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The therapeutic options for CTX-M-carrying isolates are scarce, forcing the reexamination of the therapeutic possibilities of \u03b2-lactams plus \u03b2-lactamase inhibitors (BBLIs). Inhibitor-resistant CTX-M \u03b2-lactamases (IR-CTX-M) have not hitherto been described in natural isolates. In this study, 168 cultures of the hypermutagenic<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Escherichia coli<\/jats:named-content>GB20 strain carrying plasmid pBGS18 with different<jats:italic>bla<\/jats:italic><jats:sub>CTX-M<\/jats:sub>genes were submitted to parallel experimental evolution assays in the presence of increasing concentrations of a combination of amoxicillin and clavulanate. Fourteen CTX-M \u03b2-lactamases belonging to the three most representative clusters (CTX-M-1, -2, and -9) and the two main phenotypes (cefotaxime resistance and cefotaxime-ceftazidime resistance) were studied. Three types of IR-CTX-M mutants were detected, having mutations S130G, K234R, and S237G, which are associated with different resistance patterns. The most frequently recovered mutation was S130G, which conferred the highest resistance levels to BBLIs (reaching 12 \u03bcg\/ml for amoxicillin-clavulanate and 96 \u03bcg\/ml for piperacillin-tazobactam when acquired by CTX-M-1 cluster enzymes). The S130G change also provided a clear antagonistic pleiotropy effect, strongly decreasing the enzyme's activity against all cephalosporins tested. A double mutation, S130G L169S, partially restored the resistance against cephalosporins. A complex pattern observed in CTX-M-58, carrying P167S and S130G or K234R changes, conferred ESBL and IR phenotypes simultaneously. The K234R and S237G changes had a smaller effect in providing inhibitor resistance. In summary, IR-CTX-M enzymes might evolve under exposure to BBLIs, and the probability is higher for enzymes belonging to the CTX-M-1 cluster. However, this process could be delayed by antagonistic pleiotropy.<\/jats:p>","DOI":"10.1128\/aac.00178-11","type":"journal-article","created":{"date-parts":[[2011,7,26]],"date-time":"2011-07-26T03:57:58Z","timestamp":1311652678000},"page":"4530-4536","update-policy":"http:\/\/dx.doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":38,"title":["<i>In Vitro<\/i>Selection of Variants Resistant to \u03b2-Lactams plus \u03b2-Lactamase Inhibitors in CTX-M \u03b2-Lactamases: Predicting the<i>In Vivo<\/i>Scenario?"],"prefix":"10.1128","volume":"55","author":[{"given":"Aida","family":"Ripoll","sequence":"first","affiliation":[{"name":"Servicio de Microbiolog\u00eda and CIBER en Epidemiolog\u00eda y Salud P\u00fablica (CIBERESP), Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), Madrid, Spain"}]},{"given":"Fernando","family":"Baquero","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda and CIBER en Epidemiolog\u00eda y Salud P\u00fablica (CIBERESP), Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), Madrid, Spain"},{"name":"Unidad de Resistencia a Antibi\u00f3ticos y Virulencia Bacteriana (RYC-CSIC), Madrid, Spain"}]},{"given":"\u00c2ngela","family":"Novais","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda and CIBER en Epidemiolog\u00eda y Salud P\u00fablica (CIBERESP), Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), Madrid, Spain"},{"name":"REQUIMTE, Laborat\u00f3rio de Microbiologia, Faculdade de Farm\u00e1cia, Universidade do Porto, Porto, Portugal"}]},{"given":"Mario J.","family":"Rodr\u00edguez-Dom\u00ednguez","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda and CIBER en Epidemiolog\u00eda y Salud P\u00fablica (CIBERESP), Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), Madrid, Spain"}]},{"given":"Maria-Carmen","family":"Turrientes","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda and CIBER en Epidemiolog\u00eda y Salud P\u00fablica (CIBERESP), Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), Madrid, Spain"}]},{"given":"Rafael","family":"Cant\u00f3n","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda and CIBER en Epidemiolog\u00eda y Salud P\u00fablica (CIBERESP), Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), Madrid, Spain"},{"name":"Unidad de Resistencia a Antibi\u00f3ticos y Virulencia Bacteriana (RYC-CSIC), Madrid, Spain"}]},{"given":"Juan-Carlos","family":"Gal\u00e1n","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda and CIBER en Epidemiolog\u00eda y Salud P\u00fablica (CIBERESP), Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), Madrid, Spain"},{"name":"Unidad de Resistencia a Antibi\u00f3ticos y Virulencia Bacteriana (RYC-CSIC), Madrid, Spain"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.47.9.2958-2961.2003"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.diagmicrobio.2007.02.013"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.7.1657"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.45.8.2269-2275.2001"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01009-09"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-0691.2007.01849.x"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1089\/mdr.2009.0031"},{"key":"e_1_3_2_9_2","first-page":"750","article-title":"Detection of Enterobacteriaceae isolates carrying metallo-beta-lactamase\u2014United States, 2010","volume":"59","author":"Centers for Disease Control and Prevention","year":"2010","unstructured":"Centers for Disease Control and Prevention. 2010. 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