767c166a060ec4fc8d586e0e880e455b pmc_9241897.pdf 47efc01f970d9b1010e76af8bde6b72f24a0556b pmc_9241897.pdf 8b10f1c79a9ad92609ad5b3ebef88f02684ab620f2cca93a285e2f10bb827566 pmc_9241897.pdf Title: Comparison of Ceftolozane/Tazobactam Infusion Regimens in a Hollow-Fiber Infection Model against Extensively Drug-Resistant Pseudomonas aeruginosa Isolates Subject: Research Article Keywords: ceftolozane/tazobactam; hollow-fiber; PK/PD; XDR; Pseudomonas aeruginosa Author: María Milagro Montero;Sandra Domene-Ochoa;Carla López-Causapé;Inmaculada López-Montesinos;Sonia Luque;Luisa Sorlí;Núria Campillo;Eduardo Padilla;Núria Prim;Lorena Ferrer Alapont;Santiago Grau;Antonio Oliver;Juan P. 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referenced object 'lBB29' cannot be found Offset: 705493 MIMEtype: application/pdf PDFMetadata: Objects: 340 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: false CenterWindow: false DisplayDocTitle: true NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: RESULTS Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Children: Item: Title: In vitro susceptibility and resistance mechanisms. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f Item: Title: Estimated frequency of mutants. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4eb7f003 Item: Title: HFIM. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@eafc191 Item: Title: Drug concentrations. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612fc6eb Item: Title: DISCUSSION Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1060b431 Item: Title: MATERIALS AND METHODS Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612679d6 Children: Item: Title: Bacterial isolates and resistance mechanisms. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@11758f2a Item: Title: Antibiotics. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@e720b71 Item: Title: Estimated frequency of spontaneous mutants. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1b26f7b2 Item: Title: In vitro antimicrobial susceptibility testing. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@491cc5c9 Item: Title: HFIM. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@74ad1f1f Item: Title: Drug concentrations. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6a1aab78 Item: Title: Descriptive statistics. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@462d5aee Item: Title: ACKNOWLEDGMENTS Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@69b0fd6f Item: Title: REFERENCES Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@757942a1 Info: Title: Comparison of Ceftolozane/Tazobactam Infusion Regimens in a Hollow-Fiber Infection Model against Extensively Drug-Resistant Pseudomonas aeruginosa Isolates Author: María Milagro Montero;Sandra Domene-Ochoa;Carla López-Causapé;Inmaculada López-Montesinos;Sonia Luque;Luisa Sorlí;Núria Campillo;Eduardo Padilla;Núria Prim;Lorena Ferrer Alapont;Santiago Grau;Antonio Oliver;Juan P. Horcajada Subject: Research Article Keywords: ceftolozane/tazobactam; hollow-fiber; PK/PD; XDR; Pseudomonas aeruginosa Creator: PTC Arbortext Advanced Print Publisher 11.1.4012/W Producer: Adobe LiveCycle PDF Generator; modified using iText® 5.5.13.2 ©2000-2020 iText Group NV (AGPL-version) CreationDate: Thu Jun 16 15:12:48 CEST 2022 ModDate: Fri Jun 17 19:03:50 CEST 2022 ID: 0x9eab6d9cb55d5169dd19a8aaffc4797c, 0x2bf42484f86bb2b2ccd2cdca15a70ed2 Filters: FilterPipeline: FlateDecode Images: Image: NisoImageMetadata: FormatName: image/png ImageWidth: 67 ImageHeight: 67 BitsPerSample: 8 BitsPerSampleUnit: integer Filter: FlateDecode Fonts: Type1: Font: BaseFont: KAEFKD+AdvOT07517017+fb FontSubset: true FirstChar: 1 LastChar: 1 FontDescriptor: FontName: KAEFKD+AdvOT07517017+fb Flags: Symbolic FontBBox: 0, 0, 683, 721 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: KAEFMF+AdvP7DA6 FontSubset: true FirstChar: 98 LastChar: 98 FontDescriptor: FontName: KAEFMF+AdvP7DA6 Flags: Nonsymbolic FontBBox: -20, -208, 1000, 770 FontFile3: true Encoding: WinAnsiEncoding Font: BaseFont: KAEFMG+AdvP4C4E74 FontSubset: true FirstChar: 1 LastChar: 1 FontDescriptor: FontName: KAEFMG+AdvP4C4E74 Flags: Symbolic FontBBox: -20, -958, 1114, 770 FontFile3: true EncodingDictionary: Differences: true Font: BaseFont: KAEGJC+AdvOT153e3c55.B FontSubset: true FirstChar: 177 LastChar: 177 FontDescriptor: FontName: KAEGJC+AdvOT153e3c55.B Flags: Nonsymbolic FontBBox: -83, -236, 929, 947 FontFile3: true Encoding: WinAnsiEncoding Font: BaseFont: KAEFCM+AdvOTce3d9a73 FontSubset: true FirstChar: 40 LastChar: 250 FontDescriptor: FontName: KAEFCM+AdvOTce3d9a73 Flags: Nonsymbolic FontBBox: -42, -250, 858, 889 FontFile3: true Encoding: WinAnsiEncoding Font: BaseFont: KAEFDN+AdvOT56309c18.I FontSubset: true FirstChar: 46 LastChar: 117 FontDescriptor: FontName: KAEFDN+AdvOT56309c18.I Flags: Nonsymbolic FontBBox: -103, -250, 914, 882 FontFile3: true Encoding: WinAnsiEncoding Font: BaseFont: KAEFIO+AdvOT3b30f6db.B FontSubset: true FirstChar: 46 LastChar: 121 FontDescriptor: FontName: KAEFIO+AdvOT3b30f6db.B Flags: Nonsymbolic FontBBox: -39, -250, 875, 897 FontFile3: true Encoding: WinAnsiEncoding Font: BaseFont: KAEFIP+AdvOT46dcae81 FontSubset: true FirstChar: 37 LastChar: 250 FontDescriptor: FontName: KAEFIP+AdvOT46dcae81 Flags: Nonsymbolic FontBBox: -46, -250, 838, 879 FontFile3: true Encoding: WinAnsiEncoding Font: BaseFont: KAEFJA+AdvOT46dcae81+fb FontSubset: true FirstChar: 1 LastChar: 3 FontDescriptor: FontName: KAEFJA+AdvOT46dcae81+fb Flags: Symbolic FontBBox: 0, 0, 742, 721 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: KAEFJB+AdvOT65f8a23b.I FontSubset: true FirstChar: 45 LastChar: 120 FontDescriptor: FontName: KAEFJB+AdvOT65f8a23b.I Flags: Nonsymbolic FontBBox: -112, -250, 894, 873 FontFile3: true Encoding: WinAnsiEncoding Font: BaseFont: KAEFJC+AdvOT46dcae81+20 FontSubset: true FirstChar: 146 LastChar: 151 FontDescriptor: FontName: KAEFJC+AdvOT46dcae81+20 Flags: Nonsymbolic FontBBox: -9, -205, 1126, 868 FontFile3: true Encoding: WinAnsiEncoding Font: BaseFont: KAEFHM+AdvOT07517017 FontSubset: true FirstChar: 40 LastChar: 243 FontDescriptor: FontName: KAEFHM+AdvOT07517017 Flags: Nonsymbolic FontBBox: -49, -250, 816, 867 FontFile3: true Encoding: WinAnsiEncoding Font: BaseFont: KAEFMD+AdvP80675 FontSubset: true FirstChar: 46 LastChar: 54 FontDescriptor: FontName: KAEFMD+AdvP80675 Flags: Nonsymbolic FontBBox: -20, -229, 1010, 812 FontFile3: true Encoding: WinAnsiEncoding Font: BaseFont: KAEFIN+AdvOT07517017+20 FontSubset: true FirstChar: 146 LastChar: 146 FontDescriptor: FontName: KAEFIN+AdvOT07517017+20 Flags: Nonsymbolic FontBBox: -6, -209, 1046, 868 FontFile3: true Encoding: WinAnsiEncoding Font: BaseFont: KAEFME+AdvOTd0125be5.BI FontSubset: true FirstChar: 73 LastChar: 118 FontDescriptor: FontName: KAEFME+AdvOTd0125be5.BI Flags: Nonsymbolic FontBBox: -95, -250, 930, 889 FontFile3: true Encoding: WinAnsiEncoding XMP: Comparison of Ceftolozane/Tazobactam Infusion Regimens in a Hollow-Fiber Infection Model against Extensively Drug-Resistant Pseudomonas aeruginosa Isolates 10.1128/spectrum.00892-22 María Milagro Montero Sandra Domene-Ochoa Carla López-Causapé Inmaculada López-Montesinos Sonia Luque Luisa Sorlí Núria Campillo Eduardo Padilla Núria Prim Lorena Ferrer Alapont Santiago Grau Antonio Oliver Juan P. Horcajada Research Article Research Article ceftolozane/tazobactam hollow-fiber PK/PD XDR Pseudomonas aeruginosa American Society for Microbiology Montero et al. Copyright © 2022 Montero et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. 20220613 2022 ABSTRACT The aim of this study was to compare the efficacy of intermittent (1-h), extended (4-h), and continuous ceftolozane-tazobactam (C/T) infusion against three extensively drug-resistant (XDR) sequence type (ST) 175 P. aeruginosa isolates with different susceptibilities to C/T (MIC = 2 to 16 mg/L) in a 7-day hollow-fiber infection model (HFIM). C/T in continuous infusion achieved the largest reduction in total number of bacterial colonies in the overall treatment arms for both C/T-susceptible and -resistant isolates. It was also the only regimen with bactericidal activity against all three isolates. These data suggest that continuous C/T infusion should be considered a potential treatment for infections caused by XDR P. aeruginosa isolates, including nonsusceptible ones. Proper use of C/T dosing regimens may lead to better clinical management of XDR P. aeruginosa infections. IMPORTANCE Ceftolozane-tazobactam (C/T) is an antipseudomonal antibiotic with a high clinical impact in treating infection caused by extensively drug-resistant (XDR) Pseudomonas aeruginosa isolates, but resistance is emerging. Given its time-dependent behavior, C/T continuous infusion can improve exposure and therefore the pharmacokinetic/pharmacodynamic target attainment. We compared the efficacy of intermittent, extended, and continuous C/T infusion against three XDR ST175 P. aeruginosa isolates with different C/T MICs by means of an in vitro dynamic hollow-fiber model. We demonstrated that C/T in continuous infusion achieved the largest reduction in bacterial density in the overall treatment arms for both susceptible and resistant isolates. It was also the only regimen with bactericidal activity against all three isolates. Through this study, we want to demonstrate that developing individually tailored antimicrobial treatments is becoming essential. Our results support the role of C/T level monitoring and of dose adjustments for better clinical management and outcomes. 20220309 20220520 2165-0497 Pages: Page: Label: 1 Annotations: Annotation: Subtype: Link Rect: 50, 565, 140, 574 Annotation: Subtype: Link Rect: 50, 554, 98, 563 Annotation: Subtype: Link Rect: 50, 543, 107, 552 Annotation: Subtype: Link Rect: 129, 543, 198, 552 Annotation: Subtype: Link Rect: 261, 43, 265, 52 Destination: 111 Annotation: Subtype: Link Rect: 265, 43, 269, 52 Destination: 111 Annotation: Subtype: Link Rect: 269, 43, 274, 52 Destination: 111 Annotation: Subtype: Link Rect: 417, 124, 513, 131 Annotation: Subtype: Link Rect: 400, 115, 456, 122 Annotation: Subtype: Link Rect: 444, 24, 526, 31 Annotation: Subtype: Link Rect: 508, 683, 544, 719 Page: Label: 2 Annotations: Annotation: Subtype: Link Rect: 297, 690, 302, 699 Destination: 111 Annotation: Subtype: Link Rect: 315, 666, 319, 675 Destination: 111 Annotation: Subtype: Link Rect: 98, 606, 102, 615 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