{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:06:40Z","timestamp":1790644000296,"version":"4.1.0"},"reference-count":24,"publisher":"Microbiology Society","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,10,6]]},"abstract":"<jats:p>\n                  <jats:bold>Introduction.<\/jats:bold> The presence of heteroresistant subpopulations and the development of resistance during drug exposure (adaptive resistance) limits colistin\u2019s efficacy against carbapenemase-producing <jats:italic>\n                     <jats:named-content content-type=\"species\">\n                        <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/doi.org\/10.1601\/nm.10789\" xlink:type=\"simple\">Klebsiella pneumoniae<\/jats:ext-link>\n                     <\/jats:named-content>\n                  <\/jats:italic> (CP-Kp) isolates.<\/jats:p>\n               <jats:p>\n                  <jats:bold>Hypothesis\/Gap statement<\/jats:bold>. The pharmacokinetic\/pharmacodynamic (PK\/PD) characteristics of both types of colistin resistance against CP-Kp are unknown.<\/jats:p>\n               <jats:p>\n                  <jats:bold>Aim.<\/jats:bold> We therefore studied the PK\/PD characteristics of colistin resistance in an <jats:italic>in vitro<\/jats:italic> PK\/PD model simulating clinical colistin exposures.<\/jats:p>\n               <jats:p>\n                  <jats:bold>Methods.<\/jats:bold> Two <jats:italic>\n                     <jats:named-content content-type=\"species\">\n                        <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/doi.org\/10.1601\/nm.10789\" xlink:type=\"simple\">K. pneumoniae<\/jats:ext-link>\n                     <\/jats:named-content>\n                  <\/jats:italic> clinical isolates, one non-CP-Kp and one CP-Kp, with colistin MICs of 0.5\u20131\u2009mg\u2009l<jats:sup>\u22121<\/jats:sup> at a final inoculum of 10<jats:sup>7<\/jats:sup>\u2009c.f.u.\u2009ml<jats:sup>\u22121<\/jats:sup> were used in an <jats:italic>in vitro<\/jats:italic> PK\/PD dialysis\/diffusion closed model simulating 4.5 MU q12h and 3 MU q8h clinical dosing regimens. Heteroresistant (HRS, bacteria with stable high-level resistance present before drug exposure) and adaptive resistant (ARS, bacteria with reversible low-level resistance emerging after drug exposure) subpopulations were measured and optimal PK\/PD targets for reducing both ARS and HRS were determined. Cumulative fractional response (CFR) was calculated with Monte Carlo simulation for 9 MU q24h, 4.5 MU q12h and 3 MU q8h clinical dosing regimens.<\/jats:p>\n               <jats:p>\n                  <jats:bold>Results.<\/jats:bold> A 2\u20135 log<jats:sub>10<\/jats:sub>c.f.u. ml<jats:sup>\u20131<\/jats:sup> decrease of the total bacterial population was observed within the first 2\u2009h of exposure, followed by regrowth at 12\u2009h. Colistin exposure was positively and negatively correlated with HRS and ARS 24\u20130 h c.f.u. ml<jats:sup>\u20131<\/jats:sup> changes, respectively. An optimal PK\/PD (~0.5log<jats:sub>10<\/jats:sub> increase) target of 35 fAUC\/MIC (the ratio of the area under the unbound concentration\u2013time curve to the MIC) was found for reducing both HRS and ARS of high-level resistance (MIC &gt;16\u2009mg\u2009l<jats:sup>\u22121<\/jats:sup>). The 4.5 MU q12h regimen had slightly higher CFR (74\u200a%) compared to the other dosing regimens.<\/jats:p>\n               <jats:p>\n                  <jats:bold>Conclusions.<\/jats:bold> High colistin exposures reduced high-level adaptive resistance at the expense of selection of heteroresistant subpopulations.<\/jats:p>","DOI":"10.1099\/jmm.0.001565","type":"journal-article","created":{"date-parts":[[2022,10,6]],"date-time":"2022-10-06T16:17:35Z","timestamp":1665073055000},"source":"Crossref","is-referenced-by-count":5,"title":["Pharmacodynamics of colistin resistance in carbapenemase-producing Klebsiella pneumoniae: the double-edged sword of heteroresistance and adaptive resistance"],"prefix":"10.1099","volume":"71","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8869-1509","authenticated-orcid":false,"given":"Joseph","family":"Meletiadis","sequence":"first","affiliation":[{"name":"Department of Medical Microbiology, Erasmus MC, Rotterdam, Netherlands"},{"name":"Clinical 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