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Wilbert H M Heijne - One of the best experts on this subject based on the ideXlab platform.
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genome sequencing and analysis of the filamentous fungus penicillium chrysogenum
Nature Biotechnology, 2008Co-Authors: Marco A Van Den Berg, Richard Albang, Kaj Albermann, Carlos Garciaestrada, Natalie D Fedorova, Diana M Harris, Jean-marc Daran, Jonathan H Badger, Arnold J. M. Driessen, Wilbert H M HeijneAbstract:Penicillins and derived β-lactam antibiotics are essential in healthcare. To gain more insight into Penicillin synthesis van den Berg and colleagues sequence and analyze the genome and transcriptome of the filamentous fungus Penicillium chrysogenum.
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genome sequencing and analysis of the filamentous fungus penicillium chrysogenum
Nature Biotechnology, 2008Co-Authors: Marco Van Den Berg, Richard Albang, Kaj Albermann, Carlos Garciaestrada, Natalie D Fedorova, Diana M Harris, Jean-marc Daran, Jonathan H Badger, Arnold J. M. Driessen, Wilbert H M HeijneAbstract:Industrial Penicillin production with the filamentous fungus Penicillium chrysogenum is based on an unprecedented effort in microbial strain improvement. To gain more insight into Penicillin synthesis, we sequenced the 32.19 Mb genome of P. chrysogenum Wisconsin54-1255 and identified numerous genes responsible for key steps in Penicillin production. DNA microarrays were used to compare the transcriptomes of the sequenced strain and a PenicillinG high-producing strain, grown in the presence and absence of the side-chain precursor phenylacetic acid. Transcription of genes involved in biosynthesis of valine, cysteine and alpha-aminoadipic acid-precursors for Penicillin biosynthesis-as well as of genes encoding microbody proteins, was increased in the high-producing strain. Some gene products were shown to be directly controlling beta-lactam output. Many key cellular transport processes involving Penicillins and intermediates remain to be characterized at the molecular level. Genes predicted to encode transporters were strongly overrepresented among the genes transcriptionally upregulated under conditions that stimulate PenicillinG production, illustrating potential for future genomics-driven metabolic engineering.
Carsten Bindslevjensen - One of the best experts on this subject based on the ideXlab platform.
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is a positive intracutaneous test induced by Penicillin mediated by histamine a cutaneous microdialysis study in Penicillin allergic patients
Clinical and Translational Allergy, 2017Co-Authors: Line K. Tannert, Carsten Bindslevjensen, Sidsel Falkencrone, Charlotte G. Mortz, Per Stahl SkovAbstract:Background Diagnostic workup of Penicillin allergy comprises skin testing with Penicillins, and patients are deemed allergic if skin test is positive. However, the literature suggests that skin test-positive patients may be challenge-negative, indicating that the skin test may be falsely positive.
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is a positive intracutaneous test induced by Penicillin mediated by histamine a cutaneous microdialysis study in Penicillin allergic patients
Clinical and Translational Allergy, 2017Co-Authors: Line K. Tannert, Carsten Bindslevjensen, Sidsel Falkencrone, Charlotte G. Mortz, Per Stahl SkovAbstract:Diagnostic workup of Penicillin allergy comprises skin testing with Penicillins, and patients are deemed allergic if skin test is positive. However, the literature suggests that skin test-positive patients may be challenge-negative, indicating that the skin test may be falsely positive. To investigate real-time histamine release from a positive intracutaneous test induced by Penicillin in patients with positive and negative challenges to Penicillin. Skin microdialysis was performed in 21 Penicillin-allergic patients with positive skin test, 13 non-allergic volunteers serving as negative controls, and 7 grass pollen-allergic patients serving as positive controls. Histamine was measured by microdialysis after skin test with Penicillin/grass/NaCl. Penicillin challenge was subsequently performed in 12 of the patients. Only 10/21 patients (47.6%) were skin test positive at microdialysis. During microdialysis 13 single intracutaneous tests were positive and histamine was detected in 4/13 occurring in four challenge positive patients. Thirteen/21 patients (61.9%) were deemed allergic to Penicillin; eight had positive skin test. Two patients with positive skin test were challenge negative. In grass pollen allergic patients, 7/7 had a positive intracutaneous test to grass and all released histamine in the wheals. All 13 negative controls had negative intracutaneous test to Penicillin and no histamine release. Histamine was only detected in the minority of positive intracutaneous tests with Penicillin in Penicillin-allergic patients. Other mediators may be involved.
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positive serum specific ige has a short half life in patients with Penicillin allergy and reversal does not always indicate tolerance
Clinical and Translational Allergy, 2014Co-Authors: Janni Hjortlund, Charlotte G. Mortz, Per Stahl Skov, Tore Bjerregaard Stage, Ronald Dahl, Carsten BindslevjensenAbstract:Background The positive and negative predictive values of specific IgE to Penicillins are not well established for Penicillin hypersensitivity. One reason may be that serum IgE levels to Penicillin diminish over time. The objective in this study was to investigate variations in serum half-life (T½) for specific IgE to Penicillins (s-IgE) and to evaluate the outcome of Penicillin challenges in patients with previous but not present specific IgE to Penicillins.
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the prevalence of suspected and challenge verified Penicillin allergy in a university hospital population
Basic & Clinical Pharmacology & Toxicology, 2006Co-Authors: Jakob E Borch, Klaus Ejner Andersen, Carsten BindslevjensenAbstract:Abstract: Suspected Penicillin allergy is common among hospitalised patients, but the quality of the information given by the patient is often doubtful. Alleged Penicillin allergics are likely to be treated with more toxic, broad-spectered, and more expensive antibiotics, with effects on microbial resistance patterns and public economy as a consequence. We performed a cross-sectional case-control study with two visits to all clinical departments of a large university hospital in order to find in-patients with medical files labelled “Penicillin allergy” or who reported Penicillin allergy upon admission. Patient histories were obtained via a questionnaire, and they were offered investigation for Penicillin allergy with specific IgE, basophil histamine release, skin prick tests, intradermal tests and drug challenge tests. Finally, the pharmaco-economical consequences of the Penicillin allergy were estimated. In a cohort of 3642 patients, 96 fulfilled the inclusion criteria giving a point-prevalence of alleged Penicillin allergy of 5% in a hospital in-patient population. Mean time elapsed since the alleged first reaction to Penicillin was 20 years. The skin was the most frequently affected organ (82.2%), maculo-papular exanthema (35.4%) and urticaria (10.4%) being the most frequently reported reactions. 25% did not recall the time of their reaction. 82.2% did not remember the name of the Penicillin they reacted to. 34.8% had been treated with Penicillins after suspicion of Penicillin allergy had been raised. None of these reacted to Penicillins. 33.3% of the patients receiving antibiotics during their current hospitalisation were prescribed Penicillins. 2% developed non-severe exanthema. The average acquisition costs for antibiotics to Penicillin allergic patients were € 278, compared to € 119 had they been non-allergics. The prevalence of suspected Penicillin allergy was lower than reported elsewhere. A substantial number of patients failed to recall basic information about their alleged allergy. Patients reporting Penicillin allergy upon admission and labels stating Penicillin allergy on medical files are ignored in almost a third of patients receiving antibiotics. The acquisition costs for antibiotics to Penicillin allergic patients were higher, compared to the cost had the patients been non-allergics.
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the prevalence of suspected and challenge verified Penicillin allergy in a university hospital population
Basic & Clinical Pharmacology & Toxicology, 2006Co-Authors: Jakob E Borch, Klaus Ejner Andersen, Carsten BindslevjensenAbstract:Abstract: Suspected Penicillin allergy is common among hospitalised patients, but the quality of the information given by the patient is often doubtful. Alleged Penicillin allergics are likely to be treated with more toxic, broad-spectered, and more expensive antibiotics, with effects on microbial resistance patterns and public economy as a consequence. We performed a cross-sectional case-control study with two visits to all clinical departments of a large university hospital in order to find in-patients with medical files labelled “Penicillin allergy” or who reported Penicillin allergy upon admission. Patient histories were obtained via a questionnaire, and they were offered investigation for Penicillin allergy with specific IgE, basophil histamine release, skin prick tests, intradermal tests and drug challenge tests. Finally, the pharmaco-economical consequences of the Penicillin allergy were estimated. In a cohort of 3642 patients, 96 fulfilled the inclusion criteria giving a point-prevalence of alleged Penicillin allergy of 5% in a hospital in-patient population. Mean time elapsed since the alleged first reaction to Penicillin was 20 years. The skin was the most frequently affected organ (82.2%), maculo-papular exanthema (35.4%) and urticaria (10.4%) being the most frequently reported reactions. 25% did not recall the time of their reaction. 82.2% did not remember the name of the Penicillin they reacted to. 34.8% had been treated with Penicillins after suspicion of Penicillin allergy had been raised. None of these reacted to Penicillins. 33.3% of the patients receiving antibiotics during their current hospitalisation were prescribed Penicillins. 2% developed non-severe exanthema. The average acquisition costs for antibiotics to Penicillin allergic patients were € 278, compared to € 119 had they been non-allergics. The prevalence of suspected Penicillin allergy was lower than reported elsewhere. A substantial number of patients failed to recall basic information about their alleged allergy. Patients reporting Penicillin allergy upon admission and labels stating Penicillin allergy on medical files are ignored in almost a third of patients receiving antibiotics. The acquisition costs for antibiotics to Penicillin allergic patients were higher, compared to the cost had the patients been non-allergics.
Jean-marc Daran - One of the best experts on this subject based on the ideXlab platform.
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exploring and dissecting genome wide gene expression responses of penicillium chrysogenum to phenylacetic acid consumption and Penicilling production
BMC Genomics, 2009Co-Authors: Diana M Harris, Zita A Van Der Krogt, Paul Klaassen, Leonie M Raamsdonk, Susanne Hage, Marco Van Den Berg, Roel A L Bovenberg, Jack T Pronk, Jean-marc DaranAbstract:Since the discovery of the antibacterial activity of Penicillin by Fleming 80 years ago, improvements of Penicillin titer were essentially achieved by classical strain improvement through mutagenesis and screening. The recent sequencing of Penicillium chrysogenum strain Wisconsin1255-54 and the availability of genomics tools such as DNA-microarray offer new perspective. In studies on β-lactam production by P. chrysogenum, addition and omission of a side-chain precursor is commonly used to generate producing and non-producing scenarios. To dissect effects of PenicillinG production and of its side-chain precursor phenylacetic acid (PAA), a derivative of a PenicillinG high-producing strain without a functional Penicillin-biosynthesis gene cluster was constructed. In glucose-limited chemostat cultures of the high-producing and cluster-free strains, PAA addition caused a small reduction of the biomass yield, consistent with PAA acting as a weak-organic-acid uncoupler. Microarray-based analysis on chemostat cultures of the high-producing and cluster-free strains, grown in the presence and absence of PAA, showed that: (i) Absence of a Penicillin gene cluster resulted in transcriptional upregulation of a gene cluster putatively involved in production of the secondary metabolite aristolochene and its derivatives, (ii) The homogentisate pathway for PAA catabolism is strongly transcriptionally upregulated in PAA-supplemented cultures (iii) Several genes involved in nitrogen and sulfur metabolism were transcriptionally upregulated under PenicillinG producing conditions only, suggesting a drain of amino-acid precursor pools. Furthermore, the number of candidate genes for Penicillin transporters was strongly reduced, thus enabling a focusing of functional analysis studies. This study demonstrates the usefulness of combinatorial transcriptome analysis in chemostat cultures to dissect effects of biological and process parameters on gene expression regulation. This study provides for the first time clear-cut target genes for metabolic engineering, beyond the three genes of the β-lactam pathway.
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genome sequencing and analysis of the filamentous fungus penicillium chrysogenum
Nature Biotechnology, 2008Co-Authors: Marco A Van Den Berg, Richard Albang, Kaj Albermann, Carlos Garciaestrada, Natalie D Fedorova, Diana M Harris, Jean-marc Daran, Jonathan H Badger, Arnold J. M. Driessen, Wilbert H M HeijneAbstract:Penicillins and derived β-lactam antibiotics are essential in healthcare. To gain more insight into Penicillin synthesis van den Berg and colleagues sequence and analyze the genome and transcriptome of the filamentous fungus Penicillium chrysogenum.
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genome sequencing and analysis of the filamentous fungus penicillium chrysogenum
Nature Biotechnology, 2008Co-Authors: Marco Van Den Berg, Richard Albang, Kaj Albermann, Carlos Garciaestrada, Natalie D Fedorova, Diana M Harris, Jean-marc Daran, Jonathan H Badger, Arnold J. M. Driessen, Wilbert H M HeijneAbstract:Industrial Penicillin production with the filamentous fungus Penicillium chrysogenum is based on an unprecedented effort in microbial strain improvement. To gain more insight into Penicillin synthesis, we sequenced the 32.19 Mb genome of P. chrysogenum Wisconsin54-1255 and identified numerous genes responsible for key steps in Penicillin production. DNA microarrays were used to compare the transcriptomes of the sequenced strain and a PenicillinG high-producing strain, grown in the presence and absence of the side-chain precursor phenylacetic acid. Transcription of genes involved in biosynthesis of valine, cysteine and alpha-aminoadipic acid-precursors for Penicillin biosynthesis-as well as of genes encoding microbody proteins, was increased in the high-producing strain. Some gene products were shown to be directly controlling beta-lactam output. Many key cellular transport processes involving Penicillins and intermediates remain to be characterized at the molecular level. Genes predicted to encode transporters were strongly overrepresented among the genes transcriptionally upregulated under conditions that stimulate PenicillinG production, illustrating potential for future genomics-driven metabolic engineering.
Diana M Harris - One of the best experts on this subject based on the ideXlab platform.
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exploring and dissecting genome wide gene expression responses of penicillium chrysogenum to phenylacetic acid consumption and Penicilling production
BMC Genomics, 2009Co-Authors: Diana M Harris, Zita A Van Der Krogt, Paul Klaassen, Leonie M Raamsdonk, Susanne Hage, Marco Van Den Berg, Roel A L Bovenberg, Jack T Pronk, Jean-marc DaranAbstract:Since the discovery of the antibacterial activity of Penicillin by Fleming 80 years ago, improvements of Penicillin titer were essentially achieved by classical strain improvement through mutagenesis and screening. The recent sequencing of Penicillium chrysogenum strain Wisconsin1255-54 and the availability of genomics tools such as DNA-microarray offer new perspective. In studies on β-lactam production by P. chrysogenum, addition and omission of a side-chain precursor is commonly used to generate producing and non-producing scenarios. To dissect effects of PenicillinG production and of its side-chain precursor phenylacetic acid (PAA), a derivative of a PenicillinG high-producing strain without a functional Penicillin-biosynthesis gene cluster was constructed. In glucose-limited chemostat cultures of the high-producing and cluster-free strains, PAA addition caused a small reduction of the biomass yield, consistent with PAA acting as a weak-organic-acid uncoupler. Microarray-based analysis on chemostat cultures of the high-producing and cluster-free strains, grown in the presence and absence of PAA, showed that: (i) Absence of a Penicillin gene cluster resulted in transcriptional upregulation of a gene cluster putatively involved in production of the secondary metabolite aristolochene and its derivatives, (ii) The homogentisate pathway for PAA catabolism is strongly transcriptionally upregulated in PAA-supplemented cultures (iii) Several genes involved in nitrogen and sulfur metabolism were transcriptionally upregulated under PenicillinG producing conditions only, suggesting a drain of amino-acid precursor pools. Furthermore, the number of candidate genes for Penicillin transporters was strongly reduced, thus enabling a focusing of functional analysis studies. This study demonstrates the usefulness of combinatorial transcriptome analysis in chemostat cultures to dissect effects of biological and process parameters on gene expression regulation. This study provides for the first time clear-cut target genes for metabolic engineering, beyond the three genes of the β-lactam pathway.
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genome sequencing and analysis of the filamentous fungus penicillium chrysogenum
Nature Biotechnology, 2008Co-Authors: Marco A Van Den Berg, Richard Albang, Kaj Albermann, Carlos Garciaestrada, Natalie D Fedorova, Diana M Harris, Jean-marc Daran, Jonathan H Badger, Arnold J. M. Driessen, Wilbert H M HeijneAbstract:Penicillins and derived β-lactam antibiotics are essential in healthcare. To gain more insight into Penicillin synthesis van den Berg and colleagues sequence and analyze the genome and transcriptome of the filamentous fungus Penicillium chrysogenum.
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genome sequencing and analysis of the filamentous fungus penicillium chrysogenum
Nature Biotechnology, 2008Co-Authors: Marco Van Den Berg, Richard Albang, Kaj Albermann, Carlos Garciaestrada, Natalie D Fedorova, Diana M Harris, Jean-marc Daran, Jonathan H Badger, Arnold J. M. Driessen, Wilbert H M HeijneAbstract:Industrial Penicillin production with the filamentous fungus Penicillium chrysogenum is based on an unprecedented effort in microbial strain improvement. To gain more insight into Penicillin synthesis, we sequenced the 32.19 Mb genome of P. chrysogenum Wisconsin54-1255 and identified numerous genes responsible for key steps in Penicillin production. DNA microarrays were used to compare the transcriptomes of the sequenced strain and a PenicillinG high-producing strain, grown in the presence and absence of the side-chain precursor phenylacetic acid. Transcription of genes involved in biosynthesis of valine, cysteine and alpha-aminoadipic acid-precursors for Penicillin biosynthesis-as well as of genes encoding microbody proteins, was increased in the high-producing strain. Some gene products were shown to be directly controlling beta-lactam output. Many key cellular transport processes involving Penicillins and intermediates remain to be characterized at the molecular level. Genes predicted to encode transporters were strongly overrepresented among the genes transcriptionally upregulated under conditions that stimulate PenicillinG production, illustrating potential for future genomics-driven metabolic engineering.
Antonino Romano - One of the best experts on this subject based on the ideXlab platform.
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tolerability of cefazolin and ceftibuten in patients with ige mediated aminoPenicillin allergy
The Journal of Allergy and Clinical Immunology: In Practice, 2020Co-Authors: Antonino Romano, Rocco Luigi Valluzzi, Cristiano Caruso, Alessandra Zaffiro, Donato Quaratino, Francesco GaetaAbstract:Background Side-chain similarities or identities constitute the predominant factor for cross-reactivity between Penicillins and cephalosporins, whereas differences in the side-chain structure seem to account for the absence of such cross-reactivity. Objective We sought to assess the cross-reactivity between Penicillins and 2 cephalosporins (ie, cefazolin and ceftibuten) that have side chains different from those of Penicillins, as well as to evaluate the possibility of using these cephalosporins in Penicillin-allergic subjects. Methods We conducted a prospective study of 131 consecutive subjects who had suffered 170 immediate reactions (mostly anaphylaxis) to Penicillins and had positive skin test results to at least 1 Penicillin reagent. All patients underwent skin tests with cefazolin and ceftibuten. Patients with negative results were challenged with them. Results One participant had positive skin test results to cefazolin and ceftibuten, as well as to all other reagents tested, including aztreonam and carbapenems. All 129 subjects who underwent challenges with cefazolin and ceftibuten tolerated them. One subject refused cephalosporin challenges. Conclusions Subjects with an IgE-mediated hypersensitivity to Penicillins could be treated with cephalosporins such as cefazolin and ceftibuten, which are among the cephalosporins that have side-chain determinants different from those of Penicillins. Nevertheless, in patients with such hypersensitivity who need these alternative β-lactams, pretreatment skin tests are advisable because of the possibility of coexisting sensitivities or, much less frequently, of a sensitivity to an antigenic determinant of the common β-lactam ring.
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tolerability of aztreonam and carbapenems in patients with ige mediated hypersensitivity to Penicillins
The Journal of Allergy and Clinical Immunology, 2015Co-Authors: Francesco Gaeta, Rocco Luigi Valluzzi, Michela Maggioletti, Cristiano Caruso, C Alonzi, Antonino RomanoAbstract:Background Studies performed on samples larger than 100 subjects with a documented IgE-mediated hypersensitivity to Penicillins have demonstrated a cross-reactivity rate of approximately 1% between Penicillins and both imipenem and meropenem, whereas a single study found a cross-reactivity rate of 6.2% with aztreonam in 16 such subjects. Objective To assess the cross-reactivity and tolerability of aztreonam and 3 carbapenems (imipenem-cilastatin, meropenem, and ertapenem) in patients with documented IgE-mediated hypersensitivity to Penicillins. Methods A total of 212 consecutive subjects with immediate reactions to Penicillins and positive results on skin tests to at least 1 Penicillin reagent underwent skin tests with aztreonam and carbapenems; subjects with negative results were challenged with escalating doses of aztreonam and carbapenems. Results All subjects displayed negative skin test results to both aztreonam and carbapenems; 211 accepted challenges and tolerated them. Challenges were not followed by full therapeutic courses. Conclusions These data indicate the tolerability of both aztreonam and carbapenems in Penicillin-allergic subjects. In those who especially require these alternative β-lactams, however, we recommend pretreatment skin tests, both because rare cases of cross-reactivity have been reported and because negative results indicate tolerability.
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IgE-mediated hypersensitivity to cephalosporins: cross-reactivity and tolerability of Penicillins, monobactams, and carbapenems.
The Journal of allergy and clinical immunology, 2010Co-Authors: Antonino Romano, Francesco Gaeta, Rocco Luigi Valluzzi, Cristiano Caruso, Gabriele Rumi, Philippe BousquetAbstract:Background: There have been few studies regarding the cross-reactivity and tolerability of Penicillins, aztreonam, and carbapenems in large samples of subjects with cephalosporin allergy. Objective: We sought to evaluate the possibility of using Penicillins, monobactams, and carbapenems in subjects with cephalosporin allergy who especially require them. Methods: We conducted a prospective study of 98 consecutive subjects who had 106 immediate reactions (mostly anaphylactic shock) to cephalosporins and had positive skin test results for these drugs. To assess the cross-reactivity with Penicillins, monobactams, and carbapenems and the tolerability of such alternative b-lactams, all subjects underwent skin tests and serum-specific IgE assays with Penicillin reagents, as well as skin tests with aztreonam, imipenem/cilastatin, and meropenem. Subjects with negative test results were challenged with meropenem, imipenem/cilastatin, aztreonam, and amoxicillin. Results: Positive allergologic test results to Penicillins were displayed by 25 (25.5%) subjects, including 1 with positive results to all reagents tested and another with a positive result to aztreonam. Another subject had positive results to both ceftazidime and aztreonam. A reaction to cephalosporins with side-chain structures similar or identical to those of Penicillins was a significant predictor of cross-reactivity because of an increased 3-fold risk of positive results on allergologic tests with Penicillin determinants. Challenges with alternative b-lactams were tolerated, with the exception of 1 urticarial reaction to imipenem/cilastatin. Conclusions: About 25% of subjects with cephalosporin allergy had positive results to Penicillins, 3.1% to aztreonam, 2% to imipenem/cilastatin, and 1% to meropenem. In those who especially require alternative b-lactams, pretreatment skin tests are advisable because negative results indicate tolerability of the b-lactam concerned. (J Allergy Clin Immunol 2010;126:994-9.)
