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      Subinhibitory Dalbavancin Attenuates Exotoxin Production from Methicillin-Sensitive and Methicillin-Resistant Staphylococcus aureus In Vitro

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          ABSTRACT

          This study investigated the effects of subinhibitory doses of the lipoglycopeptide antibiotic dalbavancin on Staphylococcus aureus toxin production in vitro. S. aureus toxin production levels were compared to those seen with the natural glycopeptide antibiotic vancomycin and with representative beta-lactam and oxazolidinone antibiotics. While neither dalbavancin nor vancomycin adversely affected toxin production, of these glycopeptide antibiotics, only dalbavancin significantly attenuated toxin production at subinhibitory concentrations. These findings support the recent success of dalbavancin for treatment of staphylococcal infections.

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          The role of the Panton-Valentine leucocidin toxin in staphylococcal disease: a systematic review and meta-analysis

          Laura Shallcross, Ellen Fragaszy, Anne Johnson … (2013)
          Summary Background Invasive community-onset staphylococcal disease has emerged worldwide associated with Panton-Valentine leucocidin (PVL) toxin. Whether PVL is pathogenic or an epidemiological marker is unclear. We investigate the role of PVL in disease, colonisation, and clinical outcome. Methods We searched Medline and Embase for original research reporting the prevalence of PVL genes among Staphylococcus aureus pneumonia, bacteraemia, musculoskeletal infection, skin and soft-tissue infection, or colonisation published before Oct 1, 2011. We calculated odds ratios (ORs) to compare patients with PVL-positive colonisation and each infection relative to the odds of PVL-positive skin and soft-tissue infection. We did meta-analyses to estimate odds of infection or colonisation with a PVL-positive strain with fixed-effects or random-effects models, depending on the results of tests for heterogeneity. Results Of 509 articles identified by our search strategy, 76 studies from 31 countries met our inclusion criteria. PVL strains are strongly associated with skin and soft-tissue infections, but are comparatively rare in pneumonia (OR 0·37, 95% CI 0·22–0·63), musculoskeletal infections (0·44, 0·19–0·99), bacteraemias (0·10, 0·06–0·18), and colonising strains (0·07, 0·01–0·31). PVL-positive skin and soft-tissue infections are more likely to be treated surgically than are PVL-negative infections, and children with PVL-positive musculoskeletal disease might have increased morbidity. For other forms of disease we identified no evidence that PVL affects outcome. Interpretation PVL genes are consistently associated with skin and soft-tissue infections and are comparatively rare in invasive disease. This finding challenges the view that PVL mainly causes invasive disease with poor prognosis. Population-based studies are needed to define the role of PVL in mild, moderate, and severe disease and to inform control strategies. Funding None.
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            Targeting of alpha-hemolysin by active or passive immunization decreases severity of USA300 skin infection in a mouse model.

            Adam D. Kennedy, Olaf Schneewind, Adeline Whitney … (2010)
            Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections are predominantly those affecting skin and soft tissues. Although progress has been made, our knowledge of the molecules that contribute to the pathogenesis of CA-MRSA skin infections is incomplete. We tested the hypothesis that alpha-hemolysin (Hla) contributes to the severity of USA300 skin infections in mice and determined whether vaccination against Hla reduces disease severity. Isogenic hla-negative (Deltahla) strains caused skin lesions in a mouse infection model that were significantly smaller than those caused by wild-type USA300 and Newman strains. Moreover, infection due to wild-type strains produced dermonecrotic skin lesions, whereas there was little or no dermonecrosis in mice infected with Deltahla strains. Passive immunization with Hla-specific antisera or active immunization with a nontoxigenic form of Hla significantly reduced the size of skin lesions caused by USA300 and prevented dermonecrosis. We conclude that Hla is a potential target for therapeutics or vaccines designed to moderate severe S. aureus skin infections.
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              Impact of antibiotics on expression of virulence-associated exotoxin genes in methicillin-sensitive and methicillin-resistant Staphylococcus aureus.

              Dennis L Stevens, Yongsheng Ma, Daniel B Salmi … (2007)
              Extracellular protein toxins contribute to the pathogenesis of a wide variety of Staphylococcus aureus infections. The present study investigated the effects that cell-wall active antibiotics and protein-synthesis inhibitors have on transcription and translation of genes for Panton-Valentine leukocidin, alpha-hemolysin, and toxic-shock syndrome toxin 1, in both methicillin-sensitive and methicillin-resistant S. aureus. Subinhibitory concentrations of nafcillin induced and prolonged mRNA for Panton-Valentine leukocidin, alpha-toxin, and toxic-shock syndrome toxin 1 and increased toxin production. In contrast, clindamycin and linezolid markedly suppressed translation, but not transcription, of toxin genes. These results suggest (1) that protein-synthesis inhibition is an important consideration in the selection of antimicrobial agents to treat serious infections caused by toxin-producing gram-positive pathogens and (2) that, by inducing and enhancing toxin production, inadvertent use of beta-lactam antibiotics to treat methicillin-resistant S. aureus infections may contribute to worse outcomes.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Antimicrob Agents Chemother
                Journal ID (iso-abbrev): Antimicrob. Agents Chemother
                Journal ID (hwp): aac
                Journal ID (pmc): aac
                Journal ID (publisher-id): AAC
                Title: Antimicrobial Agents and Chemotherapy
                Publisher: American Society for Microbiology (1752 N St., N.W., Washington, DC )
                ISSN (Print): 0066-4804
                ISSN (Electronic): 1098-6596
                Publication date (Electronic preprint): 5 September 2017
                Publication date (Electronic): 24 October 2017
                Publication date Collection: November 2017
                Volume: 61
                Issue: 11
                Electronic Location Identifier: e01090-17
                Affiliations
                [a ]Idaho Veterans Research and Education Foundation, Boise, Idaho, USA
                [b ]Infectious Diseases Section, Veterans Affairs Medical Center, Boise, Idaho, USA
                [c ]University of Washington School of Medicine, Seattle, Washington, USA
                [d ]Biomolecular Research Center, Boise State University, Boise, Idaho, USA
                Author notes
                Address correspondence to Sarah E. Hobdey, Sarah.Hobdey@ 123456va.gov .
                [*]

                Present address: Pamela Dockstader, Idaho State University, Meridian, Idaho, USA; Stephen M. Davidson, University of Arizona, Tucson, Arizona, USA.

                Citation Hobdey SE, Katahira EJ, Dockstader P, Davidson SM, Bond L, Bolz DD, Bryant AE, Stevens DL. 2017. Subinhibitory dalbavancin attenuates exotoxin production from methicillin-sensitive and methicillin-resistant Staphylococcus aureus in vitro. Antimicrob Agents Chemother 61:e01090-17. https://doi.org/10.1128/AAC.01090-17.

                Article
                Accession ID: PMC5655096 Pmcid ID: PMC5655096 Pmc-uid ID: 5655096 Publisher ID: 01090-17
                DOI: 10.1128/AAC.01090-17
                PMC ID: 5655096
                PubMed ID: 28874375
                SO-VID: d0e2fa06-70f1-4a74-a457-1a7f9a37c4d7
                Copyright © Copyright © 2017 American Society for Microbiology.
                License:

                All Rights Reserved.

                History
                Date received : 12 June 2017
                Date revision requested : 27 June 2017
                Date accepted : 22 August 2017
                Page count
                Figures: 3, Tables: 1, Equations: 0, References: 29, Pages: 6, Words: 3313
                Funding
                Funded by: Idaho State Board of Education
                Award Recipient : Laura Bond
                Funded by: Forest Research Institute, Inc.
                Award ID: DAL-IT-02
                Award Recipient : Sarah E. Hobdey
                Funded by: HHS | NIH | National Institute of General Medical Sciences, Centers of Biomedical Research Excellence
                Award ID: P20GM109007
                Award ID: P20GM103408
                Award Recipient : Sarah E. Hobdey Award Recipient : Laura Bond Award Recipient : Devin D. Bolz Award Recipient : Dennis L. Stevens
                Funded by: Idaho IDeA Network of Biomedical Research Excellence
                Award ID: P20GM103408
                Award Recipient : Amy E. Bryant
                Funded by: US Department of Veterans Affairs, Office of Research and Development
                Award Recipient : Eva J. Katahira Award Recipient : Amy E. Bryant Award Recipient : Dennis L. Stevens
                Funded by: Idaho Veterans Research and Education Foundation
                Award ID: PAVER Fellowship
                Award Recipient : Pamela Dockstader
                Funded by: HHS | NIH | National Institute of General Medical Sciences (NIGMS) https://doi.org/10.13039/100000057
                Award ID: U54GM104944
                Award Recipient : Laura Bond
                Funded by: M.J. Murdock Charitable Trust (MJ Murdock Charitable Trust) https://doi.org/10.13039/100000937
                Award Recipient : Laura Bond
                Categories
                Subject: Clinical Therapeutics
                Custom metadata
                cover-date November 2017

                Keywords: Staphylococcus aureus ,subinhibitory antibiotics,toxin production
                Data availability:
                Keywords: Staphylococcus aureus , subinhibitory antibiotics, toxin production

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