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Short-chain fatty acids (SCFAs) - acetate, propionate, and butyrate - are important bacterial fermentation metabolites regulating many important aspects of human physiology. Decreases in the concentrations of any or multiple SCFAs are associated with various detrimental effects to the host. Previous research has broadly focused on gut microbiome produced SCFAs as a group, with minimal distinction between acetate, propionate, and butyrate independently, each with significantly different host effects. In this review, we comprehensively delineate the roles of these SCFAs with emphasis on receptor affinity, signaling pathway involvement, and net host physiologic effects. Butyrate is highlighted due to its unique role in gastrointestinal-associated functions, especially maintaining gut barrier integrity. Butyrate functions by promoting epithelial tight junctions, serving as fuel for colonocyte ATP production, and modulating the immune system. Interaction with the immune system occurs locally in the gastrointestinal tract and systemically in the brain. Investigation into research conducted on butyrate production pathways and specific bacterial players involved highlights a unique risk associated with use of gram-positive targeted antibiotics. We review and discuss evidence showing the relationship between the butyrate-producing gram-positive genus, Roseburia, and susceptibility to commonly prescribed, widely used gram-positive antibiotics. Considering gut microbiome implications when choosing antibiotic therapy may benefit health outcomes in patients.

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INTRODUCTION: Infections due to multidrug-resistant organisms (MDRO) are a serious concern for public health with high morbidity and mortality. Though many antibiotics have been introduced to manage these infections, there are remaining concerns regarding the optimal management of Gram-positive MDROs. AREAS COVERED: A literature search on the PubMed/Medline database was conducted. We applied no language and time limits for the search strategy. In this narrative review, we discuss the current options for managing Gram-positive MDROs as well as non-traditional antibacterial agents in development. EXPERT OPINION: Despite their introduction more than 70 years ago, glycopeptides are still the cornerstone in treating Gram-positive infections: all registrative studies of new antibiotics have glycopeptides as control; these studies are designed as not inferior studies, therefore it is almost impossible to give recommendations other than the use of glycopeptides in the treatment of Gram-positive infections. The best evidence on treatments different from glycopeptides comes from post-hoc analysis and meta-analysis. Non-traditional antibacterial agents are being studied to aid in short and effective antibiotic therapies. The use of non-traditional antibacterial agents is not restricted to replacing traditional antibacterial agents with alternative therapies; instead, they should be used in combination with antibiotic therapies.

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New approaches to target antibacterial agents toward Gram-negative bacteria are key, given the rise of antibiotic resistance. Since the discovery of polymyxin B nonapeptide as a potent Gram-negative outer membrane (OM)-permeabilizing synergist in the early 1980s, a vast amount of literature on such synergists has been published. This Review addresses a range of peptide-based and small organic compounds that disrupt the OM to elicit a synergistic effect with antibiotics that are otherwise inactive toward Gram-negative bacteria, with synergy defined as a fractional inhibitory concentration index (FICI) of <0.5. Another requirement for the inclusion of the synergists here covered is their potentiation of a specific set of clinically used antibiotics: erythromycin, rifampicin, novobiocin, or vancomycin. In addition, we have focused on those synergists with reported activity against Gram-negative members of the ESKAPE family of pathogens namely, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and/or Acinetobacter baumannii. In cases where the FICI values were not directly reported in the primary literature but could be calculated from the published data, we have done so, allowing for more direct comparison of potency with other synergists. We also address the hemolytic activity of the various OM-disrupting synergists reported in the literature, an effect that is often downplayed but is of key importance in assessing the selectivity of such compounds for Gram-negative bacteria.

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Antimicrobial agents are currently the mainstay of treatment for bacterial infections worldwide. However, due to the increased use of antimicrobials in both human and animal medicine, pathogens have now evolved to possess high levels of multi-drug resistance, leading to the persistence and spread of difficult-to-treat infections. Several current antibacterial agents active against Gram-positive bacteria will be rendered useless in the face of increasing resistance rates. There are several emerging antibiotics under development, some of which have been shown to be more effective with an improved safety profile than current treatment regimens against Gram-positive bacteria. We will extensively discuss these antibiotics under clinical development (phase I-III clinical trials) to combat Gram-positive bacteria, such as Staphylococcus aureus, Enterococcus faecium and Streptococcus pneumoniae. We will delve into the mechanism of actions, microbiological spectrum, and, where available, the pharmacokinetics, safety profile, and efficacy of these drugs, aiming to provide a comprehensive review to the involved stakeholders.

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INTRODUCTION: The role of enterococci in infectious diseases has evolved from a gut and urinary commensal to a major pathogen of concern. Few options exist for resistant enterococci, and appropriate use of the available agents is crucial. AREAS COVERED: Herein, the authors discuss antibiotics with clinically useful activity against Enterococcus faecalis and E. faecium. The article specifically discusses: antibiotics active against enterococci and their mechanism of resistance, pharmacokinetic and pharmacodynamic principles, in vitro combinations, and clinical studies which focus on urinary tract, intra-abdominal, central nervous system, and bloodstream infections due to enterococci. EXPERT OPINION: Aminopenicillins are preferred over all other agents when enterococci are susceptible and patients can tolerate them. Daptomycin and linezolid have demonstrated clinical efficacy against vancomycin-resistant enterococci (VRE). Synergistic combinations are often warranted in complex infections of high inoculum and biofilms while monotherapies are generally appropriate for uncomplicated infections. Although active against resistant enterococci, the pharmacokinetics, efficacy and safety of tigecycline and quinupristin/dalfopristin can problematical for severe infections. For cystitis, amoxicillin, nitrofurantoin, or fosfomycin are ideal. Recently, approved agents such as tedizolid and oritavancin have good in vitro activity against VRE but clinical studies against other resistant enterococci are lacking.

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