Lundgrenthomas1458

In patients with renal impairment (n=22 of 39), the median serum concentrations of linezolid, PNU-142300, and PNU-142586 were 1.6-, 3.3-, 2.8-fold higher for linezolid, PNU-142300 and PNU-142586, respectively, compared to patients without renal impairment. Metabolite concentrations in paired samples were poorly correlated to linezolid concentrations (r2 = 0.26 for PNU-142300, and r2= 0.06 for PNU-142586). Linezolid and its metabolites share potential toxicophores that deserve characterization to mitigate higher myelosuppression risk in patients with renal impairment. Copyright © 2020 American Society for Microbiology.We characterized 29 bla CTX-M-27-harboring plasmids of Escherichia coli ST131 sublineage C1/H30R isolates from healthy individuals and long-term care facility (LTCF) residents. Most (27/29) plasmids were of the FIA, FIB, and FII multi-replicon type with the same pMLST. Several plasmids (7/23) from LTCF residents harbored only bla CTX-M-27 as the resistance gene; however, their fundamental structures were very similar to those of previously isolated bla CTX-M-27/F1A2B20 plasmids, suggesting their prevalence as a newly arising public health concern. Copyright © 2020 American Society for Microbiology.Background. Rising antibiotic resistance increasingly compromises empiric treatment. Knowing the antibiotic susceptibility of a pathogen's close genetic relative(s) may improve empiric antibiotic selection.Methods. Using genomic and phenotypic data from three separate clinically-derived databases of Escherichia coli isolates, we evaluated multiple genomic methods and statistical models for predicting antibiotic susceptibility, focusing on potentially rapidly available information such as lineage or genetic distance from archived isolates. We applied these methods to derive and validate prediction of antibiotic susceptibility to common antibiotics.Results. We evaluated 968 separate episodes of suspected and confirmed infection with Escherichia coli from three geographically and temporally separated databases in Ontario, Canada, from 2010-2018. Across all approaches, model performance (AUC) ranges for predicting antibiotic susceptibility were greatest for ciprofloxacin (0.76-0.97), and lowest for trimethoprim-sulfamethoxazole (0.51-0.80). When a model predicted a susceptible isolate, the resulting (post-test) probabilities of susceptibility were sufficient to warrant empiric therapy for most antibiotics (mean 92%). An approach combining multiple models could permit the use of narrower-spectrum oral agents in 2 out of every 3 patients while maintaining high treatment adequacy (∼90%).Conclusions. Methods based on genetic relatedness to archived samples in E. coli could be used to predict antibiotic resistance and improve antibiotic selection. Copyright © 2020 MacFadden et al.Currently, the expansion of the novel human respiratory coronavirus (known as SARS-CoV-2, COVID-2019, or 2019-nCoV) has stressed the need for therapeutic alternatives to alleviate and stop this new epidemic. The previous epidemics of high-morbidity human coronaviruses, such as the acute respiratory syndrome coronavirus (SARS-CoV) in 2003, and the Middle East respiratory syndrome corona virus (MERS-CoV) in 2012, prompted the characterization of compounds that could be potentially active against the currently emerging novel coronavirus SARS-CoV-2. The most promising compound is remdesivir (GS-5734), a nucleotide analog prodrug currently in clinical trials for treating Ebola virus infections. Remdesivir inhibited the replication of SARS-CoV and MERS-CoV in tissue cultures, and it displayed efficacy in non-human animal models. In addition, a combination of the human immunodeficiency virus type 1 (HIV-1) protease inhibitors, lopinavir/ritonavir, and interferon beta (LPV/RTV-INFb) were shown to be effective in patients infected with SARS-CoV. LPV/RTV-INFb also improved clinical parameters in marmosets and mice infected with MERS-CoV. Remarkably, the therapeutic efficacy of remdesivir appeared to be superior to that of LPV/RTV-INFb against MERS-CoV in a transgenic humanized mice model. The relatively high mortality rates associated with these three novel human coronavirus infections, SARS-CoV, MERS-CoV, and SARS-CoV-2, has suggested that pro-inflammatory responses might play a role in the pathogenesis. It remains unknown whether the generated inflammatory state should be targeted. Therapeutics that target the coronavirus alone might not be able to reverse highly pathogenic infections. This minireview aimed to provide a summary of therapeutic compounds that showed potential in fighting SARS-CoV-2 infections. Copyright © 2020 American Society for Microbiology.Delamanid (DLM), a nitro-dihydroimidazooxazole derivative currently approved for pulmonary multidrug-resistant tuberculosis (TB) therapy, is a prodrug activated by mycobacterial 7,8-didemethyl-8-hydroxy 5-deazariboflavin coenzyme (F420)-dependent nitroreductase (Ddn). Despite inhibiting the biosynthesis of a subclass of mycolic acids, the active DLM metabolite remained unknown. Comparative liquid chromatography-mass spectrometry (LC-MS) analysis of DLM metabolites revealed covalent binding of reduced DLM with a nicotinamide ring of NAD derivatives (oxidized form) in DLM-treated Mycobacterium tuberculosis var. Bacille de Calmette et Guérin. Isoniazid-resistant mutations in the type II NADH dehydrogenase gene (ndh) showed higher intracellular NADH/NAD ratio and cross-resistance to DLM, which were restored by complementation of the mutants with wild-type ndh Our data demonstrated for the first time the adduct formation of reduced DLM with NAD in mycobacterial cells and its importance in the action of DLM. Copyright © 2020 American Society for Microbiology.The effects of the multiple-dose administration of tenofovir disoproxil fumarate (TDF) on the pharmacokinetics of morinidazole (MOR) were compared in healthy subjects. Morinidazole exposure was similar between two groups, with an AUC0-∞ treatment ratio for MOR+TDF/MOR of 1.01 (90% CI 0.97, 1.06). No relevant differences were observed regarding the plasma exposure of metabolites. The renal clearance of MOR and its metabolites were not affected by tenofovir. Shield-1 nmr No unexpected safety or tolerability issues were observed. Copyright © 2020 Wu et al.