{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T13:47:15Z","timestamp":1791899235757,"version":"4.3.4"},"reference-count":40,"publisher":"American Society for Microbiology","license":[{"start":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:00:00Z","timestamp":1791849600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:00:00Z","timestamp":1791849600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Use of piperacillin-tazobactam (TZP) in the treatment of severe extended-spectrum \u03b2-lactamase (ESBL)-producing\n                      <jats:italic toggle=\"yes\">Escherichia coli<\/jats:italic>\n                      (ESBL-EC) infections is controversial. Two features may explain treatment failures: the inoculum effect and suboptimal pharmacokinetic\/pharmacodynamic (PK\/PD) target attainment, particularly in critically ill patients. To study the combined impact of the inoculum effect and a PK\/PD optimization on the\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      efficacy of TZP against ESBL-EC infections. Five-day hollow-fiber infection model simulating TZP pharmacokinetics in critically ill patients was performed: two TZP infusion regimens (4\/0.5 g q6h over 30 min, and 16\/2 g q24h continuous infusion), three ESBL-EC clinical strains:\n                      <jats:italic toggle=\"yes\">1146<\/jats:italic>\n                      (\n                      <jats:italic toggle=\"yes\">bla<\/jats:italic>\n                      <jats:sub>CTX-M-15<\/jats:sub>\n                      , MIC = 2 mg\/L),\n                      <jats:italic toggle=\"yes\">3383<\/jats:italic>\n                      (\n                      <jats:italic toggle=\"yes\">bla<\/jats:italic>\n                      <jats:sub>CTX-M-15<\/jats:sub>\n                      +\n                      <jats:italic toggle=\"yes\">bla<\/jats:italic>\n                      <jats:sub>TEM-1<\/jats:sub>\n                      , MIC = 4 mg\/L), and\n                      <jats:italic toggle=\"yes\">2262<\/jats:italic>\n                      (\n                      <jats:italic toggle=\"yes\">bla<\/jats:italic>\n                      <jats:sub>CTX-M-15<\/jats:sub>\n                      +\n                      <jats:italic toggle=\"yes\">bla<\/jats:italic>\n                      <jats:sub>OXA-1<\/jats:sub>\n                      , MIC = 8 mg\/L), and two initial inocula (5 and 7 log\n                      <jats:sub>10<\/jats:sub>\n                      CFU\/mL). Intermittent infusion was associated with systematic bacterial regrowth within 24 h, consistent with failure to reach the 100%fT &gt;4\u00d7 MIC threshold. Continuous infusion resulted in undetectable bacterial count for the strains\n                      <jats:italic toggle=\"yes\">3383<\/jats:italic>\n                      (MIC = 4 mg\/L, low inoculum) and\n                      <jats:italic toggle=\"yes\">1146<\/jats:italic>\n                      (MIC = 2 mg\/L, low and high inocula). For strain\n                      <jats:italic toggle=\"yes\">3383<\/jats:italic>\n                      , the inoculum effect was demonstrated by total bacterial killing in continuous infusion with low inoculum, whereas early regrowth (&gt;10 log\n                      <jats:sub>10<\/jats:sub>\n                      CFU\/mL) with resistance emergence (MIC &gt; 256 mg\/L) was observed with high inoculum. Strain\n                      <jats:italic toggle=\"yes\">2262<\/jats:italic>\n                      (MIC = 8 mg\/L) exhibited systematic treatment failure regardless of infusion mode or inoculum size. Continuous infusion of TZP may be considered as a carbapenem-sparing agent in ESBL-EC infection with a TZP MIC \u2264 2 mg\/L regardless of inoculum, or a TZP MIC of 4 mg\/L at low inoculum. TZP should not be used for strains with an MIC of 8 mg\/L or suspected OXA-1 co-production, irrespective of the infusion mode.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      Infections caused by extended-spectrum \u03b2-lactamase (ESBL)-producing\n                      <jats:italic toggle=\"yes\">Escherichia coli<\/jats:italic>\n                      represent a growing therapeutic challenge, particularly in critically ill patients. Carbapenems remain the reference treatment, but their overuse drives resistance emergence. Piperacillin-tazobactam is a potential carbapenem-sparing agent, but its clinical efficacy remains debated, partly due to the inoculum effect (a reduction in antibiotic activity at high bacterial densities) and suboptimal dosing regimens. Using a hollow-fiber infection model simulating the pharmacokinetics of critically ill patients, this study demonstrates that continuous infusion of piperacillin-tazobactam can overcome the inoculum effect under specific conditions, defined by the MIC of the infecting strain and the estimated bacterial density. These findings support a stratified approach to piperacillin-tazobactam use in severe ESBL-producing\n                      <jats:italic toggle=\"yes\">E. coli<\/jats:italic>\n                      infections, based on MIC, inoculum size, and \u03b2-lactamase profile, and may help clinicians identify patients who could safely receive piperacillin-tazobactam instead of a carbapenem.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.01457-26","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T13:00:15Z","timestamp":1791896415000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Impact of inoculum effect on\n                    <i>in vitro<\/i>\n                    activity of intermittent and continuous piperacillin-tazobactam infusion against ESBL-producing\n                    <i>Escherichia coli<\/i>\n                    in a hollow-fiber infection model"],"prefix":"10.1128","author":[{"given":"Marion","family":"Giry","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/051kpcy16","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medical Intensive Care, Univ Rouen Normandie, Univ de Caen Normandie, INSERM, DYNAMICURE UMR 1311, CHU de Rouen","place":["Rouen, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Baulier","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/051kpcy16","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Anaesthesiology, Critical Care and Perioperative Medicine, Univ Rouen Normandie, Univ de Caen Normandie, INSERM, DYNAMICURE UMR 1311, CHU de Rouen","place":["Rouen, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabien","family":"Lamoureux","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, CHU de Rouen","place":["Rouen, 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