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In Vitro Susceptibility of Multidrug-resistant Pseudomonas Aeruginosa Following Treatment-Emergent Resistance to Ceftolozane-Tazobactam

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 (Unpublished)

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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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Rubio, Abigailamr197@pitt.eduamr197
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorMartinson,
Committee MemberShields,
Committee MemberHarrison,
Date: 31 July 2020
Date Type: Publication
Defense Date: 9 April 2020
Approval Date: 31 July 2020
Submission Date: 15 May 2020
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 32
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Infectious Diseases and Microbiology
Degree: MPH - Master of Public Health
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Antibiotic resistance, multidrug-resistant, pseudomonas aeruginosa, ceftolozane-tazobactam
Date Deposited: 31 Jul 2020 04:35
Last Modified: 31 Jul 2020 04:35


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