{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T14:45:14Z","timestamp":1793371514842,"version":"4.5.0"},"reference-count":28,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T00:00:00Z","timestamp":1741046400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T00:00:00Z","timestamp":1741046400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development","award":["5K12 HD052892-17"],"award-info":[{"award-number":["5K12 HD052892-17"]}]},{"name":"UPMC Children's Hospital of Pittsburgh CHP Scholars"},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["1F31AI172279-01A1"],"award-info":[{"award-number":["1F31AI172279-01A1"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["7U19AI158076-03"],"award-info":[{"award-number":["7U19AI158076-03"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"name":"University of Pittsburgh School of Medicine Department of Medicine"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"published-print":{"date-parts":[[2025,3,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>\n              Identifying resistance mechanisms to novel antimicrobials informs treatment strategies during infection and antimicrobial development. Studying resistance that develops during the treatment of an infection can provide the most clinically relevant mutations conferring resistance, but cross-sectional studies frequently identify multiple candidate resistance mutations without resolving the driver mutation. We performed whole-genome sequencing of longitudinal\n              <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n              from a patient whose\n              <jats:italic>P. aeruginosa<\/jats:italic>\n              developed imipenem\/cilastatin\/relebactam and ceftolozane\/tazobactam resistance during ceftazidime\/avibactam treatment. This analysis determined new mutations that arose in isolates resistant to both imipenem\/cilastatin\/relebactam and ceftolozane\/tazobactam. Mutations in penicillin-binding protein 3\n              <jats:italic>ftsI,<\/jats:italic>\n              the MexAB-OprM repressor\n              <jats:italic>nalD<\/jats:italic>\n              , and a virulence regulator\n              <jats:italic>pvdS<\/jats:italic>\n              were found in resistant isolates. Importantly, drug efflux was not increased in the resistant isolate compared to the most closely related susceptible isolates. We conclude that mutations in peptidoglycan synthesis genes can alter the efficacy of multiple antimicrobials.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              Antibiotic resistance is a significant challenge for physicians trying to treat infections. The development of novel antibiotics to treat resistant infections has not been prioritized for decades, limiting treatment options for infections caused by many high-priority pathogens. Cross-resistance, when one mutation provides resistance to multiple antibiotics, is most problematic. Mutations that cause cross-resistance need to be considered when developing new antibiotics to guide developers toward drugs with different targets, and thus a better likelihood of efficacy. This work was undertaken to determine the mutation that caused resistance to three antibiotics for highly resistant\n              <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n              infection treatment while the bacteria were exposed to only one of these agents. The findings provide evidence that drug developers should endeavor to find effective antibiotics with new targets and that medical providers should utilize medications with different mechanisms of action in bacteria that have become resistant to even one of these three agents.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/spectrum.02312-24","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T14:00:46Z","timestamp":1739282446000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":10,"title":["Mutations leading to ceftolozane\/tazobactam and imipenem\/cilastatin\/relebactam resistance during\n            <i>in vivo<\/i>\n            exposure to ceftazidime\/avibactam in\n            <i>Pseudomonas aeruginosa<\/i>"],"prefix":"10.1128","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4545-966X","authenticated-orcid":true,"given":"Glenn J.","family":"Rapsinski","sequence":"first","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine","place":["Pittsburgh, USA"]},{"name":"Division of Infectious Disease, Department of Pediatrics, University of Pittsburgh School of Medicine","place":["Pittsburgh, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alecia B.","family":"Rokes","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine","place":["Pittsburgh, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7284-0103","authenticated-orcid":true,"given":"Daria","family":"Van Tyne","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine","place":["Pittsburgh, USA"]},{"name":"Center for Evolutionary Biology and Medicine, University of Pittsburgh School of Medicine","place":["Pittsburgh, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7726-0765","authenticated-orcid":true,"given":"Vaughn S.","family":"Cooper","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine","place":["Pittsburgh, USA"]},{"name":"Center for Evolutionary Biology and Medicine, University of Pittsburgh School of Medicine","place":["Pittsburgh, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)02724-0"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1950.tb42183.x"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00117-14"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.diagmicrobio.2024.116372"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24055010"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00408-019-00285-6"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2015.05.003"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-017-0851-9"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciac097"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.lanepe.2023.100736"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/jacamr\/dlad107"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1089\/cmb.2012.0021"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu170"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-0554-6_12"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu153"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-020-02090-4"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu033"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae268"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.01342-06"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.183.6.2151-2155.2001"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.01.089"},{"key":"e_1_3_4_23_2","unstructured":"SeemannT. 2020. 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