eprintid: 39045 rev_number: 17 userid: 9661 dir: disk0/00/03/90/45 datestamp: 2020-07-31 04:35:22 lastmod: 2020-07-31 04:35:22 status_changed: 2020-07-31 04:35:22 type: thesis_degree metadata_visibility: show contact_email: abirubio8@gmail.com item_issues_id: etd_invalid_date_39045 item_issues_id: similar_title_38624 item_issues_type: etd_invalid_date item_issues_type: similar_title item_issues_description: ETD - Invalid Date for Defense Date '0020-04-09'. Date must contain Year, Month and Day values. item_issues_description: Similar title to Rubio, Abigial (0020) In vitro susceptibility of multidrug-resistant Pseudomonas aeruginosa following treatment-emergent resistance to ceftolozane-tazobactam. Master's Thesis, University of Pittsburgh. item_issues_timestamp: 2020-05-16 06:02:25 item_issues_timestamp: 2020-05-16 06:02:25 item_issues_status: autoresolved item_issues_status: autoresolved item_issues_count: 0 eprint_status: archive creators_name: Rubio, Abigail creators_email: amr197@pitt.edu creators_id: amr197 title: In Vitro Susceptibility of Multidrug-resistant Pseudomonas Aeruginosa Following Treatment-Emergent Resistance to Ceftolozane-Tazobactam ispublished: unpub divisions: sch_gsph_infectiousdiseasesmicrobiology full_text_status: public keywords: Antibiotic resistance, multidrug-resistant, pseudomonas aeruginosa, ceftolozane-tazobactam abstract: Background: Multidrug-resistant (MDR) Pseudomonas aeruginosa is a major public health threat. Treatment with ceftolozane-tazobactam improves patient outcomes compared to salvage therapy; however, resistance has emerged in ~15% of patients following courses ranging from 7 to 53 days. Understanding the development and mechanisms of resistance in these difficult to treat MDR P. aeruginosa has public health importance. Our objective was to study the in vitro activity of alternative β-lactams in the setting of ceftolozane-tazobactam resistance. Methods: Isolates from 23 patients in whom ceftolozane-tazobactam resistance emerged were selected for analysis. Minimum inhibitory concentrations (MICs) were determined by standard broth microdilution in triplicate and interpreted by CLSI breakpoints. Mechanisms of resistance and relatedness of isolates were explored through whole-genome sequence (WGS) analysis in 15 patients from whom baseline and post-treatment isolates were available. Results: 23 baseline and 32 post-treatment isolates were included. The median baseline ceftolozane-tazobactam MIC was 2 µg/mL (range: 0.5 – 8 µg/mL). 75%, 25%, 82.6%, and 83.3% of baseline isolates were non-susceptible to ceftazidime, ceftazidime-avibactam, imipenem, and piperacillin-tazobactam respectively. Following a median 16 (range: 3- 60) days of therapy, the median post-exposure ceftolozane-tazobactam MIC was 64 µg/mL (range: 8 – >256 µg/mL). 100%, 72.7%, 69.6%, and 79.2% of post-treatment isolates were resistant to ceftazidime, ceftazidime-avibactam, imipenem, and piperacillin-tazobactam. The corresponding MIC foldchanges were 4, 8, -2, and 0, respectively. Median imipenem-relebactam MICs did not change before or after treatment with ceftolozane-tazobactam (median= 2 µg/mL for both) and 16.7% were classified as resistant. WGS data revealed several mutations in ampC and ampR sequences. Discussion: Our findings show that resistance to ceftolozane-tazobactam impacts the susceptibility of alternative β-lactams. Cross resistance occurs with ceftazidime and ceftazidimeavibactam (median 4 and 8 fold MIC increase, respectively). Imipenem MICs are decreased 2fold potentially demonstrating collateral sensitivity. Piperacillin-tazobactam MICs were unchanged and isolates remained resistant. Importantly, imipenem-relebactam MICs were unchanged suggesting the mechanism of ceftolozane-tazobactam resistance may be due to structural changes in ampC. WGS data showed a number of different mutations in both ampC and ampR. Certain mutations, such as F147L and mutations found in positions 234-244, were found to promote resistance to ceftolozane-tazobactam. date: 2020-07-31 date_type: published pages: 32 institution: University of Pittsburgh refereed: TRUE etdcommittee_type: thesis_advisor etdcommittee_type: committee_member etdcommittee_type: committee_member etdcommittee_name: Martinson, Jeremy etdcommittee_name: Shields, Ryan etdcommittee_name: Harrison, Lee etdcommittee_email: jmartins@pitt.edu etdcommittee_email: shieldsrk@upmc.edu etdcommittee_email: lharriso@edc.pitt.edu etd_defense_date: 2020-04-09 etd_approval_date: 2020-07-31 etd_submission_date: 2020-05-15 etd_release_date: 2020-07-31 etd_access_restriction: immediate etd_patent_pending: FALSE thesis_type: thesis degree: MPH citation: Rubio, Abigail (2020) In Vitro Susceptibility of Multidrug-resistant Pseudomonas Aeruginosa Following Treatment-Emergent Resistance to Ceftolozane-Tazobactam. Master's Thesis, University of Pittsburgh. (Unpublished) document_url: http://d-scholarship-dev.library.pitt.edu/39045/1/Rubio_AM_MPHThesis_4_2020.pdf