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      Resistance diagnostics as a public health tool to combat antibiotic resistance: A model-based evaluation

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          Abstract

          Rapid point-of-care resistance diagnostics (POC-RD) are a key tool in the fight against antibiotic resistance. By tailoring drug choice to infection genotype, doctors can improve treatment efficacy while limiting costs of inappropriate antibiotic prescription. Here, we combine epidemiological theory and data to assess the potential of resistance diagnostics (RD) innovations in a public health context, as a means to limit or even reverse selection for antibiotic resistance. POC-RD can be used to impose a nonbiological fitness cost on resistant strains by enabling diagnostic-informed treatment and targeted interventions that reduce resistant strains’ opportunities for transmission. We assess this diagnostic-imposed fitness cost in the context of a spectrum of bacterial population biologies and find that POC-RD have a greater potential against obligate pathogens than opportunistic pathogens already subject to selection under “bystander” antibiotic exposure during asymptomatic carriage (e.g., the pneumococcus). We close by generalizing the notion of RD-informed strategies to incorporate carriage surveillance information and illustrate that coupling transmission-control interventions to the discovery of resistant strains in carriage can potentially select against resistance in a broad range of opportunistic pathogens.

          Abstract

          Point-of-care resistance diagnostics represent an opportunity to tailor antibiotic treatment protocols to specific bacterial strains. This study shows that conditioning on both point-of-care and carriage diagnostics can produce effective patient care that also selects against resistance.

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          Most cited references47

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          Antibiotic resistance-the need for global solutions.

          The causes of antibiotic resistance are complex and include human behaviour at many levels of society; the consequences affect everybody in the world. Similarities with climate change are evident. Many efforts have been made to describe the many different facets of antibiotic resistance and the interventions needed to meet the challenge. However, coordinated action is largely absent, especially at the political level, both nationally and internationally. Antibiotics paved the way for unprecedented medical and societal developments, and are today indispensible in all health systems. Achievements in modern medicine, such as major surgery, organ transplantation, treatment of preterm babies, and cancer chemotherapy, which we today take for granted, would not be possible without access to effective treatment for bacterial infections. Within just a few years, we might be faced with dire setbacks, medically, socially, and economically, unless real and unprecedented global coordinated actions are immediately taken. Here, we describe the global situation of antibiotic resistance, its major causes and consequences, and identify key areas in which action is urgently needed. Copyright © 2013 Elsevier Ltd. All rights reserved.
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            The global burden of group A streptococcal diseases.

            The global burden of disease caused by group A streptococcus (GAS) is not known. We review recent population-based data to estimate the burden of GAS diseases and highlight deficiencies in the available data. We estimate that there are at least 517,000 deaths each year due to severe GAS diseases (eg, acute rheumatic fever, rheumatic heart disease, post-streptococcal glomerulonephritis, and invasive infections). The prevalence of severe GAS disease is at least 18.1 million cases, with 1.78 million new cases each year. The greatest burden is due to rheumatic heart disease, with a prevalence of at least 15.6 million cases, with 282,000 new cases and 233,000 deaths each year. The burden of invasive GAS diseases is unexpectedly high, with at least 663,000 new cases and 163,000 deaths each year. In addition, there are more than 111 million prevalent cases of GAS pyoderma, and over 616 million incident cases per year of GAS pharyngitis. Epidemiological data from developing countries for most diseases is poor. On a global scale, GAS is an important cause of morbidity and mortality. These data emphasise the need to reinforce current control strategies, develop new primary prevention strategies, and collect better data from developing countries.
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              Phage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa

              Increasing prevalence and severity of multi-drug-resistant (MDR) bacterial infections has necessitated novel antibacterial strategies. Ideally, new approaches would target bacterial pathogens while exerting selection for reduced pathogenesis when these bacteria inevitably evolve resistance to therapeutic intervention. As an example of such a management strategy, we isolated a lytic bacteriophage, OMKO1, (family Myoviridae) of Pseudomonas aeruginosa that utilizes the outer membrane porin M (OprM) of the multidrug efflux systems MexAB and MexXY as a receptor-binding site. Results show that phage selection produces an evolutionary trade-off in MDR P. aeruginosa, whereby the evolution of bacterial resistance to phage attack changes the efflux pump mechanism, causing increased sensitivity to drugs from several antibiotic classes. Although modern phage therapy is still in its infancy, we conclude that phages, such as OMKO1, represent a new approach to phage therapy where bacteriophages exert selection for MDR bacteria to become increasingly sensitive to traditional antibiotics. This approach, using phages as targeted antibacterials, could extend the lifetime of our current antibiotics and potentially reduce the incidence of antibiotic resistant infections.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Writing – review & editing
                Role: Data curationRole: Writing – review & editing
                Role: Data curationRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Writing – original draftRole: Writing – review & editing
                Role: Academic Editor
                Journal
                PLoS Biol
                PLoS Biol
                plos
                plosbiol
                PLoS Biology
                Public Library of Science (San Francisco, CA USA )
                1544-9173
                1545-7885
                16 May 2019
                May 2019
                16 May 2019
                : 17
                : 5
                : e3000250
                Affiliations
                [1 ] Fuqua School of Business and Department of Economics, Duke University, Durham, North Carolina, United States of America
                [2 ] School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia, United States of America
                [3 ] Center for Communicable Disease Dynamics, Department of Epidemiology and Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, United States of America
                [4 ] Center for Microbial Dynamics and Infection, Georgia Institute of Technology, Atlanta, Georgia, United States of America
                The Pennsylvania State University, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0003-3403-5765
                http://orcid.org/0000-0003-1892-9275
                Article
                PBIOLOGY-D-18-01050
                10.1371/journal.pbio.3000250
                6522007
                31095567
                1fa09594-6ccf-4fca-b032-eccafd5b9fe1
                © 2019 McAdams et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 25 October 2018
                : 12 April 2019
                Page count
                Figures: 5, Tables: 2, Pages: 18
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100004412, Human Frontier Science Program;
                Award ID: RGP0011/2014
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000030, Centers for Disease Control and Prevention;
                Award ID: OADS BAA 2016-N-17812
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000057, National Institute of General Medical Sciences;
                Award ID: U54GM088558
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000893, Simons Foundation;
                Award ID: 396001
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000050, National Heart, Lung, and Blood Institute;
                Award ID: U54GM088558
                Award Recipient :
                The project described was supported by the Centers for Disease Control (OADS BAA 2016-N-17812), the National Institute of General Medical Sciences (U54GM088558), the National Heart Lung Blood Institute (R56HL142857), the Simons Foundation (396001), the Wenner-Gren Foundations, and the Royal Physiographic Society of Lund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
                Categories
                Research Article
                Biology and Life Sciences
                Microbiology
                Microbial Control
                Antimicrobial Resistance
                Antibiotic Resistance
                Medicine and Health Sciences
                Pharmacology
                Antimicrobial Resistance
                Antibiotic Resistance
                Medicine and Health Sciences
                Pharmacology
                Drugs
                Antimicrobials
                Antibiotics
                Biology and Life Sciences
                Microbiology
                Microbial Control
                Antimicrobials
                Antibiotics
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Pathogens
                Opportunistic Pathogens
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                Drug Research and Development
                Drug Discovery
                Medicine and Health Sciences
                Pharmaceutics
                Drug Therapy
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Pathogens
                Biology and Life Sciences
                Microbiology
                Medical Microbiology
                Microbial Pathogens
                Bacterial Pathogens
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                Pathology and Laboratory Medicine
                Pathogens
                Microbial Pathogens
                Bacterial Pathogens
                Biology and Life Sciences
                Microbiology
                Microbial Control
                Antimicrobial Resistance
                Medicine and Health Sciences
                Pharmacology
                Antimicrobial Resistance
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                Life sciences
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