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Monotherapies and combinations of four aminoglycosides and three carbapenems were studied for activity against\n            <jats:named-content content-type=\"genus-species\">P. aeruginosa<\/jats:named-content>\n            strain AH298-GFP in 48-h static-concentration time-kill studies (SCTK) (inoculum: 10\n            <jats:sup>7.6<\/jats:sup>\n            CFU\/ml). The outer membrane-permeabilizing effect of tobramycin alone and in combination with imipenem was characterized via electron microscopy, confocal imaging, and the nitrocefin assay. A mechanism-based model (MBM) was developed to simultaneously describe the time course of bacterial killing and prevention of regrowth by imipenem combined with each of the four aminoglycosides. Notably, 0.25 mg\/liter of tobramycin, which was inactive in monotherapy, achieved synergy (i.e., \u22652-log\n            <jats:sub>10<\/jats:sub>\n            more killing than the most active monotherapy at 24 h) combined with imipenem. Electron micrographs, confocal image analyses, and the nitrocefin uptake data showed distinct outer membrane damage by tobramycin, which was more extensive for the combination with imipenem. The MBM indicated that aminoglycosides enhanced the imipenem target site concentration up to 4.27-fold. Tobramycin was the most potent aminoglycoside to permeabilize the outer membrane; tobramycin (0.216 mg\/liter), gentamicin (0.739 mg\/liter), amikacin (1.70 mg\/liter), or streptomycin (5.19 mg\/liter) was required for half-maximal permeabilization. In summary, our SCTK, mechanistic studies and MBM indicated that tobramycin was highly synergistic and displayed the maximum outer membrane disruption potential among the tested aminoglycosides. These findings support the optimization of highly promising antibiotic combination dosage regimens for critically ill patients.\n          <\/jats:p>","DOI":"10.1128\/aac.00722-17","type":"journal-article","created":{"date-parts":[[2017,9,12]],"date-time":"2017-09-12T00:40:28Z","timestamp":1505176828000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":33,"title":["Aminoglycoside Concentrations Required for Synergy with Carbapenems against Pseudomonas aeruginosa Determined via Mechanistic Studies and Modeling"],"prefix":"10.1128","volume":"61","author":[{"given":"Rajbharan","family":"Yadav","sequence":"first","affiliation":[{"name":"Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen B.","family":"Bulitta","sequence":"additional","affiliation":[{"name":"Center 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