{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T11:19:47Z","timestamp":1789903187733,"version":"4.0.1"},"reference-count":29,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2018,5,1]],"date-time":"2018-05-01T00:00:00Z","timestamp":1525132800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100004334","name":"Merck","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004334","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2018,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Resistance to antibiotics among bacterial pathogens is rapidly spreading, and therapeutic options against multidrug-resistant bacteria are limited. There is an urgent need for new drugs, especially those that can circumvent the broad array of resistance pathways that bacteria have evolved. In this study, we assessed the pharmacokinetic\/pharmacodynamic relationship of the novel \u03b2-lactamase inhibitor relebactam (REL; MK-7655) in a hollow-fiber infection model. REL is intended for use with the carbapenem \u03b2-lactam antibiotic imipenem for the treatment of Gram-negative bacterial infections. In this study, we used an\n            <jats:italic>in vitro<\/jats:italic>\n            hollow-fiber infection model to confirm the efficacy of human exposures associated with the phase 2 doses (imipenem at 500 mg plus REL at 125 or 250 mg administered intravenously every 6 h as a 30-min infusion) against imipenem-resistant strains of\n            <jats:named-content content-type=\"genus-species\">Pseudomonas aeruginosa<\/jats:named-content>\n            and\n            <jats:named-content content-type=\"genus-species\">Klebsiella pneumoniae<\/jats:named-content>\n            . Dose fractionation experiments confirmed that the pharmacokinetic parameter that best correlated with REL activity is the area under the concentration-time curve, consistent with findings in a murine pharmacokinetic\/pharmacodynamic model. Determination of the pharmacokinetic\/pharmacodynamic relationship between \u03b2-lactam antibiotics and \u03b2-lactamase inhibitors is complex, as there is an interdependence between their respective exposure-response relationships. Here, we show that this interdependence could be captured by treating the MIC of imipenem as dynamic: it changes with time, and this change is directly related to REL levels. For the strains tested, the percentage of the dosing interval time that the concentration remains above the dynamic MIC for imipenem was maintained at the carbapenem target of 30 to 40%, required for maximum efficacy, for imipenem at 500 mg plus REL at 250 mg.\n          <\/jats:p>","DOI":"10.1128\/aac.02323-17","type":"journal-article","created":{"date-parts":[[2018,3,1]],"date-time":"2018-03-01T13:06:25Z","timestamp":1519909585000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":51,"title":["Exploring the Pharmacokinetic\/Pharmacodynamic Relationship of Relebactam (MK-7655) in Combination with Imipenem in a Hollow-Fiber Infection Model"],"prefix":"10.1128","volume":"62","author":[{"given":"Jin","family":"Wu","sequence":"first","affiliation":[{"name":"Merck &amp; Co., Inc., Kenilworth, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fred","family":"Racine","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc., Kenilworth, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael K.","family":"Wismer","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc., Kenilworth, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Young","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc., Kenilworth, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna M.","family":"Carr","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc., Kenilworth, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing C.","family":"Xiao","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc., Kenilworth, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi","family":"Katwaru","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc., Kenilworth, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Si","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc., Kenilworth, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Harradine","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc., Kenilworth, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Motyl","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc., Kenilworth, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pratik R.","family":"Bhagunde","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc., Kenilworth, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew L.","family":"Rizk","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc., Kenilworth, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","first-page":"277","article-title":"The antibiotic resistance crisis","volume":"40","author":"Ventola CL","year":"2015","unstructured":"Ventola CL. 2015. The antibiotic resistance crisis. Pharm Ther 40:277\u2013283.","journal-title":"Pharm Ther"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkq108"},{"key":"e_1_3_2_4_2","volume-title":"Antibiotic resistance threats in the United States, 2013","author":"Centers for Disease Control and Prevention","year":"2013","unstructured":"Centers for Disease Control and Prevention. 2013. Antibiotic resistance threats in the United States, 2013. U.S. Department of Health and Human Services, Atlanta, GA. http:\/\/www.cdc.gov\/drugresistance\/pdf\/ar-threats-2013-508.pdf."},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi700300u"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00826-13"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2013.12.101"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.05927-11"},{"key":"e_1_3_2_9_2","volume-title":"Abstr 50th Intersci Conf Antimicrob Agents ChemotherAmerican Society for Microbiology","author":"Powles MA","year":"2010","unstructured":"Powles MA, Galgoci A, Misura A, Liberator P, Hammond M. 2010. In vivo efficacy of the beta-lactamase inhibitor, MK-7655, in combination with imipenem in murine models of infection, abstr F1-2140. Abstr 50th Intersci Conf Antimicrob Agents Chemother, Boston, MA. American Society for Microbiology, Washington, DC."},{"key":"e_1_3_2_10_2","volume-title":"Abstr 50th Intersci Conf Antimicrob Agents Chemother, Boston, MA","author":"Young K","year":"2010","unstructured":"Young K, Raghoobar SL, Hairston NN, Painter RE, Racine F, Dorso KL, Park YW, Ogawa AM, Wisniewski D, Hermes J, Blizzard TA, Hammond ML, Motyl MR. 2010. In vitro activity of the class A and C \u03b2-lactamase inhibitor MK-7655, abstr F1-2139. Abstr 50th Intersci Conf Antimicrob Agents Chemother, Boston, MA. American Society for Microbiology, Washington, DC."},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00633-16"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1086\/510079"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00037-09"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.06113-11"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1001043"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/15.suppl_A.131"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00469-15"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.13.4.570"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkn294"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/civ425"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.36.9.2046"},{"key":"e_1_3_2_22_2","first-page":"S38","article-title":"Relevance of pharmacokinetics and pharmacodynamics in the selection of antibiotics for respiratory tract infections","volume":"9","author":"Drusano GL","year":"1997","unstructured":"Drusano GL, Craig WA. 1997. Relevance of pharmacokinetics and pharmacodynamics in the selection of antibiotics for respiratory tract infections. J Chemother 9(Suppl 3):S38\u2013S44.","journal-title":"J Chemother"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200039030-00002"},{"key":"e_1_3_2_24_2","volume-title":"Guideline on the use of pharmacokinetics and pharmacodynamics in the development of antibacterial medicinal products","author":"European Medicines Agency","year":"2015","unstructured":"European Medicines Agency. 2015. Guideline on the use of pharmacokinetics and pharmacodynamics in the development of antibacterial medicinal products. European Medicines Agency, Stockholm, Sweden. http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/Scientific_guideline\/2015\/09\/WC500194333.pdf."},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02282-15"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.03706-14"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1086\/344653"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/47.4.500"},{"key":"e_1_3_2_29_2","volume-title":"Tenth edition: approved standard","author":"Clinical and Laboratory Standards Institute","year":"2015","unstructured":"Clinical and Laboratory Standards Institute. 2015. M07-A10: methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Tenth edition: approved standard. Clinical and Laboratory Standards Institute, Wayne, PA."},{"key":"e_1_3_2_30_2","volume-title":"Twenty-seventh informational supplement","author":"Clinical and Laboratory Standards Institute","year":"2016","unstructured":"Clinical and Laboratory Standards Institute. 2016. M100-S27: performance standards for antimicrobial susceptibility testing. Twenty-seventh informational supplement. 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