{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:09:23Z","timestamp":1785427763165,"version":"3.56.0"},"posted":{"date-parts":[[2025,4,10]]},"group-title":"Microbiology","reference-count":31,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T00:00:00Z","timestamp":1744243200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R35GM136407"],"award-info":[{"award-number":["R35GM136407"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,4,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Studies of antimicrobial therapeutics have traditionally neglected the contribution of the host in determining the course of treatment and its outcome. One critical host element, which shapes the dynamics of treatment is the innate immune system. Studies of chemotherapeutics and complementary therapies such as bacteriophage (phage), are commonly performed with mice that purposely have an ablated innate immune system. Here, we generate a mathematical and computer-simulation model of the joint action of antibiotics, phage, and phagocytes. Our analysis of this model highlights the need for future studies to consider the role of the host\u2019s innate immune system in determining treatment outcomes. Critically, our model predicts that the conditions under which resistance to the treatment agent(s) will emerge are much narrower than commonly anticipate. We also generate a second model to predict the dynamics of treatment when multiple phages are used. This model provides support for the application of cocktails to treat infections rather than individual phages. Overall, this study provides hypotheses that can readily be tested experimentally with both\n                  <jats:italic>in vitro<\/jats:italic>\n                  and\n                  <jats:italic>in vivo<\/jats:italic>\n                  experiments.\n                <\/jats:p>","DOI":"10.1101\/2025.04.10.648192","type":"posted-content","created":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T21:00:21Z","timestamp":1744318821000},"source":"Crossref","is-referenced-by-count":0,"title":["The joint action of antibiotics, bacteriophage, and the innate immune response in the treatment of bacterial infections"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3430-0901","authenticated-orcid":false,"given":"Brandon A.","family":"Berryhill","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0136-3965","authenticated-orcid":false,"given":"Teresa","family":"Gil-Gil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3600-2780","authenticated-orcid":false,"given":"Bruce R.","family":"Levin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025052500095717000_2025.04.10.648192v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2024.107088"},{"key":"2025052500095717000_2025.04.10.648192v1.2","doi-asserted-by":"crossref","unstructured":"M. A. Salam et al., Antimicrobial Resistance: A Growing Serious Threat for Global Public Health. Healthcare (Basel) 11 (2023).","DOI":"10.20944\/preprints202305.0555.v1"},{"key":"2025052500095717000_2025.04.10.648192v1.3","doi-asserted-by":"publisher","DOI":"10.4161\/bact.20757"},{"key":"2025052500095717000_2025.04.10.648192v1.4","doi-asserted-by":"crossref","unstructured":"B. A. Berryhill , D. L. Huseby , I. C. McCall , D. Hughes , B. R. Levin , Evaluating the potential efficacy and limitations of a phage for joint antibiotic and phage therapy of Staphylococcus aureus infections. Proc Natl Acad Sci U S A 118 (2021).","DOI":"10.1073\/pnas.2008007118"},{"key":"2025052500095717000_2025.04.10.648192v1.5","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.60551"},{"key":"2025052500095717000_2025.04.10.648192v1.6","doi-asserted-by":"crossref","unstructured":"A. H. Osman et al., The Potential of Bacteriophage-Antibiotic Combination Therapy in Treating Infections with Multidrug-Resistant Bacteria. Antibiotics (Basel) 12 (2023).","DOI":"10.3390\/antibiotics12081329"},{"key":"2025052500095717000_2025.04.10.648192v1.7","unstructured":"Anonymous, in Autoimmunity: From Bench to Bedside, J. M. Anaya , Y. Shoenfeld , A. Rojas-Villarraga , R. A. Levy , R. Cervera , Eds. (El Rosario University Press \u00a9 2013 Universidad del Rosario., Bogota (Colombia), 2013)."},{"key":"2025052500095717000_2025.04.10.648192v1.8","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofaa302"},{"key":"2025052500095717000_2025.04.10.648192v1.9","doi-asserted-by":"crossref","unstructured":"A. Carroll-Portillo , H. C. Lin , Bacteriophage and the Innate Immune System: Access and Signaling. Microorganisms 7 (2019).","DOI":"10.3390\/microorganisms7120625"},{"key":"2025052500095717000_2025.04.10.648192v1.10","doi-asserted-by":"crossref","unstructured":"S. T. Abedon , K. M. Danis-Wlodarczyk , D. J. Wozniak , Phage Cocktail Development for Bacteriophage Therapy: Toward Improving Spectrum of Activity Breadth and Depth. Pharmaceuticals (Basel) 14 (2021).","DOI":"10.3390\/ph14101019"},{"key":"2025052500095717000_2025.04.10.648192v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2017.07.005"},{"key":"2025052500095717000_2025.04.10.648192v1.12","doi-asserted-by":"publisher","DOI":"10.2307\/1935611"},{"key":"2025052500095717000_2025.04.10.648192v1.13","doi-asserted-by":"publisher","DOI":"10.1086\/282825"},{"key":"2025052500095717000_2025.04.10.648192v1.14","doi-asserted-by":"crossref","unstructured":"S. E. Luria , M. Delbr\u00fcck , Mutations of bacteria from virus sensitivity to virus resistance. Genetics 28, 491 (1943).","DOI":"10.1093\/genetics\/28.6.491"},{"key":"2025052500095717000_2025.04.10.648192v1.15","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2212121120"},{"key":"2025052500095717000_2025.04.10.648192v1.16","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00381-10"},{"key":"2025052500095717000_2025.04.10.648192v1.17","first-page":"e04091","article-title":"What\u2019s the Matter with MICs: Bacterial Nutrition, Limiting Resources, and Antibiotic Pharmacodynamics","volume":"11","year":"2023","journal-title":"Microbiology Spectrum"},{"key":"2025052500095717000_2025.04.10.648192v1.18","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.10.3670-3676.2004"},{"key":"2025052500095717000_2025.04.10.648192v1.19","first-page":"606","article-title":"The growth of bacterial cultures","volume":"139","year":"2012","journal-title":"Selected Papers in Molecular Biology by Jacques Monod"},{"key":"2025052500095717000_2025.04.10.648192v1.20","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/124.1.175"},{"key":"2025052500095717000_2025.04.10.648192v1.21","doi-asserted-by":"publisher","DOI":"10.2307\/2280232"},{"key":"2025052500095717000_2025.04.10.648192v1.22","unstructured":"J. E. Gentle , Random number generation and Monte Carlo methods (Springer, 2003), vol. 381."},{"key":"2025052500095717000_2025.04.10.648192v1.23","doi-asserted-by":"crossref","unstructured":"E. Hairer , G. Wanner , Solving Ordinary Differential Equations II. Stiff and Differential-Algebraic Problems (1996), vol. 14.","DOI":"10.1007\/978-3-642-05221-7"},{"key":"2025052500095717000_2025.04.10.648192v1.24","first-page":"277","article-title":"The antibiotic resistance crisis: part 1: causes and threats","volume":"40","year":"2015","journal-title":"P t"},{"key":"2025052500095717000_2025.04.10.648192v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2011.373"},{"key":"2025052500095717000_2025.04.10.648192v1.26","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cix1127"},{"key":"2025052500095717000_2025.04.10.648192v1.27","doi-asserted-by":"publisher","DOI":"10.4292\/wjgpt.v8.i3.162"},{"key":"2025052500095717000_2025.04.10.648192v1.28","doi-asserted-by":"publisher","DOI":"10.1101\/2024.08.23.609294"},{"key":"2025052500095717000_2025.04.10.648192v1.29","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.46.7.2095-2103.2002"},{"key":"2025052500095717000_2025.04.10.648192v1.30","first-page":"e59015","volume":"144","year":"2019","journal-title":"A Mouse Model to Assess Innate Immune Response to Staphylococcus aureus Infection"},{"key":"2025052500095717000_2025.04.10.648192v1.31","unstructured":"R. Macey , G. Oster , T. Zahnley , Berkeley Madonna user\u2019s guide. University of California, Berkeley, CA 67 (2000)."}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.04.10.648192","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T08:28:11Z","timestamp":1768465691000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.04.10.648192"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,10]]},"references-count":31,"URL":"https:\/\/doi.org\/10.1101\/2025.04.10.648192","relation":{},"subject":[],"published":{"date-parts":[[2025,4,10]]},"subtype":"preprint"}}