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      On-chip phenotypic investigation of combinatory antibiotic effects by generating orthogonal concentration gradients

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          Abstract

          We propose a microfluidic cell-based drug screening platform to investigate combinatory antibiotic effects by automatically generating concentration combinations.

          Abstract

          Combinatory therapy using two or more kinds of antibiotics is attracting considerable attention for inhibiting multi-drug resistant pathogenic bacteria. Although the therapy mostly leads to more powerful antimicrobial effects than using a single antibiotic (synergy), interference may arise from certain antibiotic combinations, resulting in the antimicrobial effect being suppressed (antagonism). Here, we present a microfluidic-based phenotypic screening chip to investigate combinatory antibiotic effects by automatically generating two orthogonal concentration gradients on a bacteria-trapping agarose gel. Computational simulations and fluorescence experiments together verify the simultaneous establishment of 121 concentration combinations, facilitating on-chip drug testing with stability and efficiency. Against Gram-negative bacteria, Pseudomonas aeruginosa, our chip allows the measurement of phenotypic growth levels, and enables various types of analyses for all antibiotic pairs to be conducted in 7 h. Furthermore, by providing a specific amount of susceptibility data, our chip enables the two reference models, Loewe additivity and Bliss independence, to be implemented, which classify the antibiotic interaction types into synergy or antagonism. These results suggest the efficacy of our chip as a cell-based drug screening platform for exploring the underlying pharmacological patterns of antibiotic interactions, with potential applications in guidance in clinical therapies and in screening other cell-type agents.

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          Most cited references61

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          Antimicrobial susceptibility testing: a review of general principles and contemporary practices.

          An important task of the clinical microbiology laboratory is the performance of antimicrobial susceptibility testing of significant bacterial isolates. The goals of testing are to detect possible drug resistance in common pathogens and to assure susceptibility to drugs of choice for particular infections. The most widely used testing methods include broth microdilution or rapid automated instrument methods that use commercially marketed materials and devices. Manual methods that provide flexibility and possible cost savings include the disk diffusion and gradient diffusion methods. Each method has strengths and weaknesses, including organisms that may be accurately tested by the method. Some methods provide quantitative results (eg, minimum inhibitory concentration), and all provide qualitative assessments using the categories susceptible, intermediate, or resistant. In general, current testing methods provide accurate detection of common antimicrobial resistance mechanisms. However, newer or emerging mechanisms of resistance require constant vigilance regarding the ability of each test method to accurately detect resistance.
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            Multi-target therapeutics: when the whole is greater than the sum of the parts.

            Drugs designed to act against individual molecular targets cannot usually combat multigenic diseases such as cancer, or diseases that affect multiple tissues or cell types such as diabetes and immunoinflammatory disorders. Combination drugs that impact multiple targets simultaneously are better at controlling complex disease systems, are less prone to drug resistance and are the standard of care in many important therapeutic areas. The combination drugs currently employed are primarily of rational design, but the increased efficacy they provide justifies in vitro discovery efforts for identifying novel multi-target mechanisms. In this review, we discuss the biological rationale for combination therapeutics, review some existing combination drugs and present a systematic approach to identify interactions between molecular pathways that could be leveraged for therapeutic benefit.
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              Combination therapy for treatment of infections with gram-negative bacteria.

              Combination antibiotic therapy for invasive infections with Gram-negative bacteria is employed in many health care facilities, especially for certain subgroups of patients, including those with neutropenia, those with infections caused by Pseudomonas aeruginosa, those with ventilator-associated pneumonia, and the severely ill. An argument can be made for empiric combination therapy, as we are witnessing a rise in infections caused by multidrug-resistant Gram-negative organisms. The wisdom of continued combination therapy after an organism is isolated and antimicrobial susceptibility data are known, however, is more controversial. The available evidence suggests that the greatest benefit of combination antibiotic therapy stems from the increased likelihood of choosing an effective agent during empiric therapy, rather than exploitation of in vitro synergy or the prevention of resistance during definitive treatment. In this review, we summarize the available data comparing monotherapy versus combination antimicrobial therapy for the treatment of infections with Gram-negative bacteria.
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                Author and article information

                Journal
                LCAHAM
                Lab on a Chip
                Lab Chip
                Royal Society of Chemistry (RSC)
                1473-0197
                1473-0189
                March 13 2019
                2019
                : 19
                : 6
                : 959-973
                Affiliations
                [1 ]Department of Mechanical Engineering
                [2 ]Korea Advanced Institute of Science and Technology
                [3 ]Daejeon
                [4 ]Republic of Korea
                [5 ]Graduate School of Nanoscience and Technology
                [6 ]Department of Biological Sciences
                [7 ]KAIST Institute for Health Science and Technology
                Article
                10.1039/C8LC01406J
                ab37f4e7-266a-4f42-98a7-601658699cdc
                © 2019

                http://rsc.li/journals-terms-of-use

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