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