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      Vancomycin Is Protective in a Neonatal Mouse Model of Staphylococcus epidermidis-Potentiated Hypoxic-Ischemic Brain Injury

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          Abstract

          Infection is correlated with increased risk of neurodevelopmental sequelae in preterm infants. In modeling neonatal brain injury, Toll-like receptor agonists have often been used to mimic infections and induce inflammation. Using the most common cause of bacteremia in preterm infants, Staphylococcus epidermidis, we present a more clinically relevant neonatal mouse model that addresses the combined effects of bacterial infection together with subsequent hypoxic-ischemic brain insult.

          ABSTRACT

          Infection is correlated with increased risk of neurodevelopmental sequelae in preterm infants. In modeling neonatal brain injury, Toll-like receptor agonists have often been used to mimic infections and induce inflammation. Using the most common cause of bacteremia in preterm infants, Staphylococcus epidermidis, we present a more clinically relevant neonatal mouse model that addresses the combined effects of bacterial infection together with subsequent hypoxic-ischemic brain insult. Currently, there is no neuroprotective treatment for the preterm population. Hence, we tested the neuroprotective effects of vancomycin with and without adjunct therapy using the anti-inflammatory agent pentoxifylline. We characterized the effects of S. epidermidis infection on the inflammatory response in the periphery and the brain, as well as the physiological changes in the central nervous system that might affect neurodevelopmental outcomes. Intraperitoneal injection of postnatal day 4 mice with a live clinical isolate of S. epidermidis led to bacteremia and induction of proinflammatory cytokines in the blood, as well as transient elevations of neutrophil and monocyte chemotactic cytokines and caspase 3 activity in the brain. When hypoxia-ischemia was induced postinfection, more severe brain damage was observed in infected animals than in saline-injected controls. This infection-induced inflammation and potentiated brain injury was inoculum dose dependent and was alleviated by the antibiotic vancomycin. Pentoxifylline did not provide any additional neuroprotective effect. Thus, we show for the first time that live S. epidermidis potentiates hypoxic-ischemic preterm brain injury and that peripheral inhibition of inflammation with antibiotics, such as vancomycin, reduces the extent of brain injury.

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          Author and article information

          Journal
          Antimicrob Agents Chemother
          Antimicrob. Agents Chemother
          aac
          aac
          AAC
          Antimicrobial Agents and Chemotherapy
          American Society for Microbiology (1752 N St., N.W., Washington, DC )
          0066-4804
          1098-6596
          21 February 2020
          March 2020
          9 December 2019
          : 64
          : 3
          : e02003-19
          Affiliations
          [a ] Center for Perinatal Medicine and Health, Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
          [b ] Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Boston, Massachusetts, USA
          [c ] Harvard Medical School, Harvard University, Boston, Massachusetts, USA
          [d ] Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
          [e ] Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
          [f ] Centre for Neonatal Research and Education, University of Western Australia, Perth, Western Australia, Australia
          [g ] Medical, Molecular and Forensic Sciences, Murdoch University, Perth, Western Australia, Australia
          [h ] Neonatal Directorate, King Edward Memorial Hospital for Women, Subiaco, Western Australia, Australia
          Author notes
          Address correspondence to Jacqueline C. Y. Lai, jacqueline.lai@ 123456neuro.gu.se , or Carina Mallard, carina.mallard@ 123456neuro.gu.se .

          Citation Lai JCY, Svedin P, Ek CJ, Mottahedin A, Wang X, Levy O, Currie A, Strunk T, Mallard C. 2020. Vancomycin is protective in a neonatal mouse model of Staphylococcus epidermidis-potentiated hypoxic-ischemic brain injury. Antimicrob Agents Chemother 64:e02003-19. https://doi.org/10.1128/AAC.02003-19.

          Author information
          https://orcid.org/0000-0001-5915-1469
          https://orcid.org/0000-0002-5764-7679
          https://orcid.org/0000-0002-5859-1945
          https://orcid.org/0000-0002-5193-3404
          https://orcid.org/0000-0001-8953-919X
          Article
          PMC7038267 PMC7038267 7038267 02003-19
          10.1128/AAC.02003-19
          7038267
          31818825
          0e71258d-6f96-44b7-b075-9a38c40bf5eb
          Copyright © 2020 American Society for Microbiology.

          All Rights Reserved.

          History
          : 4 October 2019
          : 20 October 2019
          : 6 December 2019
          Page count
          supplementary-material: 1, Figures: 7, Tables: 0, Equations: 0, References: 64, Pages: 15, Words: 9423
          Funding
          Funded by: VINNOVA VINNMER Marie-Curie;
          Award ID: 2015-01505
          Award Recipient :
          Funded by: Wilhelm and Martina Lundgrens Foundation;
          Award ID: 2016-1323
          Award ID: 2017-1966
          Award ID: 2018-2465
          Award Recipient :
          Funded by: Lilla Barnets Fund;
          Award ID: 20170806
          Award Recipient :
          Funded by: Anna-Brita and Bo Castegrens Memorial Foundation;
          Award ID: LA2017-0269
          Award Recipient :
          Funded by: ALF-agreement;
          Award ID: ALFGBG-722491
          Award Recipient :
          Funded by: ALF-agreement;
          Award ID: ALFGBG-813291
          Award Recipient :
          Funded by: Leducq Foundation;
          Award ID: DSRR_P34404
          Award Recipient :
          Funded by: Åhlen Foundation;
          Award Recipient :
          Funded by: Telethon Perth Children's Hospital Research Funds;
          Award Recipient : Award Recipient :
          Funded by: Wilhelm and Martina Lundgrens Foundation;
          Award ID: 2017-1911
          Award ID: 2018-2368
          Award Recipient :
          Funded by: Cerebral Palsy Alliance Australia;
          Award ID: PG4416
          Award Recipient :
          Funded by: Swedish Research Council Formas, https://doi.org/10.13039/501100001862;
          Award ID: VR-2017-01409
          Award Recipient :
          Funded by: Swedish Research Council Formas, https://doi.org/10.13039/501100001862;
          Award ID: VR-2018-02682
          Award Recipient :
          Funded by: Torsten Söderbergs Stiftelse (Torsten Söderberg Foundation), https://doi.org/10.13039/100007464;
          Award ID: M98/15
          Award Recipient :
          Funded by: STROKE-Riksförbundet (Swedish Stroke Association), https://doi.org/10.13039/501100008590;
          Award Recipient :
          Funded by: Hjärnfonden (Swedish Brain Foundation), https://doi.org/10.13039/501100003792;
          Award ID: FO2017-0063
          Award Recipient :
          Funded by: Hjärnfonden (Swedish Brain Foundation), https://doi.org/10.13039/501100003792;
          Award ID: F018-0090
          Award Recipient :
          Categories
          Experimental Therapeutics
          Editor's Pick
          Custom metadata
          March 2020

          neuroprotection,bacterial infection,brain injury, Staphylococcus epidermidis ,sepsis,hypoxia-ischemia,vancomycin,neonatal mice,pentoxifylline,preterm

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