Frontiers in antibiotics最新文献

Introduction: There is a significant need for new antimicrobial compounds that are effective against drug-resistant microbes. Thioredoxin reductase (TrxR) is critical in redox homeostasis and was identified as a potential drug target and confirmed through inhibition by compounds auranofin and Bay11-7085.

Methods: Additional TrxR inhibitors were designed and found to exhibit antimicrobial activity against Gram-positive (Enterococcus faecium and Staphylococcus aureus) and glutathione-deficient bacteria (Helicobacter pylori). Investigational compounds were tested for antimicrobial activity, anti-biofilm efficacy, target impact, and cytotoxicity.

Results: The first-generation molecules AU1 and AU5 inhibited TrxR activity and inhibited methicillin-resistant S. aureus strain MW2 with minimal inhibitory concentrations (MIC) of 0.125 and 0.5 μg/mL, respectively. In an S. aureus enzymatic assay, AU1 inhibited TrxR enzymatic activity in a dose-dependent manner causing a decrease in intracellular free thiols. In addition, biofilm studies demonstrated that AU1 and AU5 reduced biofilm formation at 1X MIC and disrupted mature biofilms at 4X MIC. Cytotoxicity profiles were created using human cell lines and primary cells with LD₅₀ exceeding MICs by at least 12X.

Discussion: Thus, AU1 and AU5 were TrxR inhibitors that yielded low-concentration antimicrobial activity impacting S. aureus in planktonic and biofilm forms with limited toxic liability.

Antimicrobial resistance (AMR) is a global One Health threat. A portion of AMR development can be attributed to antimicrobial use (AMU) in animals, including dairy cattle. Quantifying AMU on U.S. dairy farms is necessary to inform antimicrobial stewardship strategies and help evaluate the relationship between AMU and AMR. Many AMU indicators have been proposed for quantifying AMU in dairy cattle. However, these indicators are difficult to interpret and compare because they differ in the type of data used, the calculation approach, and the definitions of variables and parameters used in the calculation. Therefore, we selected 16 indicators (count-based, mass-based, and dose-based) applicable for quantifying AMU on U.S. dairy farms. We systematized the indicators by standardizing their variables and parameters to improve their interchangeability, interpretation, and comparability. We scored indicators against six data-driven criteria (assessing their accuracy, data and effort needs, and level of privacy concern) and five stewardship-driven criteria (assessing their ability to capture trends and inform antimicrobial stewardship). The derived standardized indicators will aid farmers and veterinarians in selecting suitable indicators based on data availability and stewardship needs on a farm. The comparison of indicators revealed a trade-off requiring farmers to balance the granularity of data necessary for an accurate indicator and effort to collect the data, and a trade-off relevant to farmers interested in data sharing to inform stewardship because more accurate indicators are typically based on more sensitive information. Indicators with better accuracy tended to score better in stewardship criteria. Overall, two dose-based indicators, estimating the number of treatments and administered doses, scored best in accuracy and stewardship. Conversely, two count-based indicators, estimating the length of AMU, and a mass-based indicator, estimating the mass of administered antimicrobials, performed best in the effort and privacy criteria. These findings are expected to benefit One Health by aiding the uptake of farm-level AMU indicators by U.S. dairy farms.

Antimicrobial resistance (AMR) is a major threat to global health and a key One Health challenge linking humans, animals, and the environment. Livestock are a key target for moderation of antimicrobial use (AMU), which is a major driver of AMR in these species. While some studies have assessed AMU and AMR in individual production systems, the evidence regarding predictors of AMU and AMR in livestock is fragmented, with significant research gaps in identifying the predictors of AMU and AMR common across farming systems. This review summarizes existing knowledge to identify key practices and critical control points determining on-farm AMU/AMR determinants for pigs, layer and broiler hens, beef and dairy cattle, sheep, turkeys, and farmed salmon in Europe. The quality and quantity of evidence differed between livestock types, with sheep, beef cattle, laying hens, turkeys and salmon underrepresented. Interventions to mitigate both AMU and/or AMR highlighted in these studies included biosecurity and herd health plans. Organic production typically showed significantly lower AMU across species, but even in antibiotic-free systems, varying AMR levels were identified in livestock microflora. Although vaccination is frequently implemented as part of herd health plans, its effects on AMU/AMR remain unclear at farm level. Social and behavioral factors were identified as important influences on AMU. The study fills a conspicuous gap in the existing AMR and One Health literatures examining links between farm management practices and AMU and AMR in European livestock production.

Antimicrobial Resistance (AMR) is one of society's most urgent global issues, requiring urgent multidisciplinary-based research and practice approaches to engage with these policies. Several global and national policy statements have been released in the last two decades, particularly emphasising the strengthening of the digital surveillance system. However, implementing these initiatives remains patchy, particularly in the context of public health systems in Low- and Middle-Income Countries. This paper argues that one of the significant reasons contributing to this sub-optimal uptake of these systems is that the top-down implementation models do not adequately cater to the needs, aspirations, and capacities of the health facility staff, who, ultimately, are the end users of the system. The paper highlights the importance of digital technology in healthcare facilities with resource constraints to promote the responsible use of antibiotics. It discusses the process of developing an evidence base for action in low- and middle-income countries (LMICs) through digitally mediated data-driven policy. This process is conceptualised as a three-phase process, which involves stabilising data entry, generating outcomes, and taking action at the local level. The paper argues the need for bottom-up implementation models, which emphasise the need to understand the practices users engage with in their everyday work and design the digital system to add value and not work to these everyday practices. The paper emphasises the importance of building local capacities to develop effective and sustainable antimicrobial stewardship (AMS) programs through enabling networking around digital solutions, creating value in networked partnerships, initiating conversations around data, and raising awareness of the digital to develop AMS programs.

Mycobacterium marinum is a waterborne pathogen responsible for tuberculosis-like infections in cold-blooded animals and is an opportunistic pathogen in humans. M. marinum is the closest genetic relative of the Mycobacterium tuberculosis complex and is a reliable surrogate for drug susceptibility testing. We synthesized and evaluated two nanoparticle (NP) formulations for compatibility with rifampicin, isoniazid, pyrazinamide, and ethambutol (PIRE), the front-line antimycobacterial drugs used in combination against active tuberculosis infections. Improved in vitro antimicrobial activity was observed with encapsulated rifampicin alone or in a cocktail of drugs formulated through co-encapsulation in amphiphilic polyanhydride NPs. Broth antimicrobial testing revealed that the encapsulation of PIRE in NP resulted in a significant increase in antimicrobial activity, with the benefit over soluble formulations at biologically relevant concentrations ranging from >10 to >3,000 fold. M. marinum-infected human macrophages treated with NP-PIRE were cleared of viable bacteria in 48 h following a single treatment, representing a >4 log reduction in colony-forming units and a >2,000-fold increase in antimicrobial activity. The amphiphilic polyanhydride nanoparticles demonstrated the ability to co-encapsulate PIRE antibiotics and enhance their antimicrobial activity against M. marinum in infected macrophages in culture and in vitro. These data suggest that polyanhydride nanoparticles are a promising nanotherapeutic for combatting Mycobacterium infections through improved intracellular targeting of encapsulated antibiotics.

Introduction: The need for new tools to treat infections is constantly growing due to the possibilities of emerging diseases related to environmental changes, climatic catastrophes, microorganism resistance, and human and animal aging, leading to an evident unbalance in the planet's health. Brazil contains the most significant portion of world biodiversity, a potential source of new antimicrobial natural products. Nonetheless, its environment, particularly its forests, and rainforests, is under threat, meaning that rapidly conducted, comprehensive research into the potential of antimicrobial activity to address this threat is urgently needed.

Methods: In this study, plants from the Amazon rainforest and the Atlantic forests were collected and tested against several pathogenic microbes relevant to humans, animals, and the environment, and subjected to large-scale susceptibility assays, bioautography, and Artemia salina toxicity assays. From the plants, 2,280 organic and aqueous extracts were obtained from different organs, namely leaves, barks, flowers, fruits, and seeds, and subjected to a large-scale susceptibility screening assay against Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Streptococcus mutans, Streptococcus sanguinis, Escherichia coli, Pseudomonas aeruginosa, Candida albicans, Malassezia pachydermatis, Malassezia furfur, and Listeria monocytogenes.

Results and discussion: The selected extracts were subjected to antimicrobial susceptibility tests to determine their inhibition zone diameters and minimum bactericidal concentrations, to bioautography, and to an Artemia salina toxicity assay, which resulted in 154 active extracts. Moreover, 111 out of 154 extracts were ranked based on scores established by the p-values and the mean rank differences in each set of test results. The final ranking identified which extracts should be studied in further phytochemical research using thin-layer chromatography techniques as a priority. The extracts obtained from plants belonging to Combretaceae, Connaraceae, Convolvulaceae, Fabaceae, Malpighiaceae, Moraceae, Piperaceae, Polygonaceae, and Salicaceae were selected as the most promising ones and used to support the identification of plant-based antimicrobial active compounds from the immense biodiversity of Brazilian forests.

Antimicrobial resistance in the intensive care unit is an ongoing global healthcare concern associated with high mortality and morbidity rates and high healthcare costs. Select groups of bacterial pathogens express different mechanisms of antimicrobial resistance. Clinicians face challenges in managing patients with multidrug-resistant bacteria in the form of a limited pool of available antibiotics, slow and potentially inaccurate conventional diagnostic microbial modalities, mimicry of non-infective conditions with infective syndromes, and the confounding of the clinical picture of organ dysfunction associated with sepsis with postoperative surgical complications such as hemorrhage and fluid shifts. Potential remedies for antimicrobial resistance include specific surveillance, adequate and systematic antibiotic stewardship, use of pharmacokinetic and pharmacodynamic techniques of therapy, and antimicrobial monitoring and adequate employment of infection control policies. Novel techniques of combating antimicrobial resistance include the use of aerosolized antibiotics for lung infections, the restoration of gut microflora using fecal transplantation, and orally administered probiotics. Newer antibiotics are urgently needed as part of the armamentarium against multidrug-resistant bacteria. In this review we discuss mechanisms and patterns of microbial resistance in a select group of drug-resistant bacteria, and preventive and remedial measures for combating antibiotic resistance in the critically ill.

Background: Antimicrobial resistance (AMR) has provoked a global health issue. Antimicrobial stewardship programs should be implemented to overcome this issue. The aim of this study was to determine the sensitivity patterns of the WHO Access, Watch, Reserve (AWaRe) group of antibiotics that assists in the selection of appropriate empiric antibiotic therapies.

Method: A descriptive, cross-sectional study was conducted for 6 months, in which 422 culture sensitivity sample reports from the Ghurki Trust Teaching Hospital's laboratory were obtained through a convenience sampling technique, and the sensitivity patterns of nine offending bacteria to the WHO AWaRe group antibiotics were determined. Descriptive statistics and differences in frequency distribution among the categorical variables were obtained using the Statistical Package for Social Sciences (SPSS) software, version 21.

Results: Among 422 culture sensitivity sample reports, Escherichia coli (16.1%) was the most common Gram-negative pathogen. Acinetobacter, E. coli, Klebsiella, and Pseudomonas showed 100% sensitivity to polymyxin-b and colistin. Proteus showed the highest sensitivity to meropenem (90%), Staphylococcus aureus showed a 98% sensitivity to linezolid, Staphylococcus epidermidis was 100% sensitive to vancomycin and linezolid, and Streptococcus showed the highest sensitivity to penicillin (100%) and vancomycin (94.7%). Polymyxin b and colistin were found to be the most effective antibiotics against Gram-negative bacteria (100%). Gram-positive bacteria were highly sensitive to linezolid (99.4%), vancomycin (98.2%), chloramphenicol (89.5%), and tigecycline (82.6%).

Conclusion: Culture sensitivity reports help to rationalize the empirical use of antibiotics in clinical practice in addressing the challenge of antimicrobial resistance. This study showed that polymyxin-b and colistin were the most effective antibiotics against Gram-negative isolates and that Gram-positive bacteria were highly susceptible to linezolid. Updated antibiograms should be used by clinicians to evaluate bacterial susceptibility patterns and rationalize antibiotic empiric therapy.

Introduction: In this work, 170 strains covering 13 species from the Lactobacillaceae family were analyzed to determine minimal inhibitory concentration (MIC) distributions to nine antimicrobial agents, and genes potentially conferring resistance. This allows a proposal of tentative Epidemiological Cut-Offs (ECOFFs) that follows the phylogeny for interpretation of resistance in the 13 species.

Methods: The 170 strains originated from different sources, geographical areas, and time periods. MICs for nine antibiotics were determined according to the ISO 10932 standard for lactobacillia and by a modified CLSI-method for Leuconostoc and Pediococcus which ensured sufficient growth. The strains were whole genome sequenced, subtyped by core genome analysis, and assessed for the presence of antibiotic resistance genes using the ResFinder and NCBI AMRFinder databases.

Results and discussion: The data provide evidence that antimicrobial susceptibility follows phylogeny instead of fermentation pattern and accordingly, tentative ECOFFs were defined. For some species the tentative ECOFFs for specific antibiotics are above the cut-off values set by the European Food Safety Authority (EFSA) which are primarily defined according to fermentation pattern or at genus level. The increased tolerance for specific antibiotics observed for some species was evaluated to be innate, as only for one strain phenotypic resistance was found to be related to an acquired resistance gene. In general, more data are needed to define ECOFFs and since the number of isolates available for industrial relevant bacterial species are often limited compared to clinically relevant species, it is important; 1) that strains are unambiguously defined at species level and subtyped through core genome analysis, 2) MIC determination are performed by use of a standardized method to define species-specific MIC distributions and 3) that known antimicrobial resistance genes are determined in whole genome sequences to support the MIC determinations.