369 research outputs found

    When to change treatment of acute invasive aspergillosis: an expert viewpoint

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    Invasive aspergillosis (IA) is an acute infection affecting patients who are immunocompromised, as a result of receiving chemotherapy for malignancy, or immunosuppressant agents for transplantation or autoimmune disease. Whilst criteria exist to define the probability of infection for clinical trials, there is little evidence in the literature or clinical guidelines on when to change antifungal treatment in patients who are receiving prophylaxis or treatment for IA. To try and address this significant gap, an advisory board of experts was convened to develop criteria for the management of IA for use in designing clinical trials, which could also be used in clinical practice. For primary treatment failure, a change in antifungal therapy should be made: (i) when mycological susceptibility testing identifies an organism from a confirmed site of infection, which is resistant to the antifungal given for primary therapy, or a resistance mutation is identified by molecular testing; (ii) at, or after, 8 days of primary antifungal treatment if there is increasing serum galactomannan, or galactomannan positivity in serum, or bronchoalveolar lavage fluid when the antigen was previously undetectable, or there is sudden clinical deterioration, or a new clearly distinct site of infection is detected; and (iii) at, or after, 15 days of primary antifungal treatment if the patient is clinically stable but with >= 2 serum galactomannan measurements persistently elevated compared with baseline or increasing, or if the original lesions on CT or other imaging, show progression by >25% in size in the context of no apparent change in immune status

    Polymorphisms within the ARNT2 and CX3CR1 Genes Are Associated with the Risk of Developing Invasive Aspergillosis.

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    Invasive aspergillosis (IA) is a life-threatening infection that affects an increasing number of patients undergoing chemotherapy or allo-transplantation, and recent studies have shown that genetic factors contribute to disease susceptibility. In this two-stage, population-based, case-control study, we evaluated whether 7 potentially functional single nucleotide polymorphisms (SNPs) within the ARNT2 and CX3CR1 genes influence the risk of IA in high-risk hematological patients. We genotyped selected SNPs in a cohort of 500 hematological patients (103 of those had been diagnosed with proven or probable IA), and we evaluated their association with the risk of developing IA. The association of the most interesting markers of IA risk was then validated in a replication population, including 474 subjects (94 IA and 380 non-IA patients). Functional experiments were also performed to confirm the biological relevance of the most interesting markers. The meta-analysis of both populations showed that carriers of the ARNT2rs1374213G, CX3CR1rs7631529A, and CX3CR1rs9823718G alleles (where the RefSeq identifier appears as a subscript) had a significantly increased risk of developing IA according to a log-additive model (P value from the meta-analysis [PMeta] = 9.8 · 10-5, PMeta = 1.5 · 10-4, and PMeta =7.9 · 10-5, respectively). Haplotype analysis also confirmed the association of the CX3CR1 haplotype with AG CGG with an increased risk of IA (P = 4.0 · 10-4). Mechanistically, we observed that monocyte-derived macrophages (MDM) from subjects carrying the ARNTR2rs1374213G allele or the GG genotype showed a significantly impaired fungicidal activity but that MDM from carriers of the ARNT2rs1374213G and CX3CR1rs9823718G or CX3CR1rs7631529A alleles had deregulated immune responses to Aspergillus conidia. These results, together with those from expression quantitative trait locus (eQTL) data browsers showing a strong correlation of the CX3CR1rs9823718G allele with lower levels of CX3CR1 mRNA in whole peripheral blood (P = 2.46 · 10-7) and primary monocytes (P = 4.31 · 10-7), highlight the role of the ARNT2 and CX3CR1 loci in modulating and predicting IA risk and provide new insights into the host immune mechanisms involved in IA development

    Polymorphisms within the ARNT2 and CX3CR1 Genes Are Associated with the Risk of Developing Invasive Aspergillosis

    No full text
    Invasive aspergillosis (IA) is a life-threatening infection that affects an increasing number of patients undergoing chemotherapy or allo-transplantation, and recent studies have shown that genetic factors contribute to disease susceptibility. In this two-stage, population-based, case-control study, we evaluated whether 7 potentially functional single nucleotide polymorphisms (SNPs) within the ARNT2 and CX3CR1 genes influence the risk of IA in high-risk hematological patients. We genotyped selected SNPs in a cohort of 500 hematological patients (103 of those had been diagnosed with proven or probable IA), and we evaluated their association with the risk of developing IA. The association of the most interesting markers of IA risk was then validated in a replication population, including 474 subjects (94 IA and 380 non-IA patients). Functional experiments were also performed to confirm the biological relevance of the most interesting markers. The meta-analysis of both populations showed that carriers of the ARNT2rs1374213G, CX3CR1rs7631529A, and CX3CR1rs9823718G alleles (where the RefSeq identifier appears as a subscript) had a significantly increased risk of developing IA according to a log-additive model (P value from the meta-analysis [PMeta]\u2009=\u20099.8 \ub7 10-5, PMeta\u2009=\u20091.5 \ub7 10-4, and PMeta\u2009=7.9 \ub7 10-5, respectively). Haplotype analysis also confirmed the association of the CX3CR1 haplotype with AG CGG with an increased risk of IA (P\u2009=\u20094.0 \ub7 10-4). Mechanistically, we observed that monocyte-derived macrophages (MDM) from subjects carrying the ARNTR2rs1374213G allele or the GG genotype showed a significantly impaired fungicidal activity but that MDM from carriers of the ARNT2rs1374213G and CX3CR1rs9823718G or CX3CR1rs7631529A alleles had deregulated immune responses to Aspergillus conidia. These results, together with those from expression quantitative trait locus (eQTL) data browsers showing a strong correlation of the CX3CR1rs9823718G allele with lower levels of CX3CR1 mRNA in whole peripheral blood (P\u2009=\u20092.46 \ub7 10-7) and primary monocytes (P\u2009=\u20094.31 \ub7 10-7), highlight the role of the ARNT2 and CX3CR1 loci in modulating and predicting IA risk and provide new insights into the host immune mechanisms involved in IA development

    Impact of fluconazole susceptibility on the outcome of patients with candidaemia: data from a population-based surveillance

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    CANDIPOP Project: B. Padilla, P. Muñoz, J. Guinea, J. R. Paño Pardo, J. García-Rodríguez, C. G. Cerrada, J. Fortún, P. Martín, E. Gómez, P. Ryan, C. Campelo, I. de los Santos, Gil, V. Buendía, B. P. Gorricho, M. Alonso, F. S. Sanz, J. M. Aguado, P. Merino, F. González Romo, M. Gorgolas, I. Gadea, J. E. Losa, A. Delgado-Iribarren, A. Ramos, Y. Romero, I. S. Romero, O. Zaragoza, M. Cuenca-Estrella, J. Rodríguez-Baño, A. I. Suarez, A. Loza, A. I. Aller García, E. Martín-Mazuelos, M. R. Pérez de Pipaón, J. Garnacho, C. Ortiz, M. Chávez, F. L. Maroto, M. Salavert, J. Pemán, J. Blanquer, D. Navarro, J. J. Camarena, R. Zaragoza, V. Abril, C. Gimeno, S. Hernández, G. Ezpeleta, E. Bereciartua, J. L. Hernández Almaraz, M. Montejo, R. A. Rivas, R. Ayarza, A. M. Planes, I. R. Camps, B. Almirante, J. Mensa, M. Almela, M. Gurgui, F. Sánchez-Reus, J. Martínez-Montauti, M. Sierra, J. P. Horcajada, L.Sorli, J. Gómez, A. Gené, M. Urrea, A. Mularoni, M.Valerio, A. Díaz-Martín, F. Puchades.[Objectives] The clinical correlation of fluconazole antifungal susceptibility testing (AST) for Candida isolates and its integration with pharmacokinetics/pharmacodynamics (PK/PD) parameters is unclear. We analysed the impact of fluconazole minimum inhibitory concentration (MIC) values, 24-hour area under the concentration–time curve (AUC24) and AUC24/MIC ratio on the outcome of candidemic patients.[Methods] We included 257 episodes of candidaemia treated with fluconazole monotherapy for ≥72 hours from a population-based surveillance conducted in 29 hospitals (CANDIPOP Project). AST was centrally performed by European Committee on Antimicrobial Susceptibility Testing (EUCAST) and Clinical and Laboratory Standards Institute (CLSI) microdilution methods. Primary outcome was clinical failure (30-day mortality and/or persistent candidaemia for ≥72 hours from initiation of therapy). Secondary outcomes included early (3–7 days) and late (3–30 days) mortality.[Results] Rates of clinical failure, early and late mortality among evaluable episodes were 32.3% (80/248), 3.1% (8/257) and 23.4% (59/248). There was no relationship between fluconazole MIC values or PK/PD parameters and clinical failure. Although MIC values ≥2 mg/L by EUCAST (positive predictive value 32.1%, negative predictive value 68.7%) and ≥0.5 mg/L by CLSI (positive predictive value 34.8%, negative predictive value 74.4%) appeared to be optimal for predicting clinical failure, no significant associations remained after multivariate adjustment (odds ratio 1.67; 95% confidence interval 0.48–5.79; p 0.423). Lack of association was consistent for alternative thresholds (including proposed clinical breakpoints). The only association found for secondary outcomes was between an AUC24/MIC ratio >400 h by CLSI and early mortality (odds ratio 0.18; 95% confidence interval 0.04–0.98; p 0.026).[Conclusions] High fluconazole MIC values did not negatively impact outcome of patients with candidaemia treated with fluconazole. No effect of PK/PD targets on the risk of clinical failure was found.Supported in part by nonrestrictive research grants from Gilead, MSD, Astellas and Pfizer. This study was cofunded by Fundación SEIMC-GESIDA; the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III (cofinanced by the European Development Regional Fund (ERDF) ‘A Way to Achieve Europe’); and the Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015). MFR holds a ‘Juan Rodés’ clinical research contract (JR14/00036) and JG a ‘Miguel Servet’ contract (CPII15/00006), both from the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III. MFR has received honoraria for talks on behalf of Pfizer and Gilead Sciences. JG has received grant support from Astellas Pharma, MICOLAB, the Mutua Madrileña Foundation and the Spanish Health Research Fund (FIS). He has been paid for talks on behalf of Gilead Sciences, Merck Sharp & Dohme, Pfizer, Astellas Pharma, Hickma Pharmaceutica and United Medical. BA has received grant support from Gilead Sciences, Pfizer and the Instituto de Salud Carlos III. He has received honoraria for talks on behalf of Gilead Sciences, Merck Sharp & Dohme, Pfizer, Astellas Pharma and Novartis. BP has received honoraria for talks on behalf of Gilead Sciences, Merck Sharp & Dohme, Pfizer, Astellas Pharma and Novartis. MCE has received grant support from Astellas Pharma, bioMérieux, Gilead Sciences, Merck Sharp & Dohme, Pfizer, Schering Plough, Soria Melguizo SA, Ferrer International, the Europea Union, the ALBAN program, the Spanish Agency for International Cooperation, the Spanish Ministry of Culture and Education, the Spanish Health Research Fund, the Instituto de Salud Carlos III (Spanish Ministry of Economy and Competitiveness), the Ramon Areces Foundation and the Mutua Madrileña Foundation

    Evaluation of the possible influence of trailing and paradoxical effects on the clinical outcome of patients with candidemia

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    CANDIPOP Project from GEIH-GEMICOMED (SEIMC) and REIPI: B. Padilla, P. Muñoz, J. Guinea, J. R. Paño Pardo, J. García-Rodríguez, C. García Cerrada, J. Fortún, P. Martín, E. Gómez, P. Ryan, C. Campelo, I. de los Santos Gil, V. Buendía, B. P. Gorricho, M. Alonso, F. S. Sanz, J. M. Aguado, P. Merino, F. González Romo, M. Gorgolas, I. Gadea, J. E. Losa, A. Delgado-Iribarren, A. Ramos, Y. Romero, I. Sánchez Romero, O. Zaragoza, M. Cuenca-Estrella, J. Rodriguez-Baño, A. Isabel Suarez, A. Loza, A. I. Aller García, E. Martín-Mazuelos, M. R. Pérez de Pipaón, J. Garnacho, C. Ortiz, M. Chávez, F. L. Maroto, M. Salavert, J. Pemán, J. Blanquer, D. Navarro, J. J. Camarena, R. Zaragoza, V. Abril, C. Gimeno, S. Hernáez, G. Ezpeleta, E. Bereciartua, J. L. Hernández Almaraz, M. Montejo, R. A. Rivas, R. Ayarza, A. M. Planes, I. R. Camps, B. Almirante, J. Mensa, M. Almela, M. Gurgui, F. Sánchez-Reus, J. Martinez-Montauti, M. Sierra, J. P. Horcajada, L. Sorli, J. Gómez, A. Gené, M. Urrea, M. Valerio, A. Díaz-Martín, F. Puchades, A. Mularoni.[Objective] Paradoxical growth (PG) and trailing effect (TE) are frequently observed during antifungal susceptibility testing (AFST). These two phenomena interfere with the determination of the minimal inhibitory concentration (MIC). The aim of this study was to assess the clinical impact of TE and PG.[Methods] We analysed the frequency of TE and PG of 690 Candida isolates collected from a population-based study performed in Spain (CANDIPOP) and correlated the results with clinical outcome of the patients.[Results] Around 70% (484/690) of the isolates exhibited TE to azoles. Candida tropicalis showed the highest presence of TE (39/53 isolates exhibited residual growth >25% of control). No TE was seen in most of the isolates from the psilosis complex. PG was mainly associated with echinocandins. In patients treated with fluconazole within the first 48 hours after blood sampling (n = 221), the presence of TE to azoles tended to be associated with lower 30-day mortality (odds ratio (OR) 0.55, 95% confidence interval (CI) 0.25–1.00) but not with clinical failure (OR 0.85, 95% CI 0.45–1.54). In the subgroup of 117 patients treated with echinocandins, the presence of PG was not associated with patient's response to antifungal treatment (OR for 30-day mortality 1.63, 95% CI 0.76–4.03; OR for clinical failure 1.17, 95% CI 0.53–2.70).[Conclusions] TE or PG are widely expressed among Candida spp., although they do not seem to influence clinical outcome.C. Rueda was funded by a Sara Borrell contract from the Fondo de Investigaciones Sanitarias (FIS, reference number CD11/00110). O. Zaragoza was funded by grant SAF2014-54336-R from the Spanish Ministry for Economics and Competitivity. The CANDIPOP study was funded by research grants from Gilead, MSD, Astellas and Pfizer and by funding from the Fundacion SEIMC-GESIDA and the Ministerio de Economía y Competitividad, Instituto de Salud Carlos III, cofinanced by the European Development Regional Fund ‘A way to achieve Europe’ ERDF and the Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015). MC-E has received grant support from Astellas Pharma, bioMerieux, Gilead Sciences, Merck Sharp & Dohme, Pfizer, Schering-Plough, Soria Melguizo SA, Ferrer International, the Europea Union, the ALBAN program, the Spanish Agency for International Cooperation, the Spanish Ministry of Culture and Education, the Spanish Health Research Fund, the Instituto de Salud Carlos III (Spanish Ministry of Economy and Competitiveness), the Ramón Areces Foundation and the Mutua Madrileña Foundation

    Empirical and targeted therapy of candidemia with fluconazole versus echinocandins: a propensity score-derived analysis of a population-based, multicentre prospective cohort

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    CANDIPOP Project from GEIH-GEMICOMED (SEIMC) and REIPI.We compared the clinical efficacy of fluconazole and echinocandins in the treatment of candidemia in real practice. The CANDIPOP study is a prospective, population-based cohort study on candidemia carried out between May 2010 and April 2011 in 29 Spanish hospitals. Using strict inclusion criteria, we separately compared the impact of empirical and targeted therapy with fluconazole or echinocandins on 30-day mortality. Cox regression, including a propensity score (PS) for receiving echinocandins, stratified analysis on the PS quartiles and PS-based matched analyses, were performed. The empirical and targeted therapy cohorts comprised 316 and 421 cases, respectively; 30-day mortality was 18.7% with fluconazole and 33.9% with echinocandins (p 0.02) in the empirical therapy group and 19.8% with fluconazole and 27.7% with echinocandins (p 0.06) in the targeted therapy group. Multivariate Cox regression analysis including PS showed that empirical therapy with fluconazole was associated with better prognosis (adjusted hazard ratio 0.38; 95% confidence interval 0.17–0.81; p 0.01); no differences were found within each PS quartile or in cases matched according to PS. Targeted therapy with fluconazole did not show a significant association with mortality in the Cox regression analysis (adjusted hazard ratio 0.77; 95% confidence interval 0.41–1.46; p 0.63), in the PS quartiles or in PS-matched cases. The results were similar among patients with severe sepsis and septic shock. Empirical or targeted treatment with fluconazole was not associated with increased 30-day mortality compared to echinocandins among adults with candidemia.BA has received grant support from Gilead Sciences, Pfizer and the Instituto de Salud Carlos III, and he has received honoraria for talks on behalf of Gilead Sciences, Merck Sharp and Dohme, Pfizer, Astellas and Novartis. MCE has received grant support from Astellas Pharma, bioMerieux, Gilead Sciences, Merck Sharp and Dohme, Pfizer, Schering Plough, Soria Melguizo SA, Ferrer International, the European Union, the ALBAN programme, the Spanish Agency for International Cooperation, the Spanish Ministry of Culture and Education, the Spanish Health Research Fund, the Instituto de Salud Carlos III, the Ramon Areces Foundation and the Mutua Madrileña Foundation. MCE has received grant support from Astellas Pharma, bioMerieux, Gilead Sciences, Merck Sharp and Dohme, Pfizer, Schering Plough, Soria Melguizo SA, Ferrer International, the European Union, the ALBAN programme, the Spanish Agency for International Cooperation, the Spanish Ministry of Culture and Education, the Spanish Health Research Fund, the Instituto de Salud Carlos III, the Ramon Areces Foundation and the Mutua Madrileña Foundation

    Polymorphisms within the ARNT2 and CX3CR1 Genes Are Associated with the Risk of Developing Invasive Aspergillosis.

    No full text
    Invasive aspergillosis (IA) is a life-threatening infection that affects an increasing number of patients undergoing chemotherapy or allo-transplantation, and recent studies have shown that genetic factors contribute to disease susceptibility. In this two-stage, population-based, case-control study, we evaluated whether 7 potentially functional single nucleotide polymorphisms (SNPs) within the ARNT2 and CX3CR1 genes influence the risk of IA in high-risk hematological patients. We genotyped selected SNPs in a cohort of 500 hematological patients (103 of those had been diagnosed with proven or probable IA), and we evaluated their association with the risk of developing IA. The association of the most interesting markers of IA risk was then validated in a replication population, including 474 subjects (94 IA and 380 non-IA patients). Functional experiments were also performed to confirm the biological relevance of the most interesting markers. The meta-analysis of both populations showed that carriers of the ARNT2rs1374213G, CX3CR1rs7631529A, and CX3CR1rs9823718G alleles (where the RefSeq identifier appears as a subscript) had a significantly increased risk of developing IA according to a log-additive model (P value from the meta-analysis [PMeta] = 9.8 · 10-5, PMeta = 1.5 · 10-4, and PMeta =7.9 · 10-5, respectively). Haplotype analysis also confirmed the association of the CX3CR1 haplotype with AG CGG with an increased risk of IA (P = 4.0 · 10-4). Mechanistically, we observed that monocyte-derived macrophages (MDM) from subjects carrying the ARNTR2rs1374213G allele or the GG genotype showed a significantly impaired fungicidal activity but that MDM from carriers of the ARNT2rs1374213G and CX3CR1rs9823718G or CX3CR1rs7631529A alleles had deregulated immune responses to Aspergillus conidia. These results, together with those from expression quantitative trait locus (eQTL) data browsers showing a strong correlation of the CX3CR1rs9823718G allele with lower levels of CX3CR1 mRNA in whole peripheral blood (P = 2.46 · 10-7) and primary monocytes (P = 4.31 · 10-7), highlight the role of the ARNT2 and CX3CR1 loci in modulating and predicting IA risk and provide new insights into the host immune mechanisms involved in IA development.status: Published onlin
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