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The use of non-standard toxicity models is a hurdle in the early development of antimicrobial peptides towards clinical applications. Herein we report an extensive in vitro and in vivo toxicity study of a library of 24 peptide-based antimicrobials with narrow spectrum activity towards veterinary pathogens. The haemolytic activity of the compounds was evaluated against four different species and the relative sensitivity against the compounds was highest for canine erythrocytes, intermediate for rat and human cells and lowest for bovine cells. Selected peptides were additionally evaluated against HeLa, HaCaT and HepG2 cells which showed increased stability towards the peptides. Therapeutic indexes of 50–500 suggest significant cellular selectivity in comparison to bacterial cells. Three peptides were administered to rats in intravenous acute dose toxicity studies up to 2–8 × MIC. None of the injected compounds induced any systemic toxic effects in vivo at the concentrations employed illustrating that the correlation between the different assays is not obvious. This work sheds light on the in vitro and in vivo toxicity of this class of promising compounds and provides insights into the relationship between the different toxicity models often employed in different manners to evaluate the toxicity of novel bioactive compounds in general.

Antifolates targeting folate biosynthesis within the shikimate-chorismate-folate metabolic pathway are ideal and selective antimicrobials, since higher eukaryotes lack this pathway and rely on an exogenous source of folate. Resistance to the available antifolates, inhibiting the folate pathway, underlines the need for novel antibiotic scaffolds and molecular targets. While para-aminobenzoic acid synthesis within the chorismate pathway constitutes a novel molecular target for antifolates, abyssomicins are its first known natural inhibitors. This review describes the abyssomicin family, a novel spirotetronate polyketide Class I antimicrobial. It summarizes synthetic and biological studies, structural, biosynthetic, and biological properties of the abyssomicin family members. This paper aims to explain their molecular target, mechanism of action, structure–activity relationship, and to explore their biological and pharmacological potential. Thirty-two natural abyssomicins and numerous synthetic analogues have been reported. The biological activity of abyssomicins includes their antimicrobial activity against Gram-positive bacteria and mycobacteria, antitumor properties, latent human immunodeficiency virus (HIV) reactivator, anti-HIV and HIV replication inducer properties. Their antimalarial properties have not been explored yet. Future analoging programs using the structure–activity relationship data and synthetic approaches may provide a novel abyssomicin structure that is active and devoid of cytotoxicity. Abyssomicin J and atrop-o-benzyl-desmethylabyssomicin C constitute promising candidates for such programs.

Antimicrobial peptides (AMPs) hold promise as the next generation of antimicrobial agents, but often suffer from rapid degradation in vivo. Modifying AMPs with non-proteinogenic residues such as peptoids (oligomers of N-alkylglycines) provides the potential to improve stability. We have identified two novel peptoid-based compounds, B1 and D2, which are effective against the canine skin pathogen Staphylococcus pseudintermedius, the main cause of antibiotic use in companion animals. We report on their potential to treat infections topically by characterizing their release from formulation and in vitro ADME properties. In vitro ADME assays included skin penetration profiles, stability to proteases and liver microsomes, and plasma protein binding. Both B1 and D2 were resistant to proteases and >98% bound to plasma proteins. While half-lives in liver microsomes for both were >2 h, peptoid D2 showed higher stability to plasma proteases than the peptide-peptoid hybrid B1 (>2 versus 0.5 h). Both compounds were suitable for administration in an oil-in-water cream formulation (50% release in 8 h), and displayed no skin permeation, in the absence or presence of skin permeability modifiers. Our results indicate that these peptoid-based drugs may be suitable as antimicrobials for local treatment of canine superficial pyoderma and that they can overcome the inherent limitations of stability encountered in peptides.

Antibiotic discovery is vital when considering the increasing antimicrobial resistance threat. The aim of this work was to provide a high-throughput screen (HTS) assay using multidrug-resistant Escherichia coli strains to enable further research into antimicrobial lead discovery and identify novel antimicrobials. This study describes a primary HTS of a diverse library of 7884 small molecules against a susceptible E. coli strain. A secondary screening of 112 molecules against four E. coli strains with different susceptibility profiles revealed NSC319726 as a potential antimicrobial lead serving as a novel template. NSC319726 is a good candidate for an analoguing program.

Transitional care programs (TCPs), where hospital care team members repeatedly follow up with discharged patients, aim to reduce post-discharge hospital or emergency department (ED) utilization and healthcare costs. We examined the effectiveness of TCPs at reducing healthcare costs, hospital readmissions, and ED visits. Centers for Medicare and Medicaid Services Bundled Payments for Care Improvement (BPCI) program adjudicated claims files and electronic health records from Greenville Memorial Hospital, Greenville, SC, were accessed. Data on post-discharge 30- and 90-day ED visits and readmissions, total costs, and episodes with costs over BPCI target prices were extracted from November 2017 to July 2020 and compared between the “TCP-Graduates” (N = 85) and “Did Not Graduate” (DNG) (N = 1310) groups. As compared to the DNG group, the TCP-Graduates group had significantly fewer 30-day (7.1% vs. 14.9%, p = 0.046) and 90-day (15.5% vs. 26.3%, p = 0.025) readmissions, episodes with total costs over target prices (25.9% vs. 36.6%, p = 0.031), and lower total cost/episode (USD 22,439 vs. USD 28,633, p = 0.018), but differences in 30-day (9.4% vs. 11.2%, p = 0.607) and 90-day (20.0% vs. 21.9%, p = 0.680) ED visits were not significant. TCP was associated with reduced post-discharge hospital readmissions, total care costs, and episodes exceeding target prices. Further studies with rigorous designs and individual-level data should test these findings.

The aim of this study was to create a new version of the French GTS-QOL adapted to adolescents with GTS aged 12-16 years (GTS-QOL-French-Ado) and to evaluate its psychometric properties. We assessed the psychometric properties of the GTS-QOL-French-Ado in 84 adolescents (mean age 13.6 years, standard deviation 1.2) in terms of factor structure, internal consistency, reliability and convergent validity with the Child Depression Inventory (CDI), the Multidimensional Anxiety Scale for Children (MASC), the Motor tic, Obsessions and compulsions, Vocal tic Evaluation Survey (MOVES) and the French \"Vécu et Santé Perçue de l'Adolescent\" (VSP-A), a generic self-administered measure of health-related quality of life (HRQoL) in adolescents. Exploratory factor analysis of the GTS-QOL-French-Ado resulted in a 5-factor solution. The GTS-QOL-French-Ado demonstrated good acceptability with missing values per subscale ranging from 0% to 1.2%, good internal consistency for four of the five subscales with Cronbach's alpha ranging from 0.56 to 0.87 and good test-retest reliability with intraclass correlation coefficients ranging from 0.74 (95% CI: 0.52-0.86) to 0.82 (95% CI: 0.66-0.91). Convergent validity was supported by correlations with CDI, MASC, MOVES, VSP-A and clinical variables. The GTS-QOL-French-Ado is the first disease-specific HRQoL tool for French-speaking adolescents with GTS aged 12-16 years, and shows good psychometric properties. Further psychometric testing on responsiveness to change would be of great interest.

Major depressive disorder with psychotic features (MDDPsy), compared to nonpsychotic MDD, involves an increased risk of suicide and failure to achieve treatment response. Symptom scales can be useful to assess patients with MDDPsy. The aim of the present study was to validate French versions of the Delusion Assessment Scale (DAS) and Psychotic Depression Assessment Scale (PDAS). One hundred patients were included. The scales were filled out by psychiatrists. Data from participants who accepted a second interview were used for inter-judge reliability. The scalability and psychometric properties of both scales were assessed. Data from 94 patients were used. Owing to low score variability between patients, the predefined threshold for scalability (≥0.40) was not reached for both scales. Factorial analysis of the DAS identified five factors, different from those of the original version. Five factors were also identified in the PDAS, of which two comprised items from the HDRS and the other three items from the BPRS. Floor and ceiling effects were observed in both scales, due in part to the construction of certain subscales. Unlike the PDAS, the DAS had good internal consistency. Multiple correlations were observed between the DAS dimensions but none between those of the PDAS. Both scales showed good inter-judge reliability. Convergent validity analyses showed correlations with HDRS, BPRS and CGI. Inter-judge reliability was calculated from a relatively small number of volunteers. The good psychometric properties of the French versions of the DAS and PDAS could help in assessing MDDPsy, in particular its psychotic features, and hence improve response to treatment and prognosis.

Minimum inhibitory concentrations (MICs) were determined for 1570 bacteria from eight geographic locations (1204 Escherichia coli, 231 other enteric gram-negative bacilli [including Citrobacter spp., Enterobacter spp., Klebsiella spp., Proteus spp., and Salmonella spp.], 31 Pseudomonas spp., 18 coagulase-positive staphylococci, 26 coagulase-negative staphylococci, and 55 streptococci and enterococci) by the National Committee for Clinical Laboratory Standards broth microdilution procedure. Antimicrobial agents tested included ampicillin, ceftiofur, enrofloxacin, erythromycin, florfenicol, gentamicin, neomycin, spectinomycin, sulfamethazine, tetracycline, and trimethoprim/sulfadiazine. Against the E. coli strains tested, ceftiofur, enrofloxacin, gentamicin, and trimethoprim/sulfadiazine were the most active compounds with MIC at which 50% of the strains are at or below ( MIC50) = 0.5, ≤0.03, 0.5, and 0.13 μg/ml, respectively, and MIC at which 90% of the strains are at or below ( MIC90) = 1.0, 0.13, 32.0, and 2.0 μg/ml, respectively. Ampicillin, florfenicol, neomycin, and spectinomycin were the next most active compounds against the E. coli strains, with MIC50= 4.0, 4.0, 16.0, and 16.0 μg/ml, respectively. MIC90values for these compounds against E. coli strains were >32.0, 8.0, 512.0, and >128.0 μg/ml, respectively. The remaining compounds exhibited limited, strain-dependent activity against the E. coli strains tested. As with the E. coli, enrofloxacin, ceftiofur, and trimethoprim/sulfadiazine were also the most active compounds against the 231 other enteric organisms tested, with MIC50≤ 1.0 μg/ml for all of these genera. The remaining compounds exhibited limited activity against these genera. Against the gram-positive cocci tested, ampicillin, enrofloxacin, ceftiofur, and trimethoprim/sulfadiazine were most active, whereas the remaining compounds exhibited strain-dependent activity. When MIC data for E. coli were summarized separately, differences were observed between the geographic locations for the various antimicrobial agents. In conclusion, ceftiofur, enrofloxacin, and trimethoprim/sulfadiazine were the most active of the compounds tested against all of the bacterial strains. /// Se determinó la concentración inhibitoria mínima de 1570 cepas bacterianas de ocho regiones geográficas (1204 Escherichia coli, 23 bacilos entéricos gram-negativos {incluyendo Citrobacter spp., Enterobacter spp, Klebsiella spp., Proteus spp., y Salmonella spp.}, 31 Pseudomonas spp, 18 Staphylococcus coagulasa positivos. 26 Staphylococcus coagulasa negativos y 55 estreptococos y enterococos) mediante el procedimiento de la microdilución en caldo del Comité Nacional de Estándares para Laboratorios Clínicos. Los agentes microbianos examinados incluyeron ampicilina, ceftiofur, enrofloxacina, eritromicina, florfenicol, gentamicina, neomicina, espectinomicina, sulfametacina, tetraciclina y trimetropina/sulfadiacina. Contra las cepas de E. coli examinadas, ceftiofur, enrofloxacina, gentamicina y trimetropina/sulfadiacina fueron los compuestos más activos con una concentración inhibitoria mínima 50% ( CIM50) de 0.5, ≤ 0.03, 0.5 y 0.13 μg/ml, respectivamente y una concentración inhibitoria mínima 90% ( CIM90) de 1.0, 0.13, 32.0 y 2.0 μg/ml, respectivamente. La ampicilina, florfenicol, neomicina y espectomicina fueron los segundos compuestos más activos contra cepas de E. coli con una concentración inhibitoria mínima 50% de 4.0, 4.0, 16.0 y 16.0 μg/ml, respectivamente. Los valones de concentración inhibitoria mínima 90% para estos compuestos fue de > 32.0, 8.0, 512.0 y > 128.0 μg/ml, respectivamente. Los otros compuestos mostraron limitada actividad dependiendo de la cepa de E. coli examinada. La enrofloxacina, ceftiofur y trimetropina/sulfadiacina fueron también los compuestos más efectivos contra 231 organismos entéricos examinados con una concentración inhibitoria mínima 50%, de ≤ 1.0 μg/ml para todos estos géneros de bacterias. Los otros compuestos exhibieron actividad limitada contra estos géneros de bacterias. Contra los cocos gram-positivos examinados la ampicilina, enrofloxacina, ceftiofur y trìmetropina/sulfadiacina fueron los más activos mientras que los otros compuestos exhibieron actividad dependiente de la cepa. Cuando la información de las concentraciones inhibitorias mínimas fueron analizadas por separado, se observaron diferencias entre las diferentes áreas geográficas para varios agentes microbianos.