{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:30:48Z","timestamp":1791419448274,"version":"4.3.3"},"reference-count":37,"publisher":"American Society for Microbiology","issue":"6","license":[{"start":{"date-parts":[[2014,6,1]],"date-time":"2014-06-01T00:00:00Z","timestamp":1401580800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2014,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    We compared the dynamics and mechanisms of resistance development to ceftazidime, meropenem, ciprofloxacin, and ceftolozane-tazobactam in wild-type (PAO1) and mutator (PAOMS, \u0394\n                    <jats:italic>mutS<\/jats:italic>\n                    )\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">P. aeruginosa<\/jats:named-content>\n                    . The strains were incubated for 24 h with 0.5 to 64\u00d7 MICs of each antibiotic in triplicate experiments. The tubes from the highest antibiotic concentration showing growth were reinoculated in fresh medium containing concentrations up to 64\u00d7 MIC for 7 consecutive days. The susceptibility profiles and resistance mechanisms were assessed in two isolated colonies from each step, antibiotic, and strain. Ceftolozane-tazobactam-resistant mutants were further characterized by whole-genome analysis through RNA sequencing (RNA-seq). The development of high-level resistance was fastest for ceftazidime, followed by meropenem and ciprofloxacin. None of the mutants selected with these antibiotics showed cross-resistance to ceftolozane-tazobactam. On the other hand, ceftolozane-tazobactam resistance development was much slower, and high-level resistance was observed for the mutator strain only. PAO1 derivatives that were moderately resistant (MICs, 4 to 8 \u03bcg\/ml) to ceftolozane-tazobactam showed only 2 to 4 mutations, which determined global pleiotropic effects associated with a severe fitness cost. High-level-resistant (MICs, 32 to 128 \u03bcg\/ml) PAOMS derivatives showed 45 to 53 mutations. Major changes in the global gene expression profiles were detected in all mutants, but only PAOMS mutants showed\n                    <jats:italic>ampC<\/jats:italic>\n                    overexpression, which was caused by\n                    <jats:italic>dacB<\/jats:italic>\n                    or\n                    <jats:italic>ampR<\/jats:italic>\n                    mutations. Moreover, all PAOMS mutants contained 1 to 4 mutations in the conserved residues of AmpC (F147L, Q157R, G183D, E247K, or V356I). Complementation studies revealed that these mutations greatly increased ceftolozane-tazobactam and ceftazidime MICs but reduced those of piperacillin-tazobactam and imipenem, compared to those in wild-type\n                    <jats:italic>ampC<\/jats:italic>\n                    . Therefore, the development of high-level resistance to ceftolozane-tazobactam appears to occur efficiently only in a\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">P. aeruginosa<\/jats:named-content>\n                    mutator background, in which multiple mutations lead to overexpression and structural modifications of AmpC.\n                  <\/jats:p>","DOI":"10.1128\/aac.02462-13","type":"journal-article","created":{"date-parts":[[2014,3,17]],"date-time":"2014-03-17T20:49:54Z","timestamp":1395089394000},"page":"3091-3099","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":240,"title":["Pseudomonas aeruginosa Ceftolozane-Tazobactam Resistance Development Requires Multiple Mutations Leading to Overexpression and Structural Modification of AmpC"],"prefix":"10.1128","volume":"58","author":[{"given":"Gabriel","family":"Cabot","sequence":"first","affiliation":[{"name":"Servicio de Microbiolog\u00eda and Unidad de Investigaci\u00f3n Hospital Universitario Son Espases, Instituto de Investigaci\u00f3n Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Bruchmann","sequence":"additional","affiliation":[{"name":"Helmholtz Center for Infection Research, Braunschweig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xavier","family":"Mulet","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda and Unidad de Investigaci\u00f3n Hospital Universitario Son Espases, Instituto de Investigaci\u00f3n Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Zamorano","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda and Unidad de Investigaci\u00f3n Hospital Universitario Son Espases, Instituto de Investigaci\u00f3n Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bartolom\u00e9","family":"Moy\u00e0","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda and Unidad de Investigaci\u00f3n Hospital Universitario Son Espases, Instituto de Investigaci\u00f3n Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Juan","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda and Unidad de Investigaci\u00f3n Hospital Universitario Son Espases, Instituto de Investigaci\u00f3n Sanitaria de Palma (IdISPa), Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Haussler","sequence":"additional","affiliation":[{"name":"Helmholtz Center for 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