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      Antimicrobial Properties on Non-Antibiotic Drugs in the Era of Increased Bacterial Resistance

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          Abstract

          In recent years, due to the dramatic increase in and global spread of bacterial resistance to a number of commonly used antibacterial agents, many studies have been directed at investigating drugs whose primary therapeutic purpose is not antimicrobial action. In an era where it is becoming increasingly difficult to find new antimicrobial drugs, it is important to understand these antimicrobial effects and their potential clinical implications. Numerous studies report the antibacterial activity of non-steroidal anti-inflammatory drugs, local anaesthetics, phenothiazines such as chlorpromazine, levomepromazine, promethazine, trifluoperazine, methdilazine and thioridazine, antidepressants, antiplatelets and statins. Several studies have explored a possible protective effect of statins inreducing the morbidity and mortality of many infectious diseases. Various non-antibiotic agents exhibit antimicrobial activity via multiple and different mechanisms of action. Further studies are required in the field to further investigate these antimicrobial properties in different populations. This is of paramount importance in the antimicrobial resistance era, where clinicians have limited therapeutic options to combat problematic infections.

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          Most cited references 42

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          Local anesthetics as antimicrobial agents: a review.

           A Dine,  R B Saint,  M. Johnson (2008)
          Since the introduction of cocaine in 1884, local anesthetics have been used as a mainstay of pain management. However, numerous studies over the past several decades have elucidated the supplemental role of local anesthetics as antimicrobial agents. In addition to their anesthetic properties, medications such as bupivacaine and lidocaine have been shown to exhibit bacteriostatic, bactericidal, fungistatic, and fungicidal properties against a wide spectrum of microorganisms. A comprehensive literature search was conducted using MEDLINE 1950-present for in vitro and in vivo studies pertaining to the antimicrobial activity of various local anesthetics on a broad range of bacterial and fungal pathogens. Studies testing the effect on microbial growth inhibition of local anesthetics alone and in combination with other agents, such as preservatives and other medications, as well as the effect of conditions such as concentration and temperature, were included for review. Outcome measures included colony counts, area-under-the-curve and time-kill curve calculations, minimum inhibitory concentrations, and post-antibiotic effect. Evidence suggests that local anesthetics as a class possess inherent antimicrobial properties against a wide spectrum of human pathogens. Multiple local anesthetics at concentrations typically used in the clinical setting (e.g., bupivacaine 0.125%-0.75%; lidocaine 1%-3%) inhibit the growth of numerous bacteria and fungi under various conditions. Different local anesthetics showed various degrees of antimicrobial capacity; bupivacaine and lidocaine, for example, inhibit growth to a significantly greater extent than does ropivacaine. Greater concentrations, longer exposure, and higher temperature each correlate with a proportional increase in microbial growth inhibition. Addition of other agents to the anesthetic solutions, such as preservatives, opioids, or intravenous anesthetics such as propofol, modify the antimicrobial activity via either synergistic or antagonistic action. Limited studies attribute the mechanism of action of antimicrobial activity of local anesthetics to a disruption of microbial cell membrane permeability, leading to leakage of cellular components and subsequent cell lysis. Local anesthetics not only serve as agents for pain control, but possess antimicrobial activity as well. In such a capacity, local anesthetics can be considered as an adjunct to traditional antimicrobial use in the clinical or laboratory setting. Additionally, caution should be exercised when administering local anesthetics prior to diagnostic procedures in which culture specimens are to be obtained, as the antimicrobial activity of the local anesthetic could lead to false-negative results or suboptimal culture yields.
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            Sertraline enhances the activity of antimicrobial agents against pathogens of clinical relevance

            Background Serotonin reuptake inhibitors were recently reported to possess antimicrobial potentials, potentiate activity of several antibiotics, reverse multidrug resistant phenotypes of bacteria and make them susceptible to previously resistant drugs. We investigated antimicrobial potentials of sertraline (SR) against ATCC strains, clinical isolates of Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa alone and in-combination with seven antibiotics. Antifungal activity was investigated against four fungal strains including Aspergillus niger, Aspergillus fumigatus, Aspergillus flavus, and Fusarium solani. Intrinsic antibacterial action and Minimum Inhibitory Concentrations (MICs) were determined using well assay, nutrient broth and agar dilution techniques. Disk diffusion and nutrient broth methods were used to study bacterial susceptibility to SR. Minimum Fungicidal Concentrations (MFCs) of SR were determined using Sabouraud dextrose Agar (SDA). Results Sertraline possesses strong intrinsic antibacterial, antifungal activities and has augmented the antibacterial activities of antibiotics. For S. aureus ATCC 6538, E. coli ATCC 8739 and P. aeruginosa ATCC 9027, the MICs of SR were 20, 40 and 60 μg ml−1, respectively, whereas 55.5% clinical isolates of S. aureus and 50% of E. coli strains were inhibited at 20 and 60 μg ml−1 of SR, respectively. Among the tested fungi, 60% of A. niger and A. fumigatus were inhibited at 40 and 80 μg ml−1, respectively. MFCs were 60 and 80 μg ml−1 for A. flavus and F. solani, respectively. Antibacterial activities of all antibiotics were significantly increased (p < 0.001) with the addition of SR 100 μg ml−1 against all tested bacteria. Conclusion Combination study revealed that SR had significantly increased the activity of antibiotics, and some previously resistant strains were made susceptible. Thus antidepressants are potential sources of resistance modifying agents when used in combination.
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              Histamine H(1)-receptor activation of nuclear factor-kappa B: roles for G beta gamma- and G alpha(q/11)-subunits in constitutive and agonist-mediated signaling.

              Nuclear factor kappa B (NF-kappa B) is an important transcription factor in inflammation that has obtained a great interest as a drug target for the treatment of various allergic conditions. In this study, we show that the histamine H(1) receptor, which is also an important player in allergic and inflammatory conditions, activates NF-kappa B in both a constitutive and agonist-dependent manner. Moreover, the observed constitutive NF-kappa B activation is inhibited by various H(1)-receptor antagonists, suggesting that inverse agonism may account, at least in part, for their ascribed antiallergic properties. Investigation of the H(1) receptor-mediated NF-kappa B activation in transfected COS-7 cells indicates that the level of the observed constitutive activity of the H(1) receptor can be modulated by the expression levels of either G alpha-proteins or G beta gamma-heterodimers. Members of the G alpha(q/11)-family of G alpha-proteins are most effective in increasing H(1) constitutive activity. Also, coexpression of G beta(2) in combination with either G gamma(1) or G gamma(2) results in an increased constitutive activity of the H(1) receptor, whereas scavenging of G beta gamma-subunits by coexpression of G alpha(t) completely neutralizes the constitutive, but not the agonist-induced, NF-kappa B activity. Our data suggest that both G alpha(q/11)- and G beta gamma-subunits play a role in the agonist-induced, H(1) receptor-mediated NF-kappa B activation, but that constitutive NF-kappa B activation by the H(1) receptor is primarily mediated through G beta gamma-subunits.
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                Author and article information

                Journal
                Antibiotics (Basel)
                Antibiotics (Basel)
                antibiotics
                Antibiotics
                MDPI
                2079-6382
                02 March 2020
                March 2020
                : 9
                : 3
                Affiliations
                [1 ]Emergency Department, University General Hospital of Patras, 26504 Patras, Greece
                [2 ]Department of Infectious Diseases, University General Hospital of Patras, 26504 Patras, Greece; sassim@ 123456upatras.gr (S.F.A.); george.panos@ 123456upatras.gr (G.P.); mmarangos@ 123456yahoo.com (M.M.)
                [3 ]Medical Department, University of Brasov, 500036 Transilvania, Romania; mariaonisor@ 123456gmail.com (M.O.O.); musetescu.daniel@ 123456gmail.com (D.-V.M.)
                [4 ]Medical Department, University of Patras, 26504 Patras, Greece; athrigas@ 123456hotmail.com
                [5 ]Department of Paediatrics, University General Hospital of Patras, 26504 Patras, Greece; gkentzid@ 123456hotmail.com
                [6 ]Department of Internal Medicine, University General Hospital of Patras, 26504 Patras, Greece
                Author notes
                [* ]Correspondence: m_lagad2004@ 123456yahoo.gr ; Tel.: +30-6983742532
                Article
                antibiotics-09-00107
                10.3390/antibiotics9030107
                7175110
                32131427
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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