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      Klinische Erfahrungen mit Cefiderocol : Neue Therapieoption bei schweren Infektionen durch multiresistente gramnegative Erreger Translated title: Clinical experience using cefiderocol

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          Abstract

          Hintergrund

          Infektionen mit antibiotikaresistenten Bakterien stellen eine hohe Gesundheitsbelastung dar, da sie mit erhöhter Letalität assoziiert sind und längerfristige dramatische Beeinträchtigungen der Lebensqualität hervorrufen können. In Deutschland erkranken jährlich etwa 54.500 Menschen an Infektionen durch antibiotikaresistente Erreger, von denen etwa 2400 Menschen versterben. Infektionen mit multiresistenten gramnegativen Bakterien (MRGN), insbesondere mit carbapenemresistenten Erregern, stellen ein besonderes Risiko dar, da nur eine begrenzte Zahl an Therapieoptionen verfügbar ist.

          Fragestellung

          Wie sind die Ergebnisse aus Studien und Compassionate-Use-Programm mit dem neuen Siderophorantibiotikum Cefiderocol, das im April 2020 von der Europäischen Arzneimittel-Agentur (EMA) bei Erwachsenen zur Behandlung von Infektionen durch aerobe gramnegative Erreger zugelassen wurde, wenn nur begrenzte Behandlungsmöglichkeiten zur Verfügung stehen? Die Zulassung ist pathogenbasiert und fokusunabhängig [ 5].

          Ergebnisse

          Cefiderocol, das über einen innovativen Zelleintrittsmechanismus verfügt, ist als erstes β‑Laktam-Antibiotikum aus der Gruppe der Cephalosporine stabil gegenüber allen klinisch relevanten β‑Laktamasen, einschließlich Carbapenemasen, und hat eine hohe In-vitro-Wirksamkeit gegenüber carbapenemresistenten MRGN. Die Ergebnisse werden durch klinische Studien bei komplizierten Harnwegsinfektionen, nosokomialer Pneumonie/Beatmungspneumonie und schweren Infektionen durch carbapenemresistente Erreger bestätigt.

          Fazit

          Klinische Studiendaten sowie die Ergebnisse aus den weltweiten Erfahrungsberichten zeigen, dass Cefiderocol eine vielversprechende Behandlungsoption für schwere Infektionen durch multiresistente, insbesondere carbapenemresistente gramnegative Bakterien darstellt.

          Translated abstract

          Background

          Infections due to antibiotic-resistant bacteria are threatening modern healthcare, and antibacterial resistance has become one of the greatest threats to public health. In Germany 54,500 patients become infected with antibiotic-resistant bacteria per year, causing about 2400 attributable deaths. Rising resistance in Gram-negative bacteria especially carbapenem-resistant pathogens is of particular concern due to the lack of effective and safe alternative treatment options.

          Objective

          The results from trials and compassionate-use programs with the new antibiotic cefiderocol, which was approved by the European Medicines Agency (EMA) in April 2020 for the treatment of adults with infections caused by aerobic Gram-negative bacteria, are summarized.

          Results

          The new β‑lactam antibiotic cefiderocol is the first siderophore cephalosporin indicated for the treatment of infections due to aerobic Gram-negative organisms in adults with limited treatment options. Its chemical structure and its unique mechanism of action confer enhanced stability against β‑lactamases including all classes of clinically relevant carbapenemases. In vitro data show high antibacterial activity against multidrug resistant Gram-negative bacteria, Enterobacterales and nonfermenters, including carbapenem-resistant strains. In clinical trials, cefiderocol showed superiority in complicated urinary tract infection in comparison to imipenem and non-inferiority versus meropenem in hospital-acquired/ventilator-associated pneumonia patients and severe infections caused by carbapenem-resistant pathogens.

          Conclusion

          Clinical trial data and case reports identified in the literature search show that cefiderocol is a promising treatment option for severe infections caused by drug-resistant Gram-negative bacteria, particularly carbapenem-resistant bacteria.

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          Most cited references24

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          Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis

          Summary Background Infections due to antibiotic-resistant bacteria are threatening modern health care. However, estimating their incidence, complications, and attributable mortality is challenging. We aimed to estimate the burden of infections caused by antibiotic-resistant bacteria of public health concern in countries of the EU and European Economic Area (EEA) in 2015, measured in number of cases, attributable deaths, and disability-adjusted life-years (DALYs). Methods We estimated the incidence of infections with 16 antibiotic resistance–bacterium combinations from European Antimicrobial Resistance Surveillance Network (EARS-Net) 2015 data that was country-corrected for population coverage. We multiplied the number of bloodstream infections (BSIs) by a conversion factor derived from the European Centre for Disease Prevention and Control point prevalence survey of health-care-associated infections in European acute care hospitals in 2011–12 to estimate the number of non-BSIs. We developed disease outcome models for five types of infection on the basis of systematic reviews of the literature. Findings From EARS-Net data collected between Jan 1, 2015, and Dec 31, 2015, we estimated 671 689 (95% uncertainty interval [UI] 583 148–763 966) infections with antibiotic-resistant bacteria, of which 63·5% (426 277 of 671 689) were associated with health care. These infections accounted for an estimated 33 110 (28 480–38 430) attributable deaths and 874 541 (768 837–989 068) DALYs. The burden for the EU and EEA was highest in infants (aged <1 year) and people aged 65 years or older, had increased since 2007, and was highest in Italy and Greece. Interpretation Our results present the health burden of five types of infection with antibiotic-resistant bacteria expressed, for the first time, in DALYs. The estimated burden of infections with antibiotic-resistant bacteria in the EU and EEA is substantial compared with that of other infectious diseases, and has increased since 2007. Our burden estimates provide useful information for public health decision-makers prioritising interventions for infectious diseases. Funding European Centre for Disease Prevention and Control.
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            Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial

            New antibiotics are needed for the treatment of patients with life-threatening carbapenem-resistant Gram-negative infections. We assessed the efficacy and safety of cefiderocol versus best available therapy in adults with serious carbapenem-resistant Gram-negative infections.
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              Past and Present Perspectives on β-Lactamases

              Karen Bush (2018)
              β-Lactamases, the major resistance determinant for β-lactam antibiotics in Gram-negative bacteria, are ancient enzymes whose origins can be traced back millions of years. These well-studied enzymes, currently numbering almost 2800 unique proteins, initially emerged from environmental sources, most likely to protect a producing bacterium from attack by naturally-occurring β-lactams. Their ancestors were presumably penicillin-binding proteins that share sequence homology with β-lactamases possessing an active site serine. Metallo-β-lactamases also exist, with one, or two, catalytically functional zinc ions. Although penicillinases in Gram-positive bacteria were reported shortly after penicillin was introduced clinically, transmissible β-lactamases that could hydrolyze recently-approved cephalosporins, monobactams and carbapenems later became important in Gram-negative pathogens. Nomenclature is based on one of two major systems. Originally, functional classifications were used, based on substrate and inhibitor profiles. A later scheme classifies β-lactamases according to amino acid sequences, resulting in class A, B, C and D enzymes. A more recent nomenclature combines the molecular and biochemical classifications into 17 functional groups that describe most β-lactamases. Some of the most problematic enzymes in the clinical community include extended-spectrum β-lactamases (ESBLs) and the serine and metallo-carbapenemases, all of which are at least partially addressed with new β-lactamase inhibitor combinations. New enzyme variants continue to be described, partly because of the ease of obtaining sequence data from whole genome sequencing studies. Often these new enzymes are devoid of any phenotypic descriptions, making it more difficult for clinicians and antibiotic researchers to address new challenges that may be posed by unusual β-lactamases.
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                Author and article information

                Contributors
                oliver.witzke@uk-essen.de
                Journal
                Med Klin Intensivmed Notfmed
                Med Klin Intensivmed Notfmed
                Medizinische Klinik, Intensivmedizin Und Notfallmedizin
                Springer Medizin (Heidelberg )
                2193-6218
                2193-6226
                1 August 2022
                1 August 2022
                : 1-7
                Affiliations
                [1 ]GRID grid.5718.b, ISNI 0000 0001 2187 5445, Klinik für Infektiologie, Westdeutsches Zentrum für Infektiologie, Universitätsmedizin Essen, , Universität Duisburg-Essen, ; Hufelandstr. 55, 45122 Essen, Deutschland
                [2 ]GRID grid.5718.b, ISNI 0000 0001 2187 5445, Klinik für Anästhesiologie und Intensivmedizin, , Universitätsmedizin Essen, Universität Duisburg-Essen, ; Essen, Deutschland
                Author notes
                [Redaktion]

                Michael Buerke, Siegen

                Author information
                http://orcid.org/0000-0002-1019-1301
                Article
                925
                10.1007/s00063-022-00925-5
                9341408
                35913604
                2c2d02ba-9aaa-48e3-ad54-e4f770a1ff8f
                © The Author(s) 2022

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                History
                : 4 August 2021
                : 1 March 2022
                : 21 April 2022
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100005612, shionogi;
                Categories
                Übersichten

                kritisch kranke patienten,pseudomonas aeruginosa,4mrgn,enterobacterales,siderophor-cephalosporin,critically ill patients,xdr,siderophore-cephalosporin

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