{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T13:22:54Z","timestamp":1788009774975,"version":"build-2784847793"},"reference-count":62,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000038","name":"U.S. Food and Drug Administration","doi-asserted-by":"publisher","award":["75F40123C00143"],"award-info":[{"award-number":["75F40123C00143"]}],"id":[{"id":"10.13039\/100000038","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":[[2026,3,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Use of mouse infection models for antimicrobial pharmacokinetic\/pharmacodynamic (PK\/PD) analysis can assist in dosing regimen design and susceptibility breakpoint development. A major hurdle for clinical translation of\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      study output is defining the model endpoint linked to clinical success. Validation of the\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      endpoint requires a clinical data set composed of success or failure linked to minimum inhibitory concentration (MIC), dosing regimen, and if possible human pharmacokinetic measures. The present studies utilized a clinical library of eight\n                      <jats:italic toggle=\"yes\">Aspergillus fumigatus<\/jats:italic>\n                      strains in a mouse pneumonia model to define the endpoint associated with humanized treatment regimens of the triazole, posaconazole. This includes wild-type strains associated with successful treatment and strains with resistance mutations leading to elevated MICs and associated with treatment failure. We found humanized posaconazole exposures resulted in a net stasis or net decrease in organism burden in the animal model compared to the start of therapy for all wild-type strains. However, a net increase in organism burden despite treatment with the humanized regimen was noted for strains with higher MIC values and defined Cyp51 mutations. The ratio of posaconazole free-drug area under the concentration-time curve to the MIC (AUC\/MIC) associated with a stasis endpoint in the mouse model was then utilized with\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      surveillance data and a human posaconazole population pharmacokinetic model to perform simulations and PK\/PD target attainment analyses. The results of these analyses demonstrated &gt;90% probability of PK\/PD target attainment for\n                      <jats:italic toggle=\"yes\">A. fumigatus<\/jats:italic>\n                      strains with MICs of \u22640.5 mg\/L, thus supporting this susceptible breakpoint threshold.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.01643-25","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T21:04:51Z","timestamp":1769807091000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Evaluation of an\n                    <i>in vivo<\/i>\n                    pulmonary aspergillosis model for triazole susceptibility breakpoint development"],"prefix":"10.1128","volume":"70","author":[{"given":"Alex","family":"Lepak","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01e4byj08","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Wisconsin","place":["Madison, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4891-6467","authenticated-orcid":true,"given":"Sujata M.","family":"Bhavnani","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02gck7e73","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute for Clinical Pharmacodynamics","place":["Schenectady, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana","family":"Castanheira","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02qv6pw23","id-type":"ROR","asserted-by":"publisher"}],"name":"Element","place":["North Liberty, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3172-0847","authenticated-orcid":true,"given":"Christopher M.","family":"Rubino","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02gck7e73","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute for Clinical Pharmacodynamics","place":["Schenectady, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey P.","family":"Hammel","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02gck7e73","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute for Clinical Pharmacodynamics","place":["Schenectady, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0452-682X","authenticated-orcid":true,"given":"M. Courtney","family":"Safir","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02gck7e73","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute for Clinical Pharmacodynamics","place":["Schenectady, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Massey","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01e4byj08","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Wisconsin","place":["Madison, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Hartman","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01e4byj08","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Wisconsin","place":["Madison, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2230-1125","authenticated-orcid":true,"given":"Paul","family":"Ambrose","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02gck7e73","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute for Clinical Pharmacodynamics","place":["Schenectady, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7927-9950","authenticated-orcid":true,"given":"David","family":"Andes","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01e4byj08","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Wisconsin","place":["Madison, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1086\/516284"},{"key":"e_1_3_3_3_2","unstructured":"Clinical laboratory standards institute. 2017. Clinical Laboratory Standards Institute. Wayne PA Clinical Laboratory Standards Institute"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2011.01.004"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a019653"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2016.11.008"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1086\/510079"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01430-10"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00116-08"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.2807\/1560-7917.ES.2016.21.30.30300"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01544-10"},{"key":"e_1_3_3_12_2","unstructured":"Merck & Co. 2014. Noxafil prescribing information. Whitehouse Station NJ Merck & Co Inc"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofae532"},{"key":"e_1_3_3_14_2","volume-title":"Reference method for broth dilution antifungal susceptibility testingof filamentous fungi","author":"Clinical Laboratory Standards Institute","year":"2017","unstructured":"Clinical Laboratory Standards Institute. 2017. Reference method for broth dilution antifungal susceptibility testingof filamentous fungi. Vol. M38."},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01599-09"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0050219"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aap7999"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00833-13"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.01234-24"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02372-18"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.01631-23"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.2180"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02819-15"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)01159-9"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(23)00692-8"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3004404"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cis195"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1086\/651262"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1111\/tid.12613"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciu591"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1080\/13693780400020113"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1086\/651263"},{"key":"e_1_3_3_33_2","unstructured":"Centers for Disease Control and Prevention. 2013. Antibiotic resistance threats in the United States:1\u2013114."},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1086\/499819"},{"key":"e_1_3_3_35_2","unstructured":"CDC. 2019. Antibiotic resistance threats in the United States 2019. U.S. Department of Health and Human Services"},{"key":"e_1_3_3_36_2","unstructured":"World Health Organization. 2022. WHO fungal priority pathogens list to guide research development and public health action"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1086\/652768"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciw326"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid1710.110226"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cir865"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmicrobiol.2016.92"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jix210"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid2106.140717"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid2201.151308"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cir179"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1097\/QCO.0000000000000005"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1097\/00006454-199603000-00015"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.42.9.2375"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00277-10"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.diagmicrobio.2008.01.010"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1592\/phco.25.5.717.63583"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.01281-23"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00478-08"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.00566-08"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01102-12"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01083-10"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.50.4.1570-1572.2006"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01157-17"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1111\/myc.13267"},{"key":"e_1_3_3_60_2","unstructured":"European Committee on Antimicrobial Susceptibility Testing (EUCAST). 2012 Posaconazole: rationale for the clinical breakpoints version 3.0"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1002\/phar.2850"},{"key":"e_1_3_3_62_2","volume-title":"M38M51S performance standards of antifungal susceptibility testing of filamentous fungi","author":"Clinical Laboratory Standards Institute","year":"2022","unstructured":"Clinical Laboratory Standards Institute. 2022. M38M51S performance standards of antifungal susceptibility testing of filamentous fungi"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01671-10"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.01643-25","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.01643-25","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T14:01:44Z","timestamp":1772632904000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/aac.01643-25"}},"subtitle":[],"editor":[{"given":"Andreas H.","family":"Groll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,3,4]]},"references-count":62,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,3,4]]}},"alternative-id":["10.1128\/aac.01643-25"],"URL":"https:\/\/doi.org\/10.1128\/aac.01643-25","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,4]]},"assertion":[{"value":"2025-10-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-05","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e01643-25"}}