{
  "abstract": "Background. Optimal antibiotic dosing regimens depend on the pharmacokinetic/pharmacodynamic (PK/PD) index that best predicts antibacterial efficacy. PK/PD targets are traditionally determined using murine infection models based on a limited number of bacterial isolates. Objective. This study aimed to investigate whether animal experiments could be replaced by in vitro time-kill experiments performed on a large collection of clinical isolates and analyzed using a modelling approach accounting for inter-strain variability. The proposed framework was evaluated using meropenem against Pseudomonas aeruginosa. Materials and Methods. In vitro time-kill experiments were performed on 66 clinical isolates of P. aeruginosa. A population pharmacodynamic model was developed from experimental data. A murine pharmacokinetic model was reproduced from literature and combined with the pharmacodynamic model to simulate in vivo bacterial burden over time. The relationships between simulated bacterial counts at 24 h and the three main PK/PD indices (fCmax/MIC, fAUC/MIC and %fT>MIC) were characterized using nonlinear mixed-effects Imax models. Results. The PK/PD index showing the strongest correlation with meropenem efficacy at 24 h was %fT>MIC (R2 = 0.989), compared with fAUC/MIC (R2 = 0.373) and fCmax/MIC (R2 = 0.284). These findings are consistent with previous studies using murine thigh infection models. The %fT>MIC target required to achieve a 2-log CFU reduction was estimated at 44%, with substantial inter-strain variability (10th and 90th percentiles: 27% and 71%, respectively). Conclusions. Using meropenem against P. aeruginosa as a proof of concept, we demonstrate that in vitro time-kill experiments combined with pharmacometric modelling can identify the same PK/PD efficacy targets as animal infection models. Moreover, performing experiments on a large panel of clinical isolates enables the quantification of inter-strain variability in PK/PD targets, providing information that may improve their translation to clinical dosing optimization.",
  "abstract_shown": true,
  "affiliations": [
    "Université de Poitiers, PHAR2, Inserm U1070, Poitiers, France"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "name": "J. M. Buyck"
    },
    {
      "name": "O. Krekounian"
    },
    {
      "name": "T. Collet"
    },
    {
      "affs": [
        0
      ],
      "name": "V. Aranzana-Climent"
    },
    {
      "name": "N. Gregoire"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/59fsx66kee0zz.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.10.750598",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.10.750598v1.full",
  "id": "59fsx66kee0zz",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.10.750598v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "pharmacology and toxicology"
    ],
    [
      "openalex",
      "2736|Antibiotics Pharmacokinetics and Efficacy"
    ]
  ],
  "openalex": "W7213277486",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.10.750598v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-10",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/59fsx66kee0zz.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:22:34Z",
      "native_id": "10.64898/2026.09.10.750598",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.10.750598v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:pharmacology and toxicology",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "Replacing In Vivo Experiments for PK/PD Target Determination Through In Vitro Time-Kill Experiments and PK/PD Modelling Incorporating Inter-strain Variability: Application to Meropenem Against Pseudomonas aeruginosa",
  "title_text": "Replacing In Vivo Experiments for PK/PD Target Determination Through In Vitro Time-Kill Experiments and PK/PD Modelling Incorporating Inter-strain Variability: Application to Meropenem Against Pseudomonas aeruginosa",
  "type": "preprint",
  "updated_at": "2026-10-30T12:22:34Z",
  "url": "https://research.draconitic.com/paper/59fsx66kee0zz",
  "venue": "bioRxiv",
  "versions": []
}