{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T12:19:15Z","timestamp":1789820355359,"version":"4.0.1"},"reference-count":74,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2017,1,1]],"date-time":"2017-01-01T00:00:00Z","timestamp":1483228800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100000925","name":"Department of Health | National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1045105"],"award-info":[{"award-number":["APP1045105"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"Department of Health | National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1101553"],"award-info":[{"award-number":["APP1101553"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Department of Health | National Health and Medical Research Council","award":["APP1062040"],"award-info":[{"award-number":["APP1062040"]}]},{"name":"Department of Health | National Health and Medical Research Council","award":["APP1062509"],"award-info":[{"award-number":["APP1062509"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2017,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Optimizing antibiotic combinations is promising to combat multidrug-resistant\n            <jats:named-content content-type=\"genus-species\">Pseudomonas aeruginosa<\/jats:named-content>\n            . This study aimed to systematically evaluate synergistic bacterial killing and prevention of resistance by carbapenem and aminoglycoside combinations and to rationally optimize combination dosage regimens via a mechanism-based mathematical model (MBM). We studied monotherapies and combinations of imipenem with tobramycin or amikacin against three difficult-to-treat double-resistant clinical\n            <jats:named-content content-type=\"genus-species\">P. aeruginosa<\/jats:named-content>\n            isolates. Viable-count profiles of total and resistant populations were quantified in 48-h static-concentration time-kill studies (inoculum, 10\n            <jats:sup>7.5<\/jats:sup>\n            CFU\/ml). We rationally optimized combination dosage regimens via MBM and Monte Carlo simulations against isolate FADDI-PA088 (MIC of imipenem [MIC\n            <jats:sub>imipenem<\/jats:sub>\n            ] of 16 mg\/liter and MIC\n            <jats:sub>tobramycin<\/jats:sub>\n            of 32 mg\/liter, i.e., both 98th percentiles according to the EUCAST database). Against this isolate, imipenem (1.5\u00d7 MIC) combined with 1 to 2 mg\/liter tobramycin (MIC, 32 mg\/liter) or amikacin (MIC, 4 mg\/liter) yielded \u22652-log\n            <jats:sub>10<\/jats:sub>\n            more killing than the most active monotherapy at 48 h and prevented resistance. For all three strains, synergistic killing without resistance was achieved by \u22650.88\u00d7 MIC\n            <jats:sub>imipenem<\/jats:sub>\n            in combination with a median of 0.75\u00d7 MIC\n            <jats:sub>tobramycin<\/jats:sub>\n            (range, 0.032\u00d7 to 2.0\u00d7 MIC\n            <jats:sub>tobramycin<\/jats:sub>\n            ) or 0.50\u00d7 MIC\n            <jats:sub>amikacin<\/jats:sub>\n            (range, 0.25\u00d7 to 0.50\u00d7 MIC\n            <jats:sub>amikacin<\/jats:sub>\n            ). The MBM indicated that aminoglycosides significantly enhanced the imipenem target site concentration up to 3-fold; achieving 50% of this synergistic effect required aminoglycoside concentrations of 1.34 mg\/liter (if the aminoglycoside MIC was 4 mg\/liter) and 4.88 mg\/liter (for MICs of 8 to 32 mg\/liter). An optimized combination regimen (continuous infusion of imipenem at 5 g\/day plus a 0.5-h infusion with 7 mg\/kg of body weight tobramycin) was predicted to achieve &gt;2.0-log\n            <jats:sub>10<\/jats:sub>\n            killing and prevent regrowth at 48 h in 90.3% of patients (median bacterial killing, &gt;4.0 log\n            <jats:sub>10<\/jats:sub>\n            CFU\/ml) against double-resistant isolate FADDI-PA088 and therefore was highly promising.\n          <\/jats:p>","DOI":"10.1128\/aac.01011-16","type":"journal-article","created":{"date-parts":[[2016,11,8]],"date-time":"2016-11-08T03:54:40Z","timestamp":1478577280000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":29,"title":["Optimization of Synergistic Combination Regimens against Carbapenem- and Aminoglycoside-Resistant Clinical Pseudomonas aeruginosa Isolates via Mechanism-Based Pharmacokinetic\/Pharmacodynamic 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 for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger L.","family":"Nation","sequence":"additional","affiliation":[{"name":"Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelia B.","family":"Landersdorfer","sequence":"additional","affiliation":[{"name":"Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia"},{"name":"Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia"},{"name":"School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cit152"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cir153"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2201"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1175325"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1099\/jmm.0.073262-0"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6976.2011.00268.x"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6976.2011.00277.x"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02624-12"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1586\/14787210.2013.845523"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.3947\/ic.2014.46.3.149"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2011.01.028"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02017607"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01680-08"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.11.4315-4321.2004"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.49.12.4920-4927.2005"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0028177"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dku567"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.26.4.546"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.04379-14"},{"key":"e_1_3_3_21_2","first-page":"203","article-title":"In vitro combination effects of doripenem with aminoglycoside or ciprofloxacin against Pseudomonas aeruginosa","volume":"64","author":"Anan N","year":"2011","unstructured":"Anan N TobaS ItoA NakamuraR TsujiM. 2011. In vitro combination effects of doripenem with aminoglycoside or ciprofloxacin against Pseudomonas aeruginosa. Jpn J Antibiot64:203\u2013216.","journal-title":"Jpn J Antibiot"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10096-005-0076-9"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/36.4.707"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(86)90490-0"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/46.6.901"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.7164\/antibiotics.55.181"},{"key":"e_1_3_3_27_2","first-page":"194","article-title":"In vitro interaction of piperacillin and imipenem\/cilastatin combined with aminoglycosides against Pseudomonas aeruginosa","volume":"53","author":"Yamashiro Y","year":"2000","unstructured":"Yamashiro Y OgakeN TakahataM MinamiS. 2000. In vitro interaction of piperacillin and imipenem\/cilastatin combined with aminoglycosides against Pseudomonas aeruginosa. Jpn J Antibiot53:194\u2013200.","journal-title":"Jpn J Antibiot"},{"key":"e_1_3_3_28_2","first-page":"288","article-title":"Combined effects of arbekacin with biapenem against in vitro and in vivo model of a mixture of MRSA and Pseudomonas aeruginosa","volume":"57","author":"Niida M","year":"2004","unstructured":"Niida M SakakibaraS KawabataT MaebashiK TakataT HikidaM. 2004. Combined effects of arbekacin with biapenem against in vitro and in vivo model of a mixture of MRSA and Pseudomonas aeruginosa. Jpn J Antibiot57:288\u2013293.","journal-title":"Jpn J Antibiot"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/24.suppl_A.233"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01650716"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00092-13"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.175.18.5798-5805.1993"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.37.4.715"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/28.6.791"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/28.1.35"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.04099-14"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2010.03793.x"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01318-06"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiu237"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1086\/498909"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0034-1398742"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/202818"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0b013e3181961bff"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200038030-00002"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dku111"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1528-1157.2001.34701.x"},{"key":"e_1_3_3_47_2","first-page":"638","article-title":"Imipenem in the treatment of patients with severe surgical infection","volume":"47","author":"Szczygiel B","year":"1992","unstructured":"Szczygiel B PertkiewiczM MeszarosJ OttoM GrochowieckiT RudnickaJ HacelI Solecka-LasakM. 1992. Imipenem in the treatment of patients with severe surgical infection. Pol Tyg Lek47:638\u2013641.","journal-title":"Pol Tyg Lek"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0b013e31824981a6"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1345\/aph.1P745"},{"key":"e_1_3_3_50_2","volume-title":"M100-S25","author":"Clinical and Laboratory Standards Institute","year":"2015","unstructured":"Clinical and Laboratory Standards Institute. 2015. Performance standards for antimicrobial susceptibility testing: 25th informational supplement. M100-S25. CLSI, Wayne, PA."},{"key":"e_1_3_3_51_2","unstructured":"European Committee on Antimicrobial Susceptibility Testing. 2015. Breakpoint tables for interpretation of MICs and zone diameters version 5.0. http:\/\/www.eucast.org\/clinical_breakpoints\/."},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1186\/cc8945"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00881-09"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.05664-11"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/42.2.227"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.12.4665-4672.2004"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1089\/mdr.2013.0229"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02800-14"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01009-08"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.03652-14"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01721-09"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00489-08"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02927-15"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1004782"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.171.4.2252-2257.1989"},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dks201"},{"key":"e_1_3_3_67_2","doi-asserted-by":"publisher","DOI":"10.1208\/aapsj0901007"},{"key":"e_1_3_3_68_2","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-011-9257-x"},{"key":"e_1_3_3_69_2","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-011-9258-9"},{"key":"e_1_3_3_70_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01477-06"},{"key":"e_1_3_3_71_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-008-0827-2"},{"key":"e_1_3_3_72_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cir166"},{"key":"e_1_3_3_73_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01410-06"},{"key":"e_1_3_3_74_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00502-11"},{"key":"e_1_3_3_75_2","volume-title":"Optimization of synergistic combinations against carbapenem- and aminoglycoside-resistant clinical isolates of Pseudomonas aeruginosa via mechanism-based modelling, poster 504","author":"Yadav R","year":"2016","unstructured":"Yadav R BulittaJB NationRL LandersdorferCB. 2016. Optimization of synergistic combinations against carbapenem- and aminoglycoside-resistant clinical isolates of Pseudomonas aeruginosa via mechanism-based modelling, poster 504. ASM Microbe 2016, Boston, MA, USA, 16 to 20 June, 2016."}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.01011-16","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.01011-16","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T20:43:41Z","timestamp":1645476221000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.01011-16"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,1]]},"references-count":74,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2017,1]]}},"alternative-id":["10.1128\/AAC.01011-16"],"URL":"https:\/\/doi.org\/10.1128\/aac.01011-16","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,1]]},"assertion":[{"value":"2016-05-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-10-30","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-12-27","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e01011-16"}}