{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:18:52Z","timestamp":1787789932028,"version":"build-2784847793"},"reference-count":32,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"French Agence Nationale pour la Recherche","award":["ANR 20-PAMR-0009"],"award-info":[{"award-number":["ANR 20-PAMR-0009"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Phage therapy is a promising approach for infections caused by multidrug-resistant Staphylococcus aureus, but its clinical development is limited by knowledge gaps in pharmacokinetic\/pharmacodynamic (PK\/PD) and potential emergence of resistance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed in vitro time-kill assays to study the effect of 3 antistaphylococcal phages (V1SA019, V1SA020, and V1SA022) against 2 S. aureus strains (SH1000 and USA300). Resistance emergence was monitored through phenotyping and whole-genome sequencing of resistant clones. Bacteria and phage counts were analyzed by means of PK\/PD modeling with a nonlinear mixed-effects approach to quantify parameter variability.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Phage-bacteria interactions followed a predator-prey pattern, resulting in fast bacterial collapse. However, bacterial regrowth attributed to resistance was observed in some experiments and was associated with the initial multiplicity of infection. All resistant clones harbored mutations in genes involved in teichoic acid biosynthesis, with associated growth defects. The PK\/PD models adequately described bacterial and phage dynamics. Phage binding rate of resistant bacteria was 35\u2013250-fold lower than that for susceptible bacteria, resulting in higher proliferation (45\u2013310-fold higher) and higher inundation thresholds (34\u2013190-fold higher). Parameters also varied between the 2 bacteria strains. Model-based simulations suggested that suppression of resistance required an initial phage dose exceeding the inundation threshold of both susceptible and resistant bacteria subpopulations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study provides a quantitative in vitro framework for understanding the S. aureus and phage codynamics and resistance emergence. The identified threshold phenomena offer insights into the experimental dose-response relationship and may guide future investigations.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/infdis\/jiag407","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T11:52:38Z","timestamp":1786017158000},"source":"Crossref","is-referenced-by-count":0,"title":["Unraveling Resistance and Thresholds in Phage Therapy Using In Vitro\n                    <i>Staphylococcus aureus<\/i>\n                    Experiments and Pharmacokinetic\/Pharmacodynamic Models"],"prefix":"10.1093","author":[{"given":"K\u00e9vin","family":"Royet","sequence":"first","affiliation":[{"name":"Equipe Pathog\u00e9nie des Staphylocoques\u2013Centre International de Recherche en Infectiologie (CIRI), Inserm, U1111, Universit\u00e9 Claude Bernard Lyon 1, CNRS, UMR 5308, Ecole Normale Sup\u00e9rieure de Lyon , Lyon ,","place":["France"]},{"name":"Laboratoire de Biom\u00e9trie et Biologie \u00c9volutive, Universit\u00e9 Claude Bernard Lyon 1, UMR CNRS 5558 , Villeurbanne ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie","family":"Blaz\u00e8re","sequence":"additional","affiliation":[{"name":"Equipe Pathog\u00e9nie des Staphylocoques\u2013Centre International de Recherche en Infectiologie (CIRI), Inserm, U1111, Universit\u00e9 Claude Bernard Lyon 1, CNRS, UMR 5308, Ecole Normale Sup\u00e9rieure de Lyon , Lyon ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilie","family":"Helluin","sequence":"additional","affiliation":[{"name":"Equipe Pathog\u00e9nie des Staphylocoques\u2013Centre International de Recherche en Infectiologie (CIRI), Inserm, U1111, Universit\u00e9 Claude Bernard Lyon 1, CNRS, UMR 5308, Ecole Normale Sup\u00e9rieure de Lyon , Lyon ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludivine","family":"Coignet","sequence":"additional","affiliation":[{"name":"Equipe Pathog\u00e9nie des Staphylocoques\u2013Centre International de Recherche en Infectiologie (CIRI), Inserm, U1111, Universit\u00e9 Claude Bernard Lyon 1, CNRS, UMR 5308, Ecole Normale Sup\u00e9rieure de Lyon , Lyon ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucile","family":"Plumet","sequence":"additional","affiliation":[{"name":"Virulence Bact\u00e9rienne et Infections Chroniques, INSERM U1047, Universit\u00e9 de Montpellier , Montpellier ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e9lanie","family":"Bonhomme","sequence":"additional","affiliation":[{"name":"Equipe Pathog\u00e9nie des Staphylocoques\u2013Centre International de Recherche en Infectiologie (CIRI), Inserm, U1111, Universit\u00e9 Claude Bernard Lyon 1, CNRS, UMR 5308, Ecole Normale Sup\u00e9rieure de Lyon , Lyon ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3716-0521","authenticated-orcid":false,"given":"Camille","family":"Kolenda","sequence":"additional","affiliation":[{"name":"Equipe Pathog\u00e9nie des Staphylocoques\u2013Centre International de Recherche en Infectiologie (CIRI), Inserm, U1111, Universit\u00e9 Claude Bernard Lyon 1, CNRS, UMR 5308, Ecole Normale Sup\u00e9rieure de Lyon , Lyon ,","place":["France"]},{"name":"Service de Bact\u00e9riologie, Centre National de R\u00e9f\u00e9rence des Staphylocoques, Institut des Agents Infectieux, Hospices Civils de Lyon , Lyon ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6605-4808","authenticated-orcid":false,"given":"Romain","family":"Garreau","sequence":"additional","affiliation":[{"name":"Laboratoire de Biom\u00e9trie et Biologie \u00c9volutive, Universit\u00e9 Claude Bernard Lyon 1, UMR CNRS 5558 , Villeurbanne ,","place":["France"]},{"name":"Facult\u00e9 de Pharmacie de Lyon, Universit\u00e9 Claude Bernard Lyon 1 , Lyon ,","place":["France"]},{"name":"Service de Pharmacie, Groupement Hospitalier Nord, Hospices Civils de Lyon , Lyon ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florent","family":"Valour","sequence":"additional","affiliation":[{"name":"Equipe Pathog\u00e9nie des Staphylocoques\u2013Centre International de Recherche en Infectiologie (CIRI), Inserm, U1111, Universit\u00e9 Claude Bernard Lyon 1, CNRS, UMR 5308, Ecole Normale Sup\u00e9rieure de Lyon , Lyon ,","place":["France"]},{"name":"Service des Maladies Infectieuses et Tropicales, Hospices Civils de Lyon , Lyon ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathieu","family":"Medina","sequence":"additional","affiliation":[{"name":"Equipe Pathog\u00e9nie des Staphylocoques\u2013Centre International de Recherche en Infectiologie (CIRI), Inserm, U1111, Universit\u00e9 Claude Bernard Lyon 1, CNRS, UMR 5308, Ecole Normale Sup\u00e9rieure de Lyon , Lyon ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Laurent","sequence":"additional","affiliation":[{"name":"Equipe Pathog\u00e9nie des Staphylocoques\u2013Centre International de Recherche en Infectiologie (CIRI), Inserm, U1111, Universit\u00e9 Claude Bernard Lyon 1, CNRS, UMR 5308, Ecole Normale Sup\u00e9rieure de Lyon , Lyon ,","place":["France"]},{"name":"Service de Bact\u00e9riologie, Centre National de R\u00e9f\u00e9rence des Staphylocoques, Institut des Agents Infectieux, Hospices Civils de Lyon , Lyon 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