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  • 1
    Online-Ressource
    Online-Ressource
    Early Use of Sarilumab in Patients Hospitalized with COVID-19 Pneumonia and Features of Systemic Inflammation: the SARICOR Randomized Clinical Trial
    American Society for Microbiology ; 2022
    In:  Antimicrobial Agents and Chemotherapy Vol. 66, No. 2 ( 2022-02-15)
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 66, No. 2 ( 2022-02-15)
    Kurzfassung: The objective of this study was to investigate the efficacy and safety of early treatment with sarilumab, added to standard of care (SOC), in hospitalized adults with COVID-19. Methods included phase II, open-label, randomized, controlled clinical trial of hospitalized patients with COVID-19 pneumonia and interleukin (IL)-6 levels ≥ 40 pg/mL and/or d-dimer  〉  1,500 ng/mL. Participants were randomized (1:1:1) to receive SOC (control group), SOC plus a single subcutaneous dose of sarilumab 200 mg (sarilumab-200 group), or SOC plus a single subcutaneous dose of sarilumab 400 mg (sarilumab-400 group). The primary outcome variable was the development of acute respiratory distress syndrome (ARDS) requiring high-flow nasal oxygenation (HFNO), non-invasive mechanical ventilation (NIMV) or invasive mechanical ventilation (IMV) at day 28. One-hundred and 15 participants (control group, n  = 39; sarilumab-200, n  = 37; sarilumab-400, n  = 39) were included. At randomization, 104 (90%) patients had supplemental oxygen and 103 (90%) received corticosteroids. Eleven (28%) patients in the control group, 10 (27%) in sarilumab-200, and five (13%) in sarilumab-400 developed the primary outcome (hazard ratio [95% CI] of sarilumab-400 vs control group: 0.41 [0.14, 1.18]; P  = 0.09). Seven (6%) patients died: three in the control group and four in sarilumab-200. There were no deaths in sarilumab-400 ( P  = 0.079, log-rank test for comparisons with the control group). In patients recently hospitalized with COVID-19 pneumonia and features of systemic inflammation, early IL-6 blockade with a single dose of sarilumab 400 mg was safe and associated with a trend for better outcomes. (This study has been registered at ClinicalTrials.gov under identifier NCT04357860.)
    Materialart: Online-Ressource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/aac.02107-21
    RVK:
    XA 24552
    Sprache: Englisch
    Verlag: American Society for Microbiology
    Publikationsdatum: 2022
    ZDB Id: 1496156-8
    SSG: 12
    SSG: 15,3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
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    New insights into the pathogenesis and transmission of Brucella pinnipedialis : systemic infection in two bottlenose dolphins ( Tursiops truncatus )
    American Society for Microbiology ; 2023
    In:  Microbiology Spectrum
    Details
    In: Microbiology Spectrum, American Society for Microbiology
    Kurzfassung: Brucella spp. are zoonotic pathogens that can affect both terrestrial and marine mammals. Brucella ceti has been identified in various cetacean species, but only one sequence type (ST27) has been reported in humans. However, it is important to conduct surveillance studies to better understand the impact of marine Brucella species on marine mammals, a typically understudied host group. Here, we describe a systemic infection by two related strains of Brucella pinnipedialis (ST25) in a couple of live-stranded bottlenose dolphins, with more severe lesions in the younger animal. Furthermore, B. pinnipedialis was first detected in milk from a female cetacean that stranded with its offspring. Our study reveals novel insights into the epidemiology and pathological consequences of B. pinnipedialis infections in cetaceans, emphasizing the crucial importance of ongoing surveillance and accurate diagnosis to understand the impact of this pathogen on marine mammal populations.
    Materialart: Online-Ressource
    ISSN: 2165-0497
    URL: Article
    DOI: 10.1128/spectrum.01997-23
    Sprache: Englisch
    Verlag: American Society for Microbiology
    Publikationsdatum: 2023
    ZDB Id: 2807133-5
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
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    Diagnostic Performance of the HCV Core Antigen Test To Identify Hepatitis C in HIV-Infected Patients: a Systematic Review and Meta-Analysis
    American Society for Microbiology ; 2023
    In:  Journal of Clinical Microbiology Vol. 61, No. 1 ( 2023-01-26)
    Details
    In: Journal of Clinical Microbiology, American Society for Microbiology, Vol. 61, No. 1 ( 2023-01-26)
    Kurzfassung: The standard algorithm for diagnosing hepatitis C virus (HCV) infection has two steps, an HCV antibody test for screening and a nucleic acid amplification test (NAAT) for confirmation. However, the HCV core antigen (HCVcAg) detection assay is an alternative for one-step diagnosis. We aimed to evaluate the diagnostic performance of the Abbott ARCHITECT HCV Ag assay to detect active hepatitis C in serum/plasma in people living with HIV/AIDS (PLWHA), through a systematic review and meta-analysis. PubMed, EMBASE, Scopus, Web of Science, and the Cochrane Library were searched until 20 September 2022 (PROSPERO, CRD42022348351 ). We included studies evaluating Abbott ARCHITECT HCV Ag assay (index assay) versus NAATs (reference test) in PLWHA coinfected with HCV who did not receive antiviral treatment for HCV. Meta-analysis was performed with the MIDAS module using Stata and random-effects models. The QUADAS-2 tool evaluated the risk of bias. The bivariate analysis was conducted on 11 studies with 2,407 samples. Pooled sensitivity was 0.95 (95% CI = 0.92 to 0.97), specificity 0.97 (95% CI = 0.93 to 0.99), positive likelihood ratio 37.76 (95% CI = 12.84 to 111.02), and negative likelihood ratio 0.06 (95% CI = 0.04 to 0.09). The area under the curve was 0.97 (95% CI = 0.20 to 1.00). For low prevalence (≤5%), the posttest probability that an individual with a positive test was a true positive ranged from 4% to 67%, whereas, at high prevalence (≥10%), the posttest probability was between 81% and 87%, indicating that a confirmatory test should be necessary, particularly with prevalence values of ≤1%. Regardless of prevalence, the probability that an individual with a negative test was a false negative was close to zero, indicating that the individual was not infected with HCV. In conclusion, the accuracy of the Abbott ARCHITECT HCV Ag assay was very good for HCV screening in serum/plasma samples from PLWHA. The clinical utility to confirm HCV infection was acceptable in high-prevalence settings (≥10%) but poor in low-prevalence settings (≤1%). Furthermore, it was excellent in excluding active HCV infection.
    Materialart: Online-Ressource
    ISSN: 0095-1137 , 1098-660X
    URL: Article
    DOI: 10.1128/jcm.01331-22
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Society for Microbiology
    Publikationsdatum: 2023
    ZDB Id: 1498353-9
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 4
    Online-Ressource
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    Cyclopropyl Carboxamides, a Chemically Novel Class of Antimalarial Agents Identified in a Phenotypic Screen
    American Society for Microbiology ; 2011
    In:  Antimicrobial Agents and Chemotherapy Vol. 55, No. 12 ( 2011-12), p. 5740-5745
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 55, No. 12 ( 2011-12), p. 5740-5745
    Kurzfassung: Malaria is one of the deadliest infectious diseases in the world, with the eukaryotic parasite Plasmodium falciparum causing the most severe form of the disease. Discovery of new classes of antimalarial drugs has become an urgent task to counteract the increasing problem of drug resistance. Screening directly for compounds able to inhibit parasite growth in vitro is one of the main approaches the malaria research community is now pursuing for the identification of novel antimalarial drug leads. Very recently, thousands of compounds with potent activity against the parasite P. falciparum have been identified and information about their molecular descriptors, antiplasmodial potency, and cytotoxicity is publicly available. Now the challenges are how to identify the most promising chemotypes for further development and how best to progress these compounds through a lead optimization program to generate antimalarial drug candidates. We report here the first chemical series to be characterized from one of those screenings, a completely novel chemical class with the generic name cyclopropyl carboxamides that has never before been described as having antimalarial or other pharmacological activities. Cyclopropyl carboxamides are potent inhibitors of drug-sensitive and -resistant strains of P. falciparum in vitro and show in vivo oral efficacy in malaria mouse models. In the present work, we describe the biological characterization of this chemical family, showing that inhibition of their still unknown target has very favorable pharmacological consequences but the compounds themselves seem to select for resistance at a high frequency.
    Materialart: Online-Ressource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.05188-11
    RVK:
    XA 24552
    Sprache: Englisch
    Verlag: American Society for Microbiology
    Publikationsdatum: 2011
    ZDB Id: 1496156-8
    SSG: 12
    SSG: 15,3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
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    Response of the Biocontrol Agent Pseudomonas pseudoalcaligenes AVO110 to Rosellinia necatrix Exudate
    American Society for Microbiology ; 2019
    In:  Applied and Environmental Microbiology Vol. 85, No. 3 ( 2019-02)
    Details
    In: Applied and Environmental Microbiology, American Society for Microbiology, Vol. 85, No. 3 ( 2019-02)
    Kurzfassung: The rhizobacterium Pseudomonas pseudoalcaligenes AVO110, isolated by the enrichment of competitive avocado root tip colonizers, controls avocado white root rot disease caused by Rosellinia necatrix . Here, we applied signature-tagged mutagenesis (STM) during the growth and survival of AVO110 in fungal exudate-containing medium with the goal of identifying the molecular mechanisms linked to the interaction of this bacterium with R. necatrix . A total of 26 STM mutants outcompeted by the parental strain in fungal exudate, but not in rich medium, were selected and named g rowth- a ttenuated m utants (GAMs). Twenty-one genes were identified as being required for this bacterial-fungal interaction, including membrane transporters, transcriptional regulators, and genes related to the metabolism of hydrocarbons, amino acids, fatty acids, and aromatic compounds. The bacterial traits identified here that are involved in the colonization of fungal hyphae include proteins involved in membrane maintenance (a dynamin-like protein and ColS) or cyclic-di-GMP signaling and chemotaxis. In addition, genes encoding a DNA helicase ( recB ) and a regulator of alginate production ( algQ ) were identified as being required for efficient colonization of the avocado rhizosphere. IMPORTANCE Diseases associated with fungal root invasion cause a significant loss of fruit tree production worldwide. The bacterium Pseudomonas pseudoalcaligenes AVO110 controls avocado white root rot disease caused by Rosellinia necatrix by using mechanisms involving competition for nutrients and niches. Here, a functional genomics approach was conducted to identify the bacterial traits involved in the interaction with this fungal pathogen. Our results contribute to a better understanding of the multitrophic interactions established among bacterial biocontrol agents, the plant rhizosphere, and the mycelia of soilborne pathogens.
    Materialart: Online-Ressource
    ISSN: 0099-2240 , 1098-5336
    URL: Article
    DOI: 10.1128/AEM.01741-18
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: American Society for Microbiology
    Publikationsdatum: 2019
    ZDB Id: 223011-2
    ZDB Id: 1478346-0
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 6
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    Aminoindoles, a Novel Scaffold with Potent Activity against Plasmodium falciparum
    American Society for Microbiology ; 2011
    In:  Antimicrobial Agents and Chemotherapy Vol. 55, No. 6 ( 2011-06), p. 2612-2622
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 55, No. 6 ( 2011-06), p. 2612-2622
    Kurzfassung: This study characterizes aminoindole molecules that are analogs of Genz-644442. Genz-644442 was identified as a hit in a screen of ∼70,000 compounds in the Broad Institute's small-molecule library and the ICCB-L compound collection at Harvard Medical School. Genz-644442 is a potent inhibitor of Plasmodium falciparum in vitro (50% inhibitory concentrations [IC 50 s], 200 to 285 nM) and inhibits P. berghei in vivo with an efficacy of 〉 99% in an adapted version of Peters' 4-day suppressive test (W. Peters, Ann. Trop. Med. Parasitol. 69:155–171, 1975). Genz-644442 became the focus of medicinal chemistry optimization; 321 analogs were synthesized and were tested for in vitro potency against P. falciparum and for in vitro absorption, distribution, metabolism, and excretion (ADME) properties. This yielded compounds with IC 50 s of approximately 30 nM. The lead compound, Genz-668764, has been characterized in more detail. It is a single enantiomer with IC 50 s of 28 to 65 nM against P. falciparum in vitro . In the 4-day P. berghei model, when it was dosed at 100 mg/kg of body weight/day, no parasites were detected on day 4 postinfection. However, parasites recrudesced by day 9. Dosing at 200 mg/kg/day twice a day resulted in cures of 3/5 animals. The compound had comparable activity against P. falciparum blood stages in a human-engrafted NOD -scid mouse model. Genz-668764 had a terminal half-life of 2.8 h and plasma trough levels of 41 ng/ml when it was dosed twice a day orally at 55 mg/kg/day. Seven-day rat safety studies showed a no-observable-adverse-effect level (NOAEL) at 200 mg/kg/day; the compound was not mutagenic in Ames tests, did not inhibit the hERG channel, and did not have potent activity against a broad panel of receptors and enzymes. Employing allometric scaling and using in vitro ADME data, the predicted human minimum efficacious dose of Genz-668764 in a 3-day once-daily dosing regimen was 421 mg/day/70 kg, which would maintain plasma trough levels above the IC 90 against P. falciparum for at least 96 h after the last dose. The predicted human therapeutic index was approximately 3, on the basis of the exposure in rats at the NOAEL. We were unable to select for parasites with 〉 2-fold decreased sensitivity to the parent compound, Genz-644442, over 270 days of in vitro culture under drug pressure. These characteristics make Genz-668764 a good candidate for preclinical development.
    Materialart: Online-Ressource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.01714-10
    RVK:
    XA 24552
    Sprache: Englisch
    Verlag: American Society for Microbiology
    Publikationsdatum: 2011
    ZDB Id: 1496156-8
    SSG: 12
    SSG: 15,3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 7
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    Risk Factors and Predictive Score for Bacteremic Biliary Tract Infections Due to Enterococcus faecalis and Enterococcus faecium: a Multicenter Cohort Study from the PROBAC Project
    American Society for Microbiology ; 2022
    In:  Microbiology Spectrum Vol. 10, No. 4 ( 2022-08-31)
    Details
    In: Microbiology Spectrum, American Society for Microbiology, Vol. 10, No. 4 ( 2022-08-31)
    Kurzfassung: Biliary-tract bloodstream infections (BT-BSI) caused by Enterococcus faecalis and E. faecium are associated with inappropriate empirical treatment and worse outcomes compared to other etiologies. The objective of this study was to investigate the risk factors for enterococcal BT-BSI. Patients with BT-BSI from the PROBAC cohort, including consecutive patients with BSI in 26 Spanish hospitals between October 2016 and March 2017, were selected; episodes caused by E. faecalis or E. faecium and other causes were compared. Independent predictors for enterococci were identified by logistic regression, and a predictive score was developed. Eight hundred fifty episodes of BT-BSI were included; 73 (8.5%) were due to target Enterococcus spp. (48 [66%] were E. faecium and 25 [34%] E. faecalis ). By multivariate analysis, the variables independently associated with Enterococcus spp. were (OR; 95% confidence interval): cholangiocarcinoma (4.48;1.32 to 15.25), hospital acquisition (3.58;2.11 to 6.07), use of carbapenems in the previous month (3.35;1.45 to 7.78), biliary prosthesis (2.19;1.24 to 3.90), and moderate or severe chronic kidney disease (1.55;1.07 to 2.26). The AUC of the model was 0.74 [95% CI0.67 to 0.80]. A score was developed, with 7, 6, 5, 4, and 2 points for these variables, respectively, with a negative predictive value of 95% for a score ≤ 6. A model, including cholangiocarcinoma, biliary prosthesis, hospital acquisition, previous carbapenems, and chronic kidney disease showed moderate prediction ability for enterococcal BT-BSI. Although the score will need to be validated, this information may be useful for deciding empirical therapy in biliary tract infections when bacteremia is suspected. IMPORTANCE Biliary tract infections are frequent, and a significant cause of morbidity and mortality. Bacteremia is common in these infections, particularly in the elderly and patients with cancer. Inappropriate empirical treatment has been associated with increased risk of mortality in bacteremic cholangitis, and the probability of receiving inactive empirical treatment is higher in episodes caused by enterococci. This is because many of the antimicrobial agents recommended in guidelines for biliary tract infections lack activity against these organisms. To the best of our knowledge, this is the first study analyzing the predictive factors for enterococcal BT-BSI and deriving a predictive score.
    Materialart: Online-Ressource
    ISSN: 2165-0497
    URL: Article
    DOI: 10.1128/spectrum.00051-22
    Sprache: Englisch
    Verlag: American Society for Microbiology
    Publikationsdatum: 2022
    ZDB Id: 2807133-5
    Standort Signatur Einschränkungen Verfügbarkeit
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