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      The Novel Oxazolidinone TBI-223 Is Effective in Three Preclinical Mouse Models of Methicillin-Resistant Staphylococcus aureus Infection

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          ABSTRACT

          Staphylococcus aureus is an important cause of various infections in humans, including bacteremia, skin and soft tissue infections, and infections associated with implanted medical devices. The emergence of hospital- and community-acquired methicillin-resistant Staphylococcus aureus (MRSA) underscores the urgent and unmet need to develop novel, safe, and effective antibiotics against these multidrug-resistant clinical isolates. Oxazolidinone antibiotics such as linezolid have excellent oral bioavailability and provide coverage against MRSA infections. However, their widespread and long-term use is often limited by adverse effects, especially myelosuppression. TBI-223 is a novel oxazolidinone with potentially reduced myelosuppression, compared to linezolid, but its efficacy against MRSA infections is unknown. Therefore, the preclinical efficacy of TBI-223 (80 and 160 mg/kg twice daily) was compared with that of linezolid (40 and 80 mg/kg twice daily) and sham treatment in mouse models of MRSA bacteremia, skin wound infection, and orthopedic-implant-associated infection. The dosage was selected based on mouse pharmacokinetic analysis of both linezolid and TBI-223, as well as measurement of the MICs. In all three models, TBI-223 and linezolid had comparable dose-dependent efficacies in reducing bacterial burden and disease severity, compared with sham-treated control mice. Taken together, these findings indicate that TBI-223 represents a novel oxazolidinone antibiotic that may provide an additional option against MRSA infections. Future studies in larger animal models and clinical trials are warranted to translate these findings to humans.

          IMPORTANCE Staphylococcus aureus is the predominant cause of bloodstream, skin, and bone infections in humans. Resistance to commonly used antibiotics is a growing concern, making it more difficult to treat staphylococcal infections. Use of the oxazolidinone antibiotic linezolid against resistant strains is hindered by high rates of adverse reactions during prolonged therapy. Here, a new oxazolidinone named TBI-223 was tested against S. aureus in three mouse models of infection, i.e., bloodstream infection, skin infection, and bone infection. We found that TBI-223 was as effective as linezolid in these three models. Previous data suggest that TBI-223 has a better safety profile than linezolid. Taken together, these findings indicate that this new agent may provide an additional option against MRSA infections. Future studies in larger animal models and clinical trials are warranted to translate these findings to humans.

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          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

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            Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management.

            Staphylococcus aureus is a major human pathogen that causes a wide range of clinical infections. It is a leading cause of bacteremia and infective endocarditis as well as osteoarticular, skin and soft tissue, pleuropulmonary, and device-related infections. This review comprehensively covers the epidemiology, pathophysiology, clinical manifestations, and management of each of these clinical entities. The past 2 decades have witnessed two clear shifts in the epidemiology of S. aureus infections: first, a growing number of health care-associated infections, particularly seen in infective endocarditis and prosthetic device infections, and second, an epidemic of community-associated skin and soft tissue infections driven by strains with certain virulence factors and resistance to β-lactam antibiotics. In reviewing the literature to support management strategies for these clinical manifestations, we also highlight the paucity of high-quality evidence for many key clinical questions.
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              Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America.

              These guidelines are intended for use by infectious disease specialists, orthopedists, and other healthcare professionals who care for patients with prosthetic joint infection (PJI). They include evidence-based and opinion-based recommendations for the diagnosis and management of patients with PJI treated with debridement and retention of the prosthesis, resection arthroplasty with or without subsequent staged reimplantation, 1-stage reimplantation, and amputation.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                Microbiol Spectr
                Microbiol Spectr
                spectrum
                Microbiology Spectrum
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                2165-0497
                15 September 2022
                Sep-Oct 2022
                15 September 2022
                : 10
                : 5
                : e02451-21
                Affiliations
                [a ] Division of Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicinegrid.471401.7, , Baltimore, Maryland, USA
                [b ] Department of Dermatology, Johns Hopkins University School of Medicinegrid.471401.7, , Baltimore, Maryland, USA
                [c ] Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
                [d ] Center for Tuberculosis Research, Johns Hopkins Universitygrid.471401.7grid.21107.35grid.471401.7, , Baltimore, Maryland, USA
                [e ] Evotec (US) Inc., Princeton, New Jersey, USA
                [f ] TB Alliance, New York, New York, USA
                [g ] Immunology, Janssen Research and Development, Spring House, Pennsylvania, USA
                Emory University School of Medicine
                Author notes

                The authors declare a conflict of interest. L.S.M. is a full-time employee of Janssen Pharmaceuticals and owns Johnson & Johnson stock. L.S.M. performed all work at his prior affiliation at Johns Hopkins University School of Medicine and he has received prior grant support from AstraZeneca, Pfizer, Boehringer Ingelheim, Regeneron Pharmaceuticals, and Moderna Therapeutics, was a paid consultant for Armirall and Janssen Research and Development, was on the scientific advisory board of Integrated Biotherapeutics and is a shareholder of Noveome Biotherapeutics, which are all developing therapeutics against infections (including S. aureus and other pathogens) and/or inflammatory conditions. A.M.U. is a full-time employee of Evotec (Princeton, NJ) and N.F. is a full-time employee of TB Alliance (New York, NY). N.K.A. has received prior grant support from Pfizer and Boehringer Ingelheim, and is a paid consultant for Janssen Pharmaceuticals.

                Author information
                https://orcid.org/0000-0002-3159-8426
                https://orcid.org/0000-0002-5622-1721
                https://orcid.org/0000-0003-1440-9889
                https://orcid.org/0000-0002-8212-8985
                Article
                02451-21 spectrum.02451-21
                10.1128/spectrum.02451-21
                9603142
                36106881
                7b01313d-1bc9-4d9d-804a-a61474a18085
                Copyright © 2022 Gordon et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                History
                : 12 April 2022
                : 30 August 2022
                Page count
                supplementary-material: 0, Figures: 5, Tables: 1, Equations: 0, References: 48, Pages: 14, Words: 8406
                Funding
                Funded by: TB alliance;
                Award Recipient : Award Recipient :
                Funded by: HHS | National Institutes of Health (NIH), FundRef https://doi.org/10.13039/100000002;
                Award ID: R01AR073665
                Award Recipient : Award Recipient :
                Funded by: HHS | National Institutes of Health (NIH), FundRef https://doi.org/10.13039/100000002;
                Award ID: R01AR069502
                Award Recipient : Award Recipient :
                Categories
                Research Article
                antimicrobial-chemotherapy, Antimicrobial Chemotherapy
                Custom metadata
                September/October 2022

                staphylococcus aureus,antibiotic resistance,oxazolidinones

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