis showed in average a more prominent growth in human macrophages. In conclusion, our results show a diverse population structure of L1 strains that is associated with the presence of specific PGL types. This includes the occurrence of mycoside B in one sub-lineage, representing the first description of a PGL in an M. tuberculosis lineage other than L2. Such differences may be important for the evolution of L1 strains, e.g., allowing adaption to different human populations.
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- 2022
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7. The Use of Comparative Genomic Analysis for the Development of Subspecies-Specific PCR Assays for Mycobacterium abscessus
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Winifred C. Akwani, Arnoud H.M. van Vliet, Jordan O. Joel, Sönke Andres, Margo Diricks, Florian P. Maurer, Mark A. Chambers, and Suzanne M. Hingley-Wilson
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Mycobacterium abscessus ,Mycobacterium bolletii ,Mycobacterium massiliense ,multiplex polymerase chain reaction ,cystic fibrosis ,genomics ,Microbiology ,QR1-502 - Abstract
Mycobacterium abscessus complex (MABC) is an important pathogen of immunocompromised patients. Accurate and rapid determination of MABC at the subspecies level is vital for optimal antibiotic therapy. Here we have used comparative genomics to design MABC subspecies-specific PCR assays. Analysis of single nucleotide polymorphisms and core genome multilocus sequence typing showed clustering of genomes into three distinct clusters representing the MABC subspecies M. abscessus, M. bolletii and M. massiliense. Pangenome analysis of 318 MABC genomes from the three subspecies allowed for the identification of 15 MABC subspecies-specific genes. In silico testing of primer sets against 1,663 publicly available MABC genomes and 66 other closely related Mycobacterium genomes showed that all assays had >97% sensitivity and >98% specificity. Subsequent experimental validation of two subspecies-specific genes each showed the PCR assays worked well in individual and multiplex format with no false-positivity with 5 other mycobacteria of clinical importance. In conclusion, we have developed a rapid, accurate, multiplex PCR-assay for discriminating MABC subspecies that could improve their detection, diagnosis and inform correct treatment choice.
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- 2022
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8. Two Pandemics, One Challenge—Leveraging Molecular Test Capacity of Tuberculosis Laboratories for Rapid COVID-19 Case-Finding
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Susanne Homolka, Laura Paulowski, Sönke Andres, Doris Hillemann, Ruwen Jou, Gunar Günther, Mareli Claassens, Martin Kuhns, Stefan Niemann, and Florian P. Maurer
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COVID-19 ,coronavirus disease ,SARS-CoV-2 ,severe acute respiratory syndrome coronavirus 2 ,viruses ,respiratory infections ,Medicine ,Infectious and parasitic diseases ,RC109-216 - Abstract
In many settings, the ongoing coronavirus disease (COVID-19) pandemic coincides with other major public health threats, in particular tuberculosis. Using tuberculosis (TB) molecular diagnostic infrastructure, which has substantially expanded worldwide in recent years, for COVID-19 case-finding might be warranted. We analyze the potential of using TB diagnostic and research infrastructures for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing. We focused on quality control by adapting the 12 Quality System Essentials framework to the COVID-19 and TB context. We conclude that diagnostic infrastructures for TB can in principle be leveraged to scale-up SARS-CoV-2 testing, in particular in resource-poor settings. TB research infrastructures also can support sequencing of SARS-CoV-2 to study virus evolution and diversity globally. However, fundamental principles of quality management must be followed for both TB and SARS-CoV-2 testing to ensure valid results and to minimize biosafety hazards, and the continuity of TB diagnostic services must be guaranteed at all times.
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- 2020
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9. Comparative analysis of phenotypic and genotypic antibiotic susceptibility patterns in Mycobacterium avium complex
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Nils Wetzstein, Thomas A. Kohl, Sönke Andres, Tilman G. Schultze, Ari Geil, Eunhee Kim, Teodora Biciusca, Christian Hügel, Michael Hogardt, Annette Lehn, Maria J.G.T. Vehreschild, Timo Wolf, Stefan Niemann, Florian P. Maurer, and Thomas A. Wichelhaus
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Infectious and parasitic diseases ,RC109-216 - Abstract
Objective: Phenotypic (Sensititre Myco, pDST) and genotypic drug susceptibility testing (GenoType NTM DR, gDST) in M. avium complex (MAC) have become available as standardized assays, but comparable data is needed. This study aimed to investigate the phenotypic and genotypic drug susceptibility patterns in MAC clinical isolates. Methods: Overall, 98 isolates from 85 patients were included. pDST and gDST were performed on all isolates and results compared regarding specificity and sensitivity using pDST as a reference method. The impact of drug instability on pDST results was studied using a biological assay over 14 days. In addition, the evolution of antimicrobial resistance was investigated in sequential isolates of 13 patients. Results: Macrolide resistance was rare, 1.2% (95% CI 0.7–7.3) of isolates in the base cohort. No aminoglycoside resistances were found, but 14.1% of the studied isolates (95% CI 7.8–23.8) showed intermediate susceptibility. The GenoType NTM DR identified two out of four macrolide-resistant isolates. Antibiotic stability was demonstrated to be poor in rifampicin, rifabutin, and doxycycylin. Conclusions: pDST results in NTM for unstable antibiotics must be interpreted with care. A combination of pDST and gDST will be useful for the guidance of antimicrobial therapy in MAC-disease. Keywords: NTM, Non-tuberculous mycobacteria, M. avium complex, M. avium, M. chimaera, M. Intracellulare, Drug susceptibility testing, DST
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- 2020
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10. Phylogenetically informative mutations in genes implicated in antibiotic resistance in Mycobacterium tuberculosis complex
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Matthias Merker, Thomas A. Kohl, Ivan Barilar, Sönke Andres, Philip W. Fowler, Erja Chryssanthou, Kristian Ängeby, Pontus Jureen, Danesh Moradigaravand, Julian Parkhill, Sharon J. Peacock, Thomas Schön, Florian P. Maurer, Timothy Walker, Claudio Köser, and Stefan Niemann
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Mycobacterium tuberculosis ,Drug resistance ,Benign mutations ,Intrinsic resistance ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background A comprehensive understanding of the pre-existing genetic variation in genes associated with antibiotic resistance in the Mycobacterium tuberculosis complex (MTBC) is needed to accurately interpret whole-genome sequencing data for genotypic drug susceptibility testing (DST). Methods We investigated mutations in 92 genes implicated in resistance to 21 anti-tuberculosis drugs using the genomes of 405 phylogenetically diverse MTBC strains. The role of phylogenetically informative mutations was assessed by routine phenotypic DST data for the first-line drugs isoniazid, rifampicin, ethambutol, and pyrazinamide from a separate collection of over 7000 clinical strains. Selected mutations/strains were further investigated by minimum inhibitory concentration (MIC) testing. Results Out of 547 phylogenetically informative mutations identified, 138 were classified as not correlating with resistance to first-line drugs. MIC testing did not reveal a discernible impact of a Rv1979c deletion shared by M. africanum lineage 5 strains on resistance to clofazimine. Finally, we found molecular evidence that some MTBC subgroups may be hyper-susceptible to bedaquiline and clofazimine by different loss-of-function mutations affecting a drug efflux pump subunit (MmpL5). Conclusions Our findings underline that the genetic diversity in MTBC has to be studied more systematically to inform the design of clinical trials and to define sound epidemiologic cut-off values (ECOFFs) for new and repurposed anti-tuberculosis drugs. In that regard, our comprehensive variant catalogue provides a solid basis for the interpretation of mutations in genotypic as well as in phenotypic DST assays.
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- 2020
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11. Correction: Rapid molecular diagnostics of tuberculosis resistance by targeted stool sequencing
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Doctor B. Sibandze, Alexander Kay, Viola Dreyer, Welile Sikhondze, Qiniso Dlamini, Andrew DiNardo, Godwin Mtetwa, Bhekumusa Lukhele, Debrah Vambe, Christoph Lange, Muyalo Glenn Dlamini, Tara Ness, Rojelio Mejia, Barbara Kalsdorf, Jan Heyckendorf, Martin Kuhns, Florian P. Maurer, Sindisiwe Dlamini, Gugu Maphalala, Stefan Niemann, and Anna Mandalakas
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Medicine ,Genetics ,QH426-470 - Published
- 2022
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12. Species-Specific Interferon-Gamma Release Assay for the Diagnosis of Mycobacterium abscessus Complex Infection
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Mathis Steindor, Florian Stehling, Margarete Olivier, Jan Kehrmann, Margo Diricks, Florian P. Maurer, Peter A. Horn, Svenja Straßburg, Matthias Welsner, Sivagurunathan Sutharsan, and Monika Lindemann
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Mycobacterium abscessus ,cystic fibrosis ,non-tuberculous mycobacteria ,pulmonary infection ,immune response ,Microbiology ,QR1-502 - Abstract
Mycobacterium abscessus complex (MABC) infection has a devastating impact on the course of cystic fibrosis (CF) and non-CF lung disease. Diagnosis of MABC pulmonary disease is challenging, and current diagnostic approaches lack accuracy, especially in CF. In this study, we aimed to establish an MABC-specific interferon-γ release assay to detect host immune responses to MABC and improve diagnostics of MABC infection by the detection of antigen-specific T cells. Four species-specific proteins of MABC were overexpressed in an Escherichia coli expression system. Purified proteins were used to stimulate peripheral blood mononuclear cells of study subjects in an ELISpot assay. Interferon-γ response of 12 subjects with established diagnosis of MABC infection (10 CF and two non-CF) was compared with 35 controls (22 CF and 13 non-CF) distributed to three control groups, 17 CF subjects without NTM infection, nine subjects with NTM infection other than MABC, and nine subjects with tuberculosis. Cellular in vitro responses in the MABC group were stronger than in the control groups, especially toward the protein MAB_0405c (39 vs. 4 spots per 300,000 PBMC, p = 0.004; data represent mean values) in all patients and also in the subgroup of CF subjects (39 spots vs. 1 spot, p = 0.003). Receiver operating characteristic curve analysis indicated that spot numbers of at least 20 were highly predictive of MABC infection (all patients: area under curve 0.773, sensitivity 58%, and specificity 94%; CF patients: area under curve 0.818, sensitivity 60%, and specificity 100%). In conclusion, we identified MAB_0405c as a protein that may stimulate MABC-specific interferon-γ secretion and may add to the diagnosis of MABC infection in affected patients.
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- 2021
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13. Nontuberculous Mycobacterial Pulmonary Disease from Mycobacterium hassiacum, Austria
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Helmut J.F. Salzer, Bakari Chitechi, Doris Hillemann, Michael Mandl, Christian Paar, Monika Mitterhumer, Bernd Lamprecht, and Florian P. Maurer
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16S rRNA ,antimycobacterials ,Austria ,bacteria ,Mycobacterium hassiacum ,nontuberculous mycobacterial pulmonary disease ,Medicine ,Infectious and parasitic diseases ,RC109-216 - Abstract
The clinical relevance of newly described nontuberculous mycobacteria is often unclear. We report a case of pulmonary infection caused by Mycobacterium hassiacum in an immunocompetent patient in Austria who had chronic obstructive pulmonary disease. Antimicrobial drug susceptibility testing showed low MICs for macrolides, aminoglycosides, fluoroquinolones, tetracyclines, imipenem, and linezolid.
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- 2020
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14. Emergence of linezolid-resistance in vancomycin-resistant Enterococcus faecium ST117 associated with increased linezolid-consumption
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Flaminia Olearo, Anna Both, Cristina Belmar Campos, Heike Hilgarth, Eva-Maria Klupp, Jan Lennart Hansen, Florian P. Maurer, Martin Christner, Martin Aepfelbacher, and Holger Rohde
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Linezolid resistance ,Vancomycin resistant Enterococcus faecium ,Linezolid consumption ,G2576T 23S rDNA mutation ,Microbiology ,QR1-502 ,Other systems of medicine ,RZ201-999 - Abstract
Objective: We aim to describe the epidemiological, clinical and microbiological characteristics of the linezolid- and vancomycin- resistant Enterococcus faecium (LVRE) in a tertiary care hospital in Germany. Methods: We conducted a retrospective analysis of 196 LVRE cases observed from 1st January 2012 to 31th December 2018. Patients’ medical charts were reviewed and available LVRE (n = 102) were subjected to whole-genome-sequencing. Antibiotic consumption was measured in defined daily dose (DDD)/100 bed-days (BD). Results: The prevalence of LVRE isolates among VRE was 6.3 % in 2018. Most patients had an onco-hematological disease (134/196, 68.4 %). From 2012–2018 an increase of +356.7 % of linezolid defined daily dose/100 bed-days was observed. In 71.4 % (90/126, 70 missing values) of the patients, linezolid was prescribed in the previous 6 months. The median exposure to linezolid was 15 days (Interquartile, IQR 9–23). 42/196 (21.4 %) patients had an LVRE-related infection with an overall 30-day mortality rate of 33 %. In 121/196 (61.7 %) patients, linezolid-susceptible VREfm were isolated before LVRE, suggesting secondary acquisition of linezolid resistance. Genetic analysis revealed that most isolates belonged to ST117 (64/102 available isolates, 62.7 %). The G2576T 23S rDNA mutation was identified as the most common resistance mechanism (96/102, 94.1 %). poxtA was identified in two isolates, while cfr, and optrA were not detected. Conclusions: Incidence of LVRE related to 23S rDNA mutations is rising and probably associated with antibiotic consumption. Restrictions in the use of linezolid may be needed in order to retain therapeutic options in VRE.
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- 2021
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15. ‘Those who cannot remember the past are condemned to repeat it’: Drug-susceptibility testing for bedaquiline and delamanid
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Claudio U. Köser, Florian P. Maurer, and Katharina Kranzer
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Infectious and parasitic diseases ,RC109-216 - Abstract
Despite being fundamental to all treatment decisions, the breakpoints that define susceptibility and resistance to conventional anti-tuberculosis (TB) drugs were traditionally defined based on expert opinion as opposed to modern microbiological principles. As a result, the breakpoints for several key drugs (i.e. amikacin, levofloxacin, and moxifloxacin) were too high, resulting in the systematic misclassification of a proportion of resistant strains as susceptible. Moreover, a recent systematic review of clinical outcome data prompted the World Health Organization (WHO) to make significant changes to its treatment guidelines. For example, capreomycin and kanamycin are no longer recommended for TB treatment because their use correlates with worse clinical outcomes. This history notwithstanding, robust breakpoints still do not exist for bedaquiline and delamanid six years after their approval. This was compounded by the fact that access to both agents for drug-susceptibility testing had initially been restricted. It is incumbent upon the European Medicines Agency, the United States Food and Drug Administration, and WHO to ensure that drug developers generate the necessary data to set breakpoints as a prerequisite for the approval of new agents. Keywords: Tuberculosis, Drug resistance, Minimum inhibitory concentration, Breakpoint, Bedaquiline, Delamanid
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- 2019
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16. Advances in rapid identification and susceptibility testing of bacteria in the clinical microbiology laboratory: implications for patient care and antimicrobial stewardship programs
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Florian P. Maurer, Martin Christner, Moritz Hentschke, and Holger Rohde
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Rapid diagnostics, MALDI-ToF, PCR, rapid susceptibility testing ,Other systems of medicine ,RZ201-999 - Abstract
Early availability of information on bacterial pathogens and their antimicrobial susceptibility is of key importance for the management of infectious diseases patients. Currently, using traditional approaches, it usually takes at least 48 hours for identification and susceptibility testing of bacterial pathogens. Therefore, the slowness of diagnostic procedures drives prolongation of empiric, potentially inappropriate, antibacterial therapies. Over the last couple of years, the improvement of available techniques (e.g. for susceptibility testing, DNA amplification assays), and introduction of novel technologies (e.g. MALDI-TOF) has fundamentally changed approaches towards pathogen identification and characterization. Importantly, these techniques offer increased diagnostic resolution while at the same time shorten the time-to-result, and are thus of obvious importance for antimicrobial stewardship. In this review, we will discuss recent advances in medical microbiology with special emphasis on the impact of novel techniques on antimicrobial stewardship programs.
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- 2017
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17. Survey of macrolide-resistant Mycoplasma pneumoniaein children with community-acquired pneumonia in Switzerland
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Patrick M. Meyer Sauteur, Barbara Bleisch, Antje Voit, Florian P. Maurer, Christa Relly, Christoph Berger, David Nadal, and Guido V. Bloemberg
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Medicine - Published
- 2014
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18. Tuberkulose im Erwachsenenalter
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Tom Schaberg, Folke Brinkmann, Cornelia Feiterna-Sperling, Hilte Geerdes-Fenge, Pia Hartmann, Brit Häcker, Barbara Hauer, Walter Haas, Jan Heyckendorf, Christoph Lange, Florian P. Maurer, Albert Nienhaus, Ralf Otto-Knapp, Martin Priwitzer, Elvira Richter, Helmut J.F. Salzer, Otto Schoch, Nicolas Schönfeld, Ralf Stahlmann, and Torsten Bauer
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Pulmonary and Respiratory Medicine - Abstract
ZusammenfassungDie Tuberkulose ist in Deutschland eine seltene, überwiegend gut behandelbare Erkrankung. Weltweit ist sie eine der häufigsten Infektionserkrankungen mit ca. 10 Millionen Neuerkrankungen/Jahr. Auch bei einer niedrigen Inzidenz in Deutschland bleibt Tuberkulose insbesondere aufgrund der internationalen Entwicklungen und Migrationsbewegungen eine wichtige Differenzialdiagnose. In Deutschland besteht, aufgrund der niedrigen Prävalenz der Erkrankung und der damit verbundenen abnehmenden klinischen Erfahrung, ein Informationsbedarf zu allen Aspekten der Tuberkulose und ihrer Kontrolle. Diese Leitlinie umfasst die mikrobiologische Diagnostik, die Grundprinzipien der Standardtherapie, die Behandlung verschiedener Organmanifestationen, den Umgang mit typischen unerwünschten Arzneimittelwirkungen, die Besonderheiten in der Diagnostik und Therapie resistenter Tuberkulose sowie die Behandlung bei TB-HIV-Koinfektion. Sie geht darüber hinaus auf Versorgungsaspekte und gesetzliche Regelungen wie auch auf die Diagnosestellung und präventive Therapie einer latenten tuberkulösen Infektion ein. Es wird ausgeführt, wann es der Behandlung durch spezialisierte Zentren bedarf.Die Aktualisierung der S2k-Leitlinie „Tuberkulose im Erwachsenenalter“ soll allen in der Tuberkuloseversorgung Tätigen als Richtschnur für die Prävention, die Diagnose und die Therapie der Tuberkulose dienen und helfen, den heutigen Herausforderungen im Umgang mit Tuberkulose in Deutschland gewachsen zu sein.
- Published
- 2022
19. Diagnostic Capacities for Multidrug-Resistant Tuberculosis in the World Health Organization European Region
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Florian P. Maurer, Natalia Shubladze, Gulmira Kalmambetova, Irina Felker, Giorgi Kuchukhidze, Claudio U. Köser, Daniela Maria Cirillo, Francis Drobniewski, Askar Yedilbayev, Soudeh Ehsani, Ana Avellón, Vladimir Chulanov, Stefan Niemann, Ecaterina Noroc, Roger Paredes, Daniel Simões, Alena Skrahina, and Maja Stanojevic
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Molecular Medicine ,Pathology and Forensic Medicine - Published
- 2022
20. Pretomanid-resistant tuberculosis
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Niklas Koehler, Sönke Andres, Matthias Merker, Viola Dreyer, Agnieszka John, Martin Kuhns, David Krieger, Eva Choong, Nick Verougstraete, Pia Abel zur Wiesch, Sebastian G. Wicha, Christina König, Barbara Kalsdorf, Patricia M. Sanchez Carballo, Dagmar Schaub, Jim Werngren, Thomas Schön, Charles A. Peloquin, Nicolas Schönfeld, Alain G. Verstraete, Laurent A. Decosterd, Rob Aarnoutse, Stefan Niemann, Florian P. Maurer, and Christoph Lange
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Microbiology (medical) ,All institutes and research themes of the Radboud University Medical Center ,lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] ,Infectious Diseases - Abstract
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- Published
- 2023
21. Clinical implications of molecular drug resistance testing for Mycobacterium tuberculosis: a 2023 TBnet/RESIST-TB consensus statement
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José Domínguez, Martin J Boeree, Emmanuelle Cambau, Dumitru Chesov, Francesca Conradie, Vivian Cox, Keertan Dheda, Andrii Dudnyk, Maha R Farhat, Sebastien Gagneux, Martin P Grobusch, Matthias I Gröschel, Lorenzo Guglielmetti, Irina Kontsevaya, Berit Lange, Frank van Leth, Christian Lienhardt, Anna M Mandalakas, Florian P Maurer, Matthias Merker, Paolo Miotto, Barbara Molina-Moya, Florence Morel, Stefan Niemann, Nicolas Veziris, Andrew Whitelaw, Charles R Horsburgh, Christoph Lange, Jose Domínguez, Martin J. Boeree, Maha R. Farhat, Martin P. Grobusch, Matthias I. Gröschel, Anna Maria Mandalakas, Florian Maurer, and Charles Robert Horsburgh
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All institutes and research themes of the Radboud University Medical Center ,lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] ,Infectious Diseases - Abstract
Contains fulltext : 291526.pdf (Publisher’s version ) (Closed access) Drug-resistant tuberculosis is a substantial health-care concern worldwide. Despite culture-based methods being considered the gold standard for drug susceptibility testing, molecular methods provide rapid information about the Mycobacterium tuberculosis mutations associated with resistance to anti-tuberculosis drugs. This consensus document was developed on the basis of a comprehensive literature search, by the TBnet and RESIST-TB networks, about reporting standards for the clinical use of molecular drug susceptibility testing. Review and the search for evidence included hand-searching journals and searching electronic databases. The panel identified studies that linked mutations in genomic regions of M tuberculosis with treatment outcome data. Implementation of molecular testing for the prediction of drug resistance in M tuberculosis is key. Detection of mutations in clinical isolates has implications for the clinical management of patients with multidrug-resistant or rifampicin-resistant tuberculosis, especially in situations when phenotypic drug susceptibility testing is not available. A multidisciplinary team including clinicians, microbiologists, and laboratory scientists reached a consensus on key questions relevant to molecular prediction of drug susceptibility or resistance to M tuberculosis, and their implications for clinical practice. This consensus document should help clinicians in the management of patients with tuberculosis, providing guidance for the design of treatment regimens and optimising outcomes. 01 april 2023
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- 2023
22. Novel synergies and isolate specificities in the drug interactions landscape ofMycobacterium abscessus
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Nhi Van, Yonatan N. Degefu, Pathricia A. Leus, Jonah Larkins-Ford, Jacob Klickstein, Florian P. Maurer, David Stone, Husain Poonawala, Cheleste M. Thorpe, Trever C. Smith, and Bree B. Aldridge
- Abstract
Mycobacterium abscessusinfections are difficult to treat and are often considered untreatable without tissue resection. Due to the intrinsic drug-resistant nature of the bacteria, combination therapy of three or more antibiotics is recommended. A major challenge in treatingM. abscessusinfections is the absence of a universal combination therapy with satisfying clinical success rates, leaving clinicians to treat infections using antibiotic lacking efficacy data. We systematically measured drug combinations inM. abscessusto establish a resource of drug interaction data and identify patterns of synergy to help design optimized combination therapies. We measured approximately 230 pairwise drug interactions among 22 antibiotics and identified 71 synergistic pairs, 54 antagonistic pairs, and four potentiator-antibiotics not previously reported. We found that commonly used drug combinations in the clinic, such as azithromycin and amikacin, are antagonistic in lab reference strain ATCC19977, whereas novel combinations, such as azithromycin and rifampicin, are synergistic. Another challenge in developing universally effective multidrug therapies forM. abscessusis the significant variation in drug response between isolates. We measured drug interactions in a focused set of 36 drug pairs across a small panel of clinical isolates with rough and smooth morphotypes. We observed highly strain-dependent drug interactions that cannot be predicted from single-drug susceptibility profiles or known drug mechanisms of action. Our study demonstrates the immense potential to identify synergistic drug combinations in the vast drug combination space and emphasizes the importance of strain-specific combination measurements for designing improved therapeutic interventions.
- Published
- 2022
23. [Tuberculosis in adulthood - The Sk2-Guideline of the German Central Committee against Tuberculosis (DZK) and the German Respiratory Society (DGP) for the diagnosis and treatment of adult tuberculosis patients]
- Author
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Tom, Schaberg, Folke, Brinkmann, Cornelia, Feiterna-Sperling, Hilte, Geerdes-Fenge, Pia, Hartmann, Brit, Häcker, Barbara, Hauer, Walter, Haas, Jan, Heyckendorf, Christoph, Lange, Florian P, Maurer, Albert, Nienhaus, Ralf, Otto-Knapp, Martin, Priwitzer, Elvira, Richter, Helmut J F, Salzer, Otto, Schoch, Nicolas, Schönfeld, Ralf, Stahlmann, and Torsten, Bauer
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Adult ,Latent Tuberculosis ,Germany ,Antitubercular Agents ,Humans ,Tuberculosis ,HIV Infections - Abstract
In Germany tuberculosis is a rare disease and usually well treatable. Worldwide it is one of the most common infectious diseases with approximately 10 million new cases every year. Even with low incidences in Germany, tuberculosis is an important differential diagnosis especially due to international developments and migration movements. With a decreasing experience there's a continuous demand on accurate and up-to-date information. This guideline covers all aspects of microbiological diagnostics, basic principles of standard therapy, treatment of extrapulmonary tuberculosis, management of side effects, special features of diagnosis and treatment of resistant tuberculosis, and treatment in TB-HIV coinfection. Also, it explains when treatment in specialized centers is required, aspects of care and legal regulations and the diagnosis and preventive therapy of latent tuberculosis infection. The update of the S2k guideline "Tuberculosis in Adults" is intended to serve as a guideline for prevention, diagnosis, and treatment of tuberculosis for all those involved in tuberculosis care and to help meet the current challenges in dealing with tuberculosis in Germany.Die Tuberkulose ist in Deutschland eine seltene, überwiegend gut behandelbare Erkrankung. Weltweit ist sie eine der häufigsten Infektionserkrankungen mit ca. 10 Millionen Neuerkrankungen/Jahr. Auch bei einer niedrigen Inzidenz in Deutschland bleibt Tuberkulose insbesondere aufgrund der internationalen Entwicklungen und Migrationsbewegungen eine wichtige Differenzialdiagnose. In Deutschland besteht, aufgrund der niedrigen Prävalenz der Erkrankung und der damit verbundenen abnehmenden klinischen Erfahrung, ein Informationsbedarf zu allen Aspekten der Tuberkulose und ihrer Kontrolle. Diese Leitlinie umfasst die mikrobiologische Diagnostik, die Grundprinzipien der Standardtherapie, die Behandlung verschiedener Organmanifestationen, den Umgang mit typischen unerwünschten Arzneimittelwirkungen, die Besonderheiten in der Diagnostik und Therapie resistenter Tuberkulose sowie die Behandlung bei TB-HIV-Koinfektion. Sie geht darüber hinaus auf Versorgungsaspekte und gesetzliche Regelungen wie auch auf die Diagnosestellung und präventive Therapie einer latenten tuberkulösen Infektion ein. Es wird ausgeführt, wann es der Behandlung durch spezialisierte Zentren bedarf.Die Aktualisierung der S2k-Leitlinie „Tuberkulose im Erwachsenenalter“ soll allen in der Tuberkuloseversorgung Tätigen als Richtschnur für die Prävention, die Diagnose und die Therapie der Tuberkulose dienen und helfen, den heutigen Herausforderungen im Umgang mit Tuberkulose in Deutschland gewachsen zu sein.
- Published
- 2022
24. C25-modified rifamycin derivatives with improved activity against Mycobacterium abscessus
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Laura Paulowski, Katherine S H Beckham, Matt D Johansen, Laura Berneking, Nhi Van, Yonatan Degefu, Sonja Staack, Flor Vasquez Sotomayor, Lucia Asar, Holger Rohde, Bree B Aldridge, Martin Aepfelbacher, Annabel Parret, Matthias Wilmanns, Laurent Kremer, Keith Combrink, Florian P Maurer, and Nelson, KE
- Abstract
Infections caused by Mycobacterium abscessus are difficult to treat due to its intrinsic resistance to most antibiotics. Formation of biofilms and the capacity of M. abscessus to survive inside host phagocytes further complicate eradication. Herein, we explored whether addition of a carbamate-linked group at the C25 position of rifamycin SV blocks enzymatic inactivation by ArrMab, an ADP-ribosyltransferase conferring resistance to rifampicin (RMP). Unlike RMP, 5j, a benzyl piperidine rifamycin derivative with a morpholino substituted C3 position and a naphthoquinone core, is not modified by purified ArrMab. Additionally, we show that the ArrMab D82 residue is essential for catalytic activity. Thermal profiling of ArrMab in the presence of 5j, RMP, or rifabutin shows that 5j does not bind to ArrMab. We found that the activity of 5j is comparable to amikacin against M. abscessus planktonic cultures and pellicles. Critically, 5j also exerts potent antimicrobial activity against M. abscessus in human macrophages and shows synergistic activity with amikacin and azithromycin.
- Published
- 2022
25. Minimum inhibitory concentrations and sequencing data have to be analysed in more detail to set provisional epidemiological cut-off values forMycobacterium tuberculosiscomplex
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Claudio U. Köser and Florian P. Maurer
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Pulmonary and Respiratory Medicine - Published
- 2023
26. Cost of multidrug resistant tuberculosis in Germany—An update
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Sönke Andres, Florian P. Maurer, Roland Diel, Giovanni Sotgiu, and Doris Hillemann
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Adult ,Male ,0301 basic medicine ,Microbiology (medical) ,medicine.medical_specialty ,Tuberculosis ,030106 microbiology ,Antitubercular Agents ,MDR-TB ,Drug resistance ,Antimicrobial resistance ,Drug Costs ,lcsh:Infectious and parasitic diseases ,03 medical and health sciences ,0302 clinical medicine ,Antibiotic resistance ,Germany ,Tuberculosis, Multidrug-Resistant ,Cost analysis ,Culture conversion ,Humans ,Medicine ,lcsh:RC109-216 ,030212 general & internal medicine ,XDR-TB ,Hospital Costs ,Monte Carlo simulation ,Average cost ,business.industry ,Incidence (epidemiology) ,Health Care Costs ,General Medicine ,Guideline ,Middle Aged ,medicine.disease ,Infectious Diseases ,Sick leave ,Emergency medicine ,Costs and Cost Analysis ,Female ,business - Abstract
Background In 2019, new therapeutic recommendations for multidrug-resistant (MDR-) and extensively drug-resistant (XDR) tuberculosis (TB) were published by the WHO, advocating the use of oral drugs and stepwise composition of antibiotic regimens. To date, the economic consequences of those recommendations in low incidence settings have not been evaluated. Objective To assess the costs of applying the new recommendations against a set of 86 MDR-TB/XDR-TB strains, each with individual phenotypic drug resistance patterns, identified in 2018/2019 by the German National Reference Center for Mycobacteria. Methods Hospitalization costs as covered by German statutory health insurance and the loss of productivity due to illness were calculated using the most recent 2018 statistical data. Costs due to combining five agents in the intensive phase and costs of outpatient monitoring were determined by Monte-Carlo simulation covering all treatment options over an 18-month period. Drug costs were compared to those arising under the approach recommended by the WHO in 2016. Results Hospitalization costs per MDR-TB patient were €30,152 and the mean costs of antimicrobials over a period of 18 months were €66,854 (range €20,671 to €187,444). Total treatment costs, including outpatient monitoring, were €73,551.56 per patient (range €30,114 to €145.878). In addition, we determined an average cost of €11,410.20 due to productivity loss over a period of 6 months sick leave. Despite a shortened minimum recommended treatment duration (18 versus 20 months), the estimated costs were 24.5% higher based on the 2019 recommendations as compared to the 2016 guideline version. Conclusion Higher costs for treating MDR-TB/XDR-TB in Germany are to be expected under the new WHO regimens. However, it must be determined whether treatment duration and costs associated with sick leave may be further reduced in the future through shorter hospital stays and earlier culture conversion.
- Published
- 2021
27. Systematic rifampicin resistance errors with Xpert® MTB/RIF Ultra: implications for regulation of genotypic assays
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D S Vidanagama, A Alabi, Evelyn Lavu, A I P Samarasinghe, Chris Coulter, S Pandey, Arnold Bainomugisa, Thomas B. Schön, Nabila Ismail, D Nadarajan, E C Kelly, U Götsch, Claudio U. Köser, Shaheed V. Omar, Doris Hillemann, Florian P. Maurer, Matthias Merker, Roland Diel, Stefan Niemann, M R Cader, Ivan Barilar, A-K Witt, and Fadillah Ismail
- Subjects
Pulmonary and Respiratory Medicine ,Infectious Diseases ,business.industry ,Genotype ,MEDLINE ,Medicine ,Rifampicin resistance ,Computational biology ,business - Published
- 2020
28. Rifapentine access in Europe:growing concerns over key tuberculosis treatment component
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Lorenzo Guglielmetti, Gunar Günther, Claude Leu, Daniela Cirillo, Raquel Duarte, Alberto L. Garcia-Basteiro, Delia Goletti, Mateja Jankovic, Liga Kuksa, Florian P. Maurer, Frédéric Méchaï, Simon Tiberi, Frank van Leth, Nicolas Veziris, Christoph Lange, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Avicenne [AP-HP], Centre National de Référence des Mycobactéries et de la Résistance aux Antituberculeux [CHU Pitié-Salpêtrière] (CNR-MyRMA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Bern, University of Namibia (UNAM), IRCCS San Raffaele Scientific Institute [Milan, Italie], Universidade do Porto = University of Porto, Directorate-General of Health [Lisbonne], Centro de Investigação em Saúde de Manhiça [Maputo, Mozambique] (CISM), Universitat de Barcelona (UB), National Institute for Infectious Diseases 'Lazzaro Spallanzani', Zagreb School of Medicine [Zagreb, Croatia] (Dubrava University Hospital), University of Zagreb, Riga East University Hospital, Riga Stradins University (RSU), Forschungszentrum Borstel - Research Center Borstel, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), German Center for Infection Research - Partner Site Hamburg-Lübeck-Borstel-Riems, German Centre for Infection Research (DZIF), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)-Université Sorbonne Paris Nord, Queen Mary University of London (QMUL), Royal Free Hospital [London, UK], Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), Amsterdam Public Health Research Institute [The Netherlands], CHU Saint-Antoine [AP-HP], Universität zu Lübeck = University of Lübeck [Lübeck], Baylor College of Medicine (BCM), Baylor University, Study Group on Mycobacteria of the European Society of Microbiology and Infectious Diseases (ESGMYC), European Society of Mycobacteriology (ESM), European Respiratory Society (ERS) and, Tuberculosis Network European Trials group (TBnet), Health Economics and Health Technology Assessment, APH - Global Health, and APH - Methodology
- Subjects
Pulmonary and Respiratory Medicine ,Antitubercular Agents/therapeutic use ,Antitubercular Agents ,Tuberculosis / epidemiology ,[SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract ,Drug Therapy ,SDG 3 - Good Health and Well-being ,Antibiotics ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Antibiotics, Antitubercular* / therapeutic use ,Tuberculosis ,Humans ,Rifampin / analogs & derivatives ,610 Medicine & health ,Antibiotics, Antitubercular ,Antitubercular Agents / therapeutic use ,Tuberculosis/drug therapy ,Tuberculosis / drug therapy ,Rifampin/analogs & derivatives ,Antitubercular/therapeutic use ,rifapentine, tuberculosis ,Europe ,Combination ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,Drug Therapy, Combination ,Rifampin ,Rifampin / therapeutic use ,Antibiotics, Antitubercular/therapeutic use - Abstract
International audience; Rifapentine, a synthetic derivate of rifampicin which was developed in 1965, has interesting pharmacological properties, including a long terminal half-life (13 h, compared to 2-3 h for rifampicin) and promising bactericidal activity against Mycobacterium tuberculosis. Despite being approved in 1998 by the US Food and Drug Administration (FDA) for the treatment of pulmonary tuberculosis, its global use has been limited by unavailability. In the past decade, new evidence has emerged to define rifapentine as a key component for treatment of active disease and latent infection with M. tuberculosis (LTBI).
- Published
- 2022
29. Origin and Global Expansion of
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Yassir A, Shuaib, Christian, Utpatel, Thomas A, Kohl, Ivan, Barilar, Margo, Diricks, Nadia, Ashraf, Lothar H, Wieler, Glennah, Kerubo, Eyob A, Mesfin, Awa Ba, Diallo, Sahal, Al-Hajoj, Perpetua, Ndung'u, Margaret M, Fitzgibbon, Farzam, Vaziri, Vitali, Sintchenko, Elena, Martinez, Sofia O, Viegas, Yang, Zhou, Aya, Azmy, Khaled, Al-Amry, Sylvain, Godreuil, Mandira, Varma-Basil, Anshika, Narang, Solomon, Ali, Patrick, Beckert, Viola, Dreyer, Mwila, Kabwe, Matthew, Bates, Michael, Hoelscher, Andrea, Rachow, Andrea, Gori, Emmanuel M, Tekwu, Larissa K, Sidze, Assam A, Jean-Paul, Veronique P, Beng, Francine, Ntoumi, Matthias, Frank, Aissatou Gaye, Diallo, Souleymane, Mboup, Belay, Tessema, Dereje, Beyene, Sadiq N, Khan, Roland, Diel, Philip, Supply, Florian P, Maurer, Harald, Hoffmann, Stefan, Niemann, and Matthias, Merker
- Subjects
Genotype ,Microbial Sensitivity Tests ,Minisatellite Repeats ,Mycobacterium tuberculosis ,Phylogeny - Published
- 2022
30. Die neuen WHO-Empfehlungen für schnelle Diagnostik und Therapie resistenter Tuberkulose in Deutschland, Österreich und der Schweiz
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Tom Schaberg, Gunar Günther, R Otto-Knapp, Christoph Lange, Florian P. Maurer, K Starzacher, B. Häcker, Torsten T. Bauer, and M Knappik
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Tuberculosis ,business.industry ,Drug resistant tuberculosis ,MEDLINE ,Guideline ,medicine.disease ,Resistant tuberculosis ,language.human_language ,German ,03 medical and health sciences ,0302 clinical medicine ,Who recommendations ,030228 respiratory system ,Family medicine ,Who guidelines ,language ,medicine ,030212 general & internal medicine ,business - Abstract
ZusammenfassungDie erfreulicherweise zunehmende Evidenz hat in den letzten Jahren mehrfache Änderungen der internationalen Empfehlungen für die Diagnostik und Therapie der resistenten Tuberkulose notwendig gemacht. In diesem Jahr hat die WHO umfassende Empfehlungen veröffentlicht, die die Entwicklungen der letzten Jahre berücksichtigen. Die aktuelle deutsche Tuberkuloseleitlinie erschien im Jahr 2017 und weicht in einigen Bereichen von diesen Empfehlungen ab. Hier werden die Neuerungen der WHO-Empfehlungen von 2020 für schnelle Diagnostik und die Therapie resistenter Tuberkulose zusammengefasst und relevante Abweichungen für Deutschland, Österreich und die Schweiz kommentiert. Eine Neubewertung der Literatur findet derzeit im Rahmen der Aktualisierung der deutschsprachigen AWMF-2k-Leitlinie statt.
- Published
- 2020
31. Bedaquiline-Resistant Tuberculosis: Dark Clouds on the Horizon
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Jan Heyckendorf, Sönke Andres, Stefan Niemann, Christoph Lange, Sabine Hofmann-Thiel, Florian P. Maurer, Rudolf Rumetshofer, Alexander Indra, Barbara Kalsdorf, Harald Hoffmann, and Matthias Merker
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Pulmonary and Respiratory Medicine ,Tuberculosis ,business.industry ,Antitubercular Agents ,Mycobacterium tuberculosis ,Drug resistance ,World Health Organization ,Critical Care and Intensive Care Medicine ,medicine.disease ,Clofazimine ,Resistant tuberculosis ,Virology ,chemistry.chemical_compound ,chemistry ,Drug Resistance, Multiple, Bacterial ,Germany ,Practice Guidelines as Topic ,Tuberculosis, Multidrug-Resistant ,Humans ,Medicine ,Diarylquinolines ,Bedaquiline ,business ,medicine.drug - Published
- 2020
32. Antibiotic Stewardship bei ambulant erworbener Pneumonie
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Miriam Songa Stegemann, Florian P. Maurer, and Fabian Leo
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medicine.medical_specialty ,business.industry ,Psychological intervention ,MEDLINE ,General Medicine ,medicine.disease ,Pneumonia ,Antibiotic resistance ,Ambulatory care ,Community-acquired pneumonia ,medicine ,Antimicrobial stewardship ,Antibiotic Stewardship ,Intensive care medicine ,business - Abstract
Antibiotic stewardship (ABS) denotes structured and continuous measures to improve the quality of prescribing anti-infectives. The aim is to achieve optimal treatment results and to minimize undesirable effects, especially the emergence of antibiotic resistance. This review summarizes the most important ABS principles based on recently published studies with implications for the management of community-acquired pneumonia. Local guidelines, education and training and “prospective audit and feedback” are established strategies to improve the management of patients with community-acquired pneumonia. However, the implementation of ABS programs requires trained personnel and may be impeded by limited structural and time resources. Hence, electronic health records and computer-based interventions are useful support for ABS programs and offer potential to facilitate ABS in inpatient and outpatient care. PCR-based rapid diagnostic tests, PCT-guided algorithms and penicillin allergy testing are suitable procedures to supplement ABS programs.
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- 2020
33. Investigating resistance in clinical Mycobacterium tuberculosis complex isolates with genomic and phenotypic antimicrobial susceptibility testing: a multicentre observational study
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Iris Finci, Audrey Albertini, Matthias Merker, Sönke Andres, Nino Bablishvili, Ivan Barilar, Tatiana Cáceres, Valeriu Crudu, Eduardo Gotuzzo, Nchimunya Hapeela, Harald Hoffmann, Christine Hoogland, Thomas A Kohl, Katharina Kranzer, Anna Mantsoki, Florian P Maurer, Mark P Nicol, Ecaterina Noroc, Sara Plesnik, Timothy Rodwell, Morten Ruhwald, Theresa Savidge, Max Salfinger, Elizabeth Streicher, Nestani Tukvadze, Robin Warren, Widaad Zemanay, Anna Zurek, Stefan Niemann, and Claudia M Denkinger
- Subjects
Microbiology (medical) ,antimicrobial susceptibility testing ,Antitubercular Agents ,Genomics ,Mycobacterium tuberculosis ,Microbiology ,Phenotype ,Infectious Diseases ,Virology ,Tuberculosis, Multidrug-Resistant ,Humans ,Tuberculosis ,multicentre observational study ,Prospective Studies ,Rifampin - Abstract
Whole-genome sequencing (WGS) of Mycobacterium tuberculosis complex has become an important tool in diagnosis and management of drug-resistant tuberculosis. However, data correlating resistance genotype with quantitative phenotypic antimicrobial susceptibility testing (AST) are scarce.In a prospective multicentre observational study, 900 clinical M tuberculosis complex isolates were collected from adults with drug-resistant tuberculosis in five high-endemic tuberculosis settings around the world (Georgia, Moldova, Peru, South Africa, and Viet Nam) between Dec 5, 2014, and Dec 12, 2017. Minimum inhibitory concentrations (MICs) and resulting binary phenotypic AST results for up to nine antituberculosis drugs were determined and correlated with resistance-conferring mutations identified by WGS.Considering WHO-endorsed critical concentrations as reference, WGS had high accuracy for prediction of resistance to isoniazid (sensitivity 98·8% [95% CI 98·5-99·0]; specificity 96·6% [95% CI 95·2-97·9]), levofloxacin (sensitivity 94·8% [93·3-97·6]; specificity 97·1% [96·7-97·6]), kanamycin (sensitivity 96·1% [95·4-96·8]; specificity 95·0% [94·4-95·7]), amikacin (sensitivity 97·2% [96·4-98·1]; specificity 98·6% [98·3-98·9]), and capreomycin (sensitivity 93·1% [90·0-96·3]; specificity 98·3% [98·0-98·7]). For rifampicin, pyrazinamide, and ethambutol, the specificity of resistance prediction was suboptimal (64·0% [61·0-67·1], 83·8% [81·0-86·5], and 40·1% [37·4-42·9], respectively). Specificity for rifampicin increased to 83·9% when borderline mutations with MICs overlapping with the critical concentration were excluded. Consequently, we highlighted mutations in M tuberculosis complex isolates that are often falsely identified as susceptible by phenotypic AST, and we identified potential novel resistance-conferring mutations.The combined analysis of mutations and quantitative phenotypes shows the potential of WGS to produce a refined interpretation of resistance, which is needed for individualised therapy, and eventually could allow differential drug dosing. However, variability of MIC data for some M tuberculosis complex isolates carrying identical mutations also reveals limitations of our understanding of the genotype and phenotype relationships (eg, including epistasis and strain genetic background).BillMelinda Gates Foundation, German Centre for Infection Research, German Research Foundation, Excellence Cluster Precision Medicine of Inflammation (EXC 2167), and Leibniz ScienceCampus EvoLUNG.
- Published
- 2022
34. The ESX-4 substrates, EsxU and EsxT, modulate Mycobacterium abscessus fitness
- Author
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Marion Lagune, Vincent Le Moigne, Matt D. Johansen, Flor Vásquez Sotomayor, Wassim Daher, Cécile Petit, Gina Cosentino, Laura Paulowski, Thomas Gutsmann, Matthias Wilmanns, Florian P. Maurer, Jean-Louis Herrmann, Fabienne Girard-Misguich, Laurent Kremer, Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche en Infectiologie de Montpellier (IRIM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Forschungszentrum Borstel - Research Center Borstel, EMBL Hamburg, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and LE MOIGNE, Vincent
- Subjects
Mycobacterium abscessus ,Immunology ,Mycobacterium tuberculosis ,0605 Microbiology, 1107 Immunology, 1108 Medical Microbiology ,Microbiology ,[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology ,Mycobacterium ,Mice ,Bacterial Proteins ,Virology ,Type VII Secretion Systems ,Mycobacterium marinum ,Genetics ,Animals ,Parasitology ,[SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology ,Molecular Biology ,Zebrafish - Abstract
ESX type VII secretion systems are complex secretion machineries spanning across the mycobacterial membrane and play an important role in pathogenicity, nutrient uptake and conjugation. We previously reported the role of ESX-4 in modulating Mycobacterium abscessus intracellular survival. The loss of EccB4 was associated with limited secretion of two effector proteins belonging to the WXG-100 family, EsxU and EsxT, and encoded by the esx-4 locus. This prompted us to investigate the function of M. abscessus EsxU and EsxT in vitro and in vivo. Herein, we show that EsxU and EsxT are substrates of ESX-4 and form a stable 1:1 heterodimer that permeabilizes artificial membranes. While expression of esxU and esxT was up-regulated in M. abscessus-infected macrophages, their absence in an esxUT deletion mutant prevented phagosomal membrane disruption while maintaining M. abscessus in an unacidified phagosome. Unexpectedly, the esxUT deletion was associated with a hyper-virulent phenotype, characterised by increased bacterial loads and mortality in mouse and zebrafish infection models. Collectively, these results demonstrate that the presence of EsxU and EsxT dampens survival and persistence of M. abscessus during infection.
- Published
- 2022
35. Emergence of bedaquiline resistance in a high tuberculosis burden country
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Christian Utpatel, Florian P. Maurer, Maja Reimann, Sönke Andres, Ivan Barilar, Stefan Niemann, Matthias Merker, Valeriu Crudu, Christoph Lange, Jan Heyckendorf, Ana Donica, Dumitru Chesov, and Elena Chesov
- Subjects
Pulmonary and Respiratory Medicine ,Drug ,medicine.medical_specialty ,Tuberculosis ,media_common.quotation_subject ,Antitubercular Agents ,Disease ,Drug resistance ,Pharmacology and Toxicology ,Microbiology in the medical area ,chemistry.chemical_compound ,Internal medicine ,Tuberculosis, Multidrug-Resistant ,medicine ,Mikrobiologi inom det medicinska området ,Humans ,Diarylquinolines ,media_common ,biology ,business.industry ,Mycobacterium tuberculosis ,medicine.disease ,biology.organism_classification ,Farmakologi och toxikologi ,Regimen ,Cross-Sectional Studies ,chemistry ,Mycobacterium tuberculosis complex ,Bedaquiline ,business ,Cohort study - Abstract
RationaleBedaquiline has been classified as a group A drug for the treatment of multidrug-resistant tuberculosis (MDR-TB) by the World Health Organization; however, globally emerging resistance threatens the effectivity of novel MDR-TB treatment regimens.ObjectivesWe analysed pre-existing and emerging bedaquiline resistance in bedaquiline-based MDR-TB therapies, and risk factors associated with treatment failure and death.MethodsIn a cross-sectional cohort study, we employed patient data, whole-genome sequencing (WGS) and phenotyping of Mycobacterium tuberculosis complex (MTBC) isolates. We could retrieve baseline isolates from 30.5% (62 out of 203) of all MDR-TB patients who received bedaquiline between 2016 and 2018 in the Republic of Moldova. This includes 26 patients for whom we could also retrieve a follow-up isolate.Measurements and main resultsAt baseline, all MTBC isolates were susceptible to bedaquiline. Among 26 patients with available baseline and follow-up isolates, four (15.3%) patients harboured strains which acquired bedaquiline resistance under therapy, while one (3.8%) patient was re-infected with a second bedaquiline-resistant strain. Treatment failure and death were associated with cavitary disease (p=0.011), and any additional drug prescribed in the bedaquiline-containing regimen with WGS-predicted resistance at baseline (OR 1.92 per unit increase, 95% CI 1.15–3.21; p=0.012).ConclusionsMDR-TB treatments based on bedaquiline require a functional background regimen to achieve high cure rates and to prevent the evolution of bedaquiline resistance. Novel MDR-TB therapies with bedaquiline require timely and comprehensive drug resistance monitoring.
- Published
- 2022
36. Sub-Lineage Specific Phenolic Glycolipid Patterns in the
- Author
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Nicolas, Gisch, Christian, Utpatel, Lisa M, Gronbach, Thomas A, Kohl, Ursula, Schombel, Sven, Malm, Karen M, Dobos, Danny C, Hesser, Roland, Diel, Udo, Götsch, Silke, Gerdes, Yassir A, Shuaib, Nyanda E, Ntinginya, Celso, Khosa, Sofia, Viegas, Glennah, Kerubo, Solomon, Ali, Sahal A, Al-Hajoj, Perpetual W, Ndung'u, Andrea, Rachow, Michael, Hoelscher, Florian P, Maurer, Dominik, Schwudke, Stefan, Niemann, Norbert, Reiling, and Susanne, Homolka
- Abstract
"Ancestral"
- Published
- 2021
37. The Use of Comparative Genomic Analysis for the Development of Subspecies-Specific PCR Assays for
- Author
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Winifred C, Akwani, Arnoud H M, van Vliet, Jordan O, Joel, Sönke, Andres, Margo, Diricks, Florian P, Maurer, Mark A, Chambers, and Suzanne M, Hingley-Wilson
- Subjects
Mycobacterium abscessus ,Humans ,Mycobacterium Infections, Nontuberculous ,Genomics ,Multiplex Polymerase Chain Reaction ,Anti-Bacterial Agents ,Mycobacterium - Published
- 2021
38. Ancient and recent differences in the intrinsic susceptibility of Mycobacterium tuberculosis complex to pretomanid
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Anna Bateson, Julio Ortiz Canseco, Timothy D. McHugh, Adam A. Witney, Silke Feuerriegel, Matthias Merker, Thomas A. Kohl, Christian Utpatel, Stefan Niemann, Sönke Andres, Katharina Kranzer, Florian P Maurer, Arash Ghodousi, Emanuele Borroni, Daniela Maria Cirillo, Maria Wijkander, Juan C. Toro, Ramona Groenheit, Jim Werngren, Diana Machado, Miguel Viveiros, Robin M. Warren, Frederick Sirgel, Anzaan Dippenaar, Claudio U. Köser, Eugene Sun, Juliano Timm, Instituto de Higiene e Medicina Tropical (IHMT), Global Health and Tropical Medicine (GHTM), and TB, HIV and opportunistic diseases and pathogens (THOP)
- Subjects
Pharmacology ,Microbiology (medical) ,Pharmacology. Therapy ,Antitubercular Agents ,Microbial Sensitivity Tests ,Mycobacterium tuberculosis ,Infectious Diseases ,SDG 3 - Good Health and Well-being ,Nitroimidazoles ,Humans ,Tuberculosis ,Pharmacology (medical) ,Human medicine ,Biology - Abstract
Objectives To develop a robust phenotypic antimicrobial susceptibility testing (AST) method with a correctly set breakpoint for pretomanid (Pa), the most recently approved anti-tuberculosis drug. Methods The Becton Dickinson Mycobacterial Growth Indicator Tube™ (MGIT) system was used at six laboratories to determine the MICs of a phylogenetically diverse collection of 356 Mycobacterium tuberculosis complex (MTBC) strains to establish the epidemiological cut-off value for pretomanid. MICs were correlated with WGS data to study the genetic basis of differences in the susceptibility to pretomanid. Results We observed ancient differences in the susceptibility to pretomanid among various members of MTBC. Most notably, lineage 1 of M. tuberculosis, which is estimated to account for 28% of tuberculosis cases globally, was less susceptible than lineages 2, 3, 4 and 7 of M. tuberculosis, resulting in a 99th percentile of 2 mg/L for lineage 1 compared with 0.5 mg/L for the remaining M. tuberculosis lineages. Moreover, we observed that higher MICs (≥8 mg/L), which probably confer resistance, had recently evolved independently in six different M. tuberculosis strains. Unlike the aforementioned ancient differences in susceptibility, these recent differences were likely caused by mutations in the known pretomanid resistance genes. Conclusions In light of these findings, the provisional critical concentration of 1 mg/L for MGIT set by EMA must be re-evaluated. More broadly, these findings underline the importance of considering the global diversity of MTBC during clinical development of drugs and when defining breakpoints for AST.
- Published
- 2021
39. TREATMENT OF MYCOBACTERIOSIS CAUSED BY MYCOBACTERIUM AVIUM SSP. HOMINISSUIS IN A GROUP OF CAPTIVE LOWLAND TAPIRS (TAPIRUS TERRESTRIS)
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Florian P. Maurer, Stefanie A. Barth, Sandra Marcordes, W. Nikolaus Kuehn-Velten, Alexander Sliwa, Lisa Grund, Doris Hillemann, and Imke Lueders
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Veterinary medicine ,General Veterinary ,biology ,medicine.drug_class ,business.industry ,Isoniazid ,General Medicine ,biology.organism_classification ,Antimycobacterial ,Clarithromycin ,Tapirus terrestris ,medicine ,Animal Science and Zoology ,Nontuberculous mycobacteria ,Respiratory system ,business ,Rifampicin ,Mycobacterium ,medicine.drug - Abstract
Tapirs are a taxonomic group with a high susceptibility to mycobacterial diseases. However, successful therapy has only been documented sporadically. Here treatment of mycobacteriosis diagnosed in three, one male and two female, lowland tapirs (Tapirus terrestris) in a zoo in Germany is reported. Two of the animals showed chronic mild respiratory signs, and conventional therapy did not improve the condition. Culture of broncho-alveolar lavage (BAL) samples was positive for Mycobacterium avium ssp. hominissuis. Upon airway endoscopy, bronchial edema and increased mucus production were visible. Initially, all three infected tapirs received oral antimycobacterial therapy consisting of 5 mg/kg body weight isoniazid, 10 mg/kg rifampicin, and 10 mg/kg clarithromycin q24h. Based on therapeutic drug level monitoring, the doses of rifampicin were adjusted to 12 and 15 mg/kg in the females and the male, respectively. The treatment with all three drugs was continued for 11 mon. Six months into treatment, the clinical condition resolved, and repeated BAL samples of all three tapirs tested negative for mycobacteria by culture. Here the approach for a treatment protocol with minimal side effects suitable to control infections with nontuberculous mycobacteria in lowland tapirs is reported.
- Published
- 2021
40. Late Breaking Abstract - Therapeutic drug monitoring in a patient with very advanced XDR-TB
- Author
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Markus Nowak, Eva Choong, Antal Martinecz, Hande Karaköse, Nick Verougstraete, Niklas Köhler, Robert A. Bonomo, Sönke Andres, Christina König, Andrew R. DiNardo, Jan Heyckendorf, Fabrizio Clarelli, Sebastian G. Wicha, Hans-Peter Grobbel, Harald Hoffmann, Charles A. Peloquin, Marga Teulen, Dagmar Schaub, Patricia Sanchez Carballo, Rob E. Aarnoutse, Matthias Merker, Stefan Niemann, Thomas B. Schön, Pia Abel zur Wiesch, Florian P. Maurer, Alain Verstraete, Christoph Lange, Dominik Schwudke, Jim Werngren, Barbara Kalsdorf, Doris Hillemann, Laurent A. Decosterd, Franziska Waldow, and Wiebke Knaack
- Subjects
medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Therapeutic drug monitoring ,medicine ,Intensive care medicine ,business - Published
- 2021
41. Prediction of anti-tuberculosis treatment duration based on a 22-gene transcriptomic model
- Author
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Sebastian Marwitz, January Weiner, Thierry Rolling, Victor Spinu, Dörte Nitschkowski, Florian P. Maurer, Marius Müller, Jan Heyckendorf, Anna M. Mandalakas, Jan Rybniker, Torsten Goldmann, Maja Reimann, Michael Hoelscher, Markus Unnewehr, Korkut Avsar, Helmut J. F. Salzer, Elmira Ibraim, Ioana D. Olaru, Andrea Rachow, Gunar Günther, Frank van Leth, Maren Schuhmann, Dagmar Schaub, Christoph Lange, Barbara Kalsdorf, Cristina Popa, Elena Terhalle, Patricia Sanchez-Carballo, Irina Kontsevaya, Isabelle Suárez, Stefan H. E. Kaufmann, Andrew R. DiNardo, Global Health, AII - Infectious diseases, APH - Global Health, APH - Methodology, and Health Economics and Health Technology Assessment
- Subjects
Adult ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Tuberculosis ,Antitubercular Agents/therapeutic use ,Treatment duration ,Antitubercular Agents ,MEDLINE ,Multidrug-Resistant/drug therapy ,610 Medicine & health ,Transcriptome ,Anti tuberculosis ,Internal medicine ,Tuberculosis, Multidrug-Resistant ,medicine ,Humans ,Tuberculosis, Pulmonary ,Gene ,Duration of Therapy ,business.industry ,Area under the curve ,medicine.disease ,Tuberculosis, Pulmonary/drug therapy ,Biomarker (medicine) ,Tuberculosis, Multidrug-Resistant/drug therapy ,business ,Pulmonary/drug therapy - Abstract
BackgroundThe World Health Organization recommends standardised treatment durations for patients with tuberculosis (TB). We identified and validated a host-RNA signature as a biomarker for individualised therapy durations for patients with drug-susceptible (DS)- and multidrug-resistant (MDR)-TB.MethodsAdult patients with pulmonary TB were prospectively enrolled into five independent cohorts in Germany and Romania. Clinical and microbiological data and whole blood for RNA transcriptomic analysis were collected at pre-defined time points throughout therapy. Treatment outcomes were ascertained by TBnet criteria (6-month culture status/1-year follow-up). A whole-blood RNA therapy-end model was developed in a multistep process involving a machine-learning algorithm to identify hypothetical individual end-of-treatment time points.Results50 patients with DS-TB and 30 patients with MDR-TB were recruited in the German identification cohorts (DS-GIC and MDR-GIC, respectively); 28 patients with DS-TB and 32 patients with MDR-TB in the German validation cohorts (DS-GVC and MDR-GVC, respectively); and 52 patients with MDR-TB in the Romanian validation cohort (MDR-RVC). A 22-gene RNA model (TB22) that defined cure-associated end-of-therapy time points was derived from the DS- and MDR-GIC data. The TB22 model was superior to other published signatures to accurately predict clinical outcomes for patients in the DS-GVC (area under the curve 0.94, 95% CI 0.9–0.98) and suggests that cure may be achieved with shorter treatment durations for TB patients in the MDR-GIC (mean reduction 218.0 days, 34.2%; pConclusionBiomarker-guided management may substantially shorten the duration of therapy for many patients with MDR-TB.
- Published
- 2021
42. Mycobacterium szulgai als Posititivkontrolle zur Detektion von Kontaminationen beim Nachweis des Mycobacterium tuberculosis-Komplexes durch eine spezifische 16S-rDNA-PCR an FFPE-Material
- Author
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Torsten Goldmann, Barbara Kalsdorf, Rosemarie Krupar, Florian P. Maurer, Sven Perner, Florian Stellmacher, and Doris Hillemann
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Sequence analysis ,Molecular pathology ,law ,Chemistry ,Molecular biology ,Polymerase chain reaction ,Pathology and Forensic Medicine ,law.invention - Abstract
Der Nachweis von Mycobacterium tuberculosis-Komplex-DNA durch PCR an formalinfixiertem Paraffinmaterial ist heutzutage integraler Bestandteil der molekularpathologischen Diagnostik. Wir beschreiben hier ein Verfahren, welches durch Anwendung von Mycobacterium szulgai als Positivkontrolle Kontaminationen detektiert und so zur Vermeidung falsch positiver Falle beitragt.
- Published
- 2021
43. Conserved and specialized functions of Type VII secretion systems in non-tuberculous mycobacteria
- Author
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Matthias Wilmanns, Matt D. Johansen, Cecile Petit, Christina Ritter, Kathrine S H Beckham, Florian P. Maurer, Flor Vásquez Sotomayor, Fabienne Girard-Misguich, Laurent Kremer, Marion Lagune, and Jean-Louis Herrmann
- Subjects
0303 health sciences ,biology ,030306 microbiology ,Mycobacterium smegmatis ,Virulence ,Mycobacterium abscessus ,biology.organism_classification ,Microbiology ,Mycobacterium tuberculosis ,03 medical and health sciences ,Secretion ,Mycobacterium xenopi ,Large group ,030304 developmental biology - Abstract
Non-tuberculous mycobacteria (NTM) are a large group of micro-organisms comprising more than 200 individual species. Most NTM are saprophytic organisms and are found mainly in terrestrial and aquatic environments. In recent years, NTM have been increasingly associated with infections in both immunocompetent and immunocompromised individuals, prompting significant efforts to understand the diverse pathogenic and signalling traits of these emerging pathogens. Since the discovery of Type VII secretion systems (T7SS), there have been significant developments regarding the role of these complex systems in mycobacteria. These specialised systems, also known as Early Antigenic Secretion (ESX) systems, are employed to secrete proteins across the inner membrane. They also play an essential role in virulence, nutrient uptake and conjugation. Our understanding of T7SS in mycobacteria has significantly benefited over the last few years, from the resolution of ESX-3 structure in Mycobacterium smegmatis , to ESX-5 structures in Mycobacterium xenopi and Mycobacterium tuberculosis . In addition, ESX-4, considered until recently as a non-functional system in both pathogenic and non-pathogenic mycobacteria, has been proposed to play an important role in the virulence of Mycobacterium abscessus ; an increasingly recognized opportunistic NTM causing severe lung diseases. These major findings have led to important new insights into the functional mechanisms of these biological systems, their implication in virulence, nutrient acquisitions and cell wall shaping, and will be discussed in this review.
- Published
- 2021
44. C25-modified rifamycin derivatives with improved activity againstMycobacterium abscessus
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Sonja Staack, Matt D. Johansen, Laura Berneking, Laura Paulowski, Lucia Asar, Nhi Van, Laurent Kremer, Yonatan Degefu, Holger Rohde, Katherine S. H. Beckham, Annabel Parret, Florian P. Maurer, Flor Vásquez Sotomayor, Keith Combrink, Bree B. Aldridge, Martin Aepfelbacher, and Matthias Wilmanns
- Subjects
Rifabutin ,biology ,Chemistry ,medicine.drug_class ,Antibiotics ,Biofilm ,Rifamycin ,Mycobacterium abscessus ,bacterial infections and mycoses ,Antimicrobial ,biology.organism_classification ,Microbiology ,Amikacin ,polycyclic compounds ,medicine ,Rifampicin ,medicine.drug - Abstract
Infections caused byMycobacterium abscessusare difficult to treat due to its intrinsic resistance to most antibiotics. Formation of biofilms and the capacity ofM. abscessusto survive inside host phagocytes further complicate eradication. Herein, we explored whether addition of a carbamate-linked group at the C25 position of rifamycin SV blocks enzymatic inactivation by ArrMab, an ADP-ribosyltransferase conferring resistance to rifampicin. Unlike rifampicin, 5j, a benzyl piperidine rifamycin derivative with a morpholino substituted C3 position, is not modified by purified ArrMab. Additionally, we show that the ArrMabD82 residue is essential for catalytic activity. Thermal profiling of ArrMabin the presence of 5j, rifampicin or rifabutin shows that 5j does not bind to ArrMab. We found that the activity of 5j is comparable to amikacin againstM. abscessusplanktonic cultures and pellicles. Critically, 5j also exerts potent antimicrobial activity againstM. abscessusin human macrophages and shows synergistic activity with amikacin and azithromycin.
- Published
- 2021
45. Conserved and specialized functions of Type VII secretion systems in non-tuberculous mycobacteria
- Author
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Marion, Lagune, Cecile, Petit, Flor Vásquez, Sotomayor, Matt D, Johansen, Kathrine S H, Beckham, Christina, Ritter, Fabienne, Girard-Misguich, Matthias, Wilmanns, Laurent, Kremer, Florian P, Maurer, and Jean-Louis, Herrmann
- Subjects
Bacterial Proteins ,Virulence ,Cell Wall ,Type VII Secretion Systems ,Humans ,Mycobacterium Infections, Nontuberculous ,Nontuberculous Mycobacteria - Abstract
Non-tuberculous mycobacteria (NTM) are a large group of micro-organisms comprising more than 200 individual species. Most NTM are saprophytic organisms and are found mainly in terrestrial and aquatic environments. In recent years, NTM have been increasingly associated with infections in both immunocompetent and immunocompromised individuals, prompting significant efforts to understand the diverse pathogenic and signalling traits of these emerging pathogens. Since the discovery of Type VII secretion systems (T7SS), there have been significant developments regarding the role of these complex systems in mycobacteria. These specialised systems, also known as Early Antigenic Secretion (ESX) systems, are employed to secrete proteins across the inner membrane. They also play an essential role in virulence, nutrient uptake and conjugation. Our understanding of T7SS in mycobacteria has significantly benefited over the last few years, from the resolution of ESX-3 structure in
- Published
- 2021
46. Nontuberculous Mycobacterial Pulmonary Disease from Mycobacterium hassiacum, Austria
- Author
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Doris Hillemann, Christian Paar, Florian P. Maurer, Bakari Chitechi, Monika Mitterhumer, Michael Mandl, Helmut J. F. Salzer, and Bernd Lamprecht
- Subjects
Lung Diseases ,Microbiology (medical) ,Imipenem ,Epidemiology ,medicine.drug_class ,030231 tropical medicine ,Mycobacterium Infections, Nontuberculous ,Pulmonary disease ,lcsh:Medicine ,Pulmonary infection ,Microbial Sensitivity Tests ,Antimycobacterial ,Microbiology ,lcsh:Infectious and parasitic diseases ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Research Letter ,medicine ,Humans ,Clinical significance ,lcsh:RC109-216 ,030212 general & internal medicine ,16S rRNA ,bacteria ,Mycobacterium hassiacum ,Mycobacteriaceae ,biology ,business.industry ,lcsh:R ,biology.organism_classification ,bacterial infections and mycoses ,antimycobacterials ,tuberculosis and other mycobacteria ,Nontuberculous Mycobacterial Pulmonary Disease from Mycobacterium hassiacum, Austria ,Infectious Diseases ,chemistry ,Austria ,Linezolid ,NTM-PD ,nontuberculous mycobacterial pulmonary disease ,Nontuberculous mycobacteria ,business ,medicine.drug - Abstract
The clinical relevance of newly described nontuberculous mycobacteria is often unclear. We report a case of pulmonary infection caused by Mycobacterium hassiacum in an immunocompetent patient in Austria who had chronic obstructive pulmonary disease. Antimicrobial drug susceptibility testing showed low MICs for macrolides, aminoglycosides, fluoroquinolones, tetracyclines, imipenem, and linezolid.
- Published
- 2020
47. What is the role of the EUCAST reference method for MIC testing of the Mycobacterium tuberculosis complex?
- Author
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Miguel Santin, Claudio U. Köser, Emmanuelle Cambau, Gunnar Kahlmeter, Delia Goletti, Florian P. Maurer, Jim Werngren, Miguel Viveiros, Mateja Janković, Jakko van Ingen, Daniela Maria Cirillo, Sophia B. Georghiou, Christian G. Giske, John D. Turnidge, Thomas B. Schön, and Gerard Lina
- Subjects
Microbiology (medical) ,Microbial Viability ,Tuberculosis ,biology ,business.industry ,Antitubercular Agents ,Microbial Sensitivity Tests ,Mycobacterium tuberculosis ,General Medicine ,biology.organism_classification ,medicine.disease ,Drug susceptibility testingEUCASTMDRMICTuberculosis ,Microbiology ,Infectious Diseases ,lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] ,Bacterial Proteins ,Mycobacterium tuberculosis complex ,Mutation ,Humans ,Medicine ,business - Abstract
This is a commentary about the role of EUCAST reference method for MIC testing of the Mycobacterium tuberculosis complex?
- Published
- 2020
48. The landscape of diagnostic mycobacteriology in Germany–challenges of decentralised care
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Jan Rupp, Ioana D. Olaru, Florian P. Maurer, E Mintken, and Katharina Kranzer
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Mycobacterium Infections, Nontuberculous ,Microbial Sensitivity Tests ,Smear microscopy ,Tuberculosis diagnosis ,Interquartile range ,Germany ,Surveys and Questionnaires ,Internal medicine ,Humans ,Tuberculosis ,Medicine ,Bacteriological Techniques ,Microscopy ,biology ,business.industry ,Nontuberculous Mycobacteria ,Mycobacterium tuberculosis ,Drug susceptibility ,Mycobacterium Infections ,biology.organism_classification ,Infectious Diseases ,Mycobacterium tuberculosis complex ,Laboratories ,business - Abstract
OBJECTIVE: To perform a nationwide inventory of diagnostic mycobacteriology services in Germany.METHOD: A survey was conducted among participants of the national mycobacteriology external quality assurance scheme asking for smear microscopy techniques, molecular assays, culture systems and drug susceptibility testing (DST) capacities for Mycobacterium tuberculosis complex (MTBC) and non-tuberculous mycobacteria (NTM), and numbers of processed/culture-positive samples, and DSTs performed in 2016.RESULTS: We found that 170/238 laboratories (71.4%) provided data. Numbers of samples processed for culture varied between 35 and 40 000 (median 1856, interquartile range [IQR] 761-3500). Specimen numbers culture-positive for MTBC or NTM ranged from 0 to 1895 (median 46, IQR 17-116), and from 0 to 833 (median 30, IQR 13-71), respectively. Numbers of performed first-line susceptibility tests varied between 3 and 1400 (median 36, IQR 28-78). Eight laboratories performed DST for NTM. Also, 26.9% of all laboratories did not offer rapid genotypic DST (gDST) from primary samples.CONCLUSION: The landscape of diagnostic mycobacteriology in Germany is highly heterogenic with considerable variations in sample numbers and testing methodologies. Shortcomings exist with respect to fluorochrome staining of primary samples, rapid gDST of MTBC, and DST of NTM. National guidelines need to be adapted accordingly.
- Published
- 2019
49. Rifamycin derivatives active against pathogenic rapidly-growing mycobacteria
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Bryant De Jesus, Sebastian Schmidl, Andrea Ramirez Ramos, Petronilo Morin, Stephanie Spring, Florian P. Maurer, Kira Elizondo, and Keith D. Combrink
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medicine.drug_class ,Clinical Biochemistry ,Pharmaceutical Science ,Microbial Sensitivity Tests ,Mycobacterium abscessus ,Monoclonal antibody ,01 natural sciences ,Biochemistry ,Mycobacterium ,Microbiology ,Mycobacterium tuberculosis ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Molecular Biology ,Molecular Structure ,biology ,010405 organic chemistry ,Chemistry ,Mycobacterium smegmatis ,Organic Chemistry ,Rifamycin ,bacterial infections and mycoses ,biology.organism_classification ,Rifamycins ,Anti-Bacterial Agents ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Molecular Medicine ,Rifampicin ,medicine.drug - Abstract
Infections due to rapidly growing mycobacteria (RGM), and in particular the RGM species Mycobacterium abscessus (Mab), are very difficult to treat and reports on novel therapeutic options are scarce. A hallmark of all pathogenic RGM species is their resistance to the four first-line drugs used to treat infections with Mycobacterium tuberculosis including rifampicin. This study demonstrates that modification of the rifampicin scaffold can restore rifampicin activity against the three most commonly isolated pathogenic RGM species including Mab. We also note that the structure-activity relationship for Mab is different as compared to the non-pathogenic RGM species Mycobacterium smegmatis.
- Published
- 2019
50. Secretome characterization of clinical isolates from the Mycobacterium abscessus complex provides insight into antigenic differences
- Author
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Rogelio Hernández-Pando, Florian P. Maurer, Flor Vásquez Sotomayor, Sönke Andres, Thomas Kohl, Stefan Niemann, Fernanda Cornejo-Granados, Juan Manuel Hurtado-Ramírez, Adrián Ochoa-Leyva, and Christian Utpatel
- Subjects
Bioinformatics ,In silico ,Mycobacterium Infections, Nontuberculous ,Virulence ,QH426-470 ,In silico analysis ,Mycobacterium abscessus ,Proteomics ,Homology (biology) ,Microbiology ,03 medical and health sciences ,Genetics ,Humans ,Gene ,030304 developmental biology ,M. abscessus subspecies ,0303 health sciences ,biology ,030306 microbiology ,Research ,Mycobacterium tuberculosis ,Antigenicity ,biology.organism_classification ,Vaccinology ,Secretory protein ,TP248.13-248.65 ,Biotechnology ,Mycobacterium - Abstract
Background Mycobacterium abscessus (MAB) is a widely disseminated pathogenic non-tuberculous mycobacterium (NTM). Like with the M. tuberculosis complex (MTBC), excreted / secreted (ES) proteins play an essential role for its virulence and survival inside the host. Here, we used a robust bioinformatics pipeline to predict the secretome of the M. abscessus ATCC 19977 reference strain and 15 clinical isolates belonging to all three MAB subspecies, M. abscessus subsp. abscessus, M. abscessus subsp. bolletii, and M. abscessus subsp. massiliense. Results We found that ~ 18% of the proteins encoded in the MAB genomes were predicted as secreted and that the three MAB subspecies shared > 85% of the predicted secretomes. MAB isolates with a rough (R) colony morphotype showed larger predicted secretomes than isolates with a smooth (S) morphotype. Additionally, proteins exclusive to the secretomes of MAB R variants had higher antigenic densities than those exclusive to S variants, independent of the subspecies. For all investigated isolates, ES proteins had a significantly higher antigenic density than non-ES proteins. We identified 337 MAB ES proteins with homologues in previously investigated M. tuberculosis secretomes. Among these, 222 have previous experimental support of secretion, and some proteins showed homology with protein drug targets reported in the DrugBank database. The predicted MAB secretomes showed a higher abundance of proteins related to quorum-sensing and Mce domains as compared to MTBC indicating the importance of these pathways for MAB pathogenicity and virulence. Comparison of the predicted secretome of M. abscessus ATCC 19977 with the list of essential genes revealed that 99 secreted proteins corresponded to essential proteins required for in vitro growth. Conclusions This study represents the first systematic prediction and in silico characterization of the MAB secretome. Our study demonstrates that bioinformatics strategies can help to broadly explore mycobacterial secretomes including those of clinical isolates and to tailor subsequent, complex and time-consuming experimental approaches accordingly. This approach can support systematic investigation exploring candidate proteins for new vaccines and diagnostic markers to distinguish between colonization and infection. All predicted secretomes were deposited in the Secret-AAR web-server (http://microbiomics.ibt.unam.mx/tools/aar/index.php).
- Published
- 2021
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