{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T18:53:22Z","timestamp":1789844002849,"version":"4.0.1"},"reference-count":39,"publisher":"American Society for Microbiology","issue":"12","license":[{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100003710","name":"Korea Health Industry Development Institute","doi-asserted-by":"publisher","award":["HI23C121600"],"award-info":[{"award-number":["HI23C121600"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003710","name":"Korea Health Industry Development Institute","doi-asserted-by":"publisher","award":["P0023226"],"award-info":[{"award-number":["P0023226"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Brain Korea 21 FOUR Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mSystems"],"published-print":{"date-parts":[[2025,12,17]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Bacteriophages are emerging as promising alternatives to antibiotics for multidrug-resistant (MDR) infections. However, their unique pharmacokinetic and pharmacodynamic (PKPD) properties arising from host-dependent amplification present challenges for dose selection and clinical translation. Here, we present a mechanistic PKPD model informed by\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      kinetic assays and\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      mouse studies of phage therapy targeting MDR\n                      <jats:italic toggle=\"yes\">Pseudomonas aeruginosa<\/jats:italic>\n                      . The model extends the classical predator-prey model by addressing dormancy-related bacterial persistence and partitioning bacterial subpopulations based on phage susceptibility profiles. Simulations revealed a non-monotonous dose-exposure curve driven by dose-dependent reduction of phage replication and the importance of cross-resistance in selecting optimal phage cocktails.\n                      <jats:italic toggle=\"yes\">In vivo<\/jats:italic>\n                      , host immunity was identified as a crucial component in inhibiting bacterial regrowth, with bistable outcomes dependent on initial bacterial load and immune competence. Dose-ranging simulations under varying immune statuses suggest that long-term bacterial load is solely determined by host immune function. However, higher doses transiently reduce bacterial load to a greater extent and thereby suppress immune activation. In immunocompetent hosts, phage cocktails can enhance maximal bacterial load reduction when administered at doses higher than a critical threshold. In conclusion, our PKPD framework enables optimal selection of phage cocktails and dosing regimens, supports rational design of first-in-human trials of phage therapy, and potentially advances model-informed drug development for replication-competent biologics.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        In this study, we construct an integrative model of phage-bacteria dynamics and investigate whether its calibration to\n                        <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                        kinetic assay data can inform the rational design of phage therapy regimens and cocktails. Our findings demonstrate a dose range within which lower phage doses yield higher long-term exposure, presenting a fundamentally different framework for dose optimization. Analysis of phage cocktails reveals that combining phages with low cross-resistance delays the regrowth of phage-resistant bacteria\n                        <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                        . The extended\n                        <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                        model elucidates key differences between\n                        <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                        and\n                        <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                        outcomes and highlights the importance of the host\u2019s immune response in suppressing the growth of phage-resistant bacteria. Phage cocktails to combat phage resistance are therefore of less importance in immune-competent individuals but can enhance bacterial killing when administered at sufficiently high doses. We propose that this modeling framework holds potential for model-informed drug development by quantitatively characterizing bacteria-phage dynamics using preclinical data. Furthermore, it may facilitate the interpretation of\n                        <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                        therapeutic outcomes through a mechanistic understanding derived from\n                        <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                        observations.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/msystems.01384-25","type":"journal-article","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T12:18:24Z","timestamp":1763036304000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":10,"title":["Model-informed development of bacteriophage therapy: bridging\n                    <i>in vitro<\/i>\n                    and\n                    <i>in vivo<\/i>\n                    efficacy against multidrug-resistant\n                    <i>Pseudomonas aeruginosa<\/i>"],"prefix":"10.1128","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2894-5323","authenticated-orcid":true,"given":"Jun Seok","family":"Cha","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01wjejq96","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacology, Yonsei University","place":["Seodaemun-gu, Republic of Korea"]},{"id":[{"id":"https:\/\/ror.org\/01wjejq96","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine","place":["Seodaemun-gu, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyungnam","family":"Kim","sequence":"additional","affiliation":[{"name":"Microbiotix Co., Ltd","place":["Seoul, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hwa 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