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      A Dimer, but Not Monomer, of Tobramycin Potentiates Ceftolozane against Multidrug-Resistant and Extensively Drug-Resistant Pseudomonas aeruginosa and Delays Resistance Development

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          Abstract

          Ceftolozane-tazobactam is a potent β-lactam/β-lactamase inhibitor combination approved for the treatment of complicated intraabdominal and complicated urinary tract infections and, more recently, the treatment of hospital-acquired and ventilator-associated bacterial pneumonia. Although the activities of ceftolozane are not enhanced by tazobactam against Pseudomonas aeruginosa, it remains the most potent antipseudomonal agent approved to date.

          ABSTRACT

          Ceftolozane-tazobactam is a potent β-lactam/β-lactamase inhibitor combination approved for the treatment of complicated intraabdominal and complicated urinary tract infections and, more recently, the treatment of hospital-acquired and ventilator-associated bacterial pneumonia. Although the activities of ceftolozane are not enhanced by tazobactam against Pseudomonas aeruginosa, it remains the most potent antipseudomonal agent approved to date. Emerging data worldwide has included reports of microbiological failure in patients with serious bacterial infections caused by multidrug-resistant (MDR) P. aeruginosa as a result of ceftolozane resistance developed within therapy. The objective of this study is to compare the efficacy of a tobramycin homodimer plus ceftolozane versus ceftolozane-tazobactam alone against MDR and extensively drug-resistant (XDR) P. aeruginosa. Tobramycin homodimer, a synthetic dimer of two monomeric units of tobramycin, was developed to abrogate the ribosomal properties of tobramycin with a view to mitigating aminoglycoside-related toxicity and resistance. Herein, we report that tobramycin homodimer, a nonribosomal aminoglycoside derivative, potentiates the activities of ceftolozane versus MDR/XDR P. aeruginosa in vitro and delays the emergence of resistance to ceftolozane-tazobactam in the wild-type PAO1 strain. This combination is also more potent than a standard ceftazidime-avibactam combination against these isolates. Conversely, a tobramycin monomer with intrinsic ribosomal properties does not potentiate ceftolozane under similar conditions. Susceptibility and checkerboard studies were assessed using serial 2-fold dilution assays, following the Clinical and Laboratory Standards Institute (CLSI) guidelines. This strategy provides an avenue to further preserve the clinical utility of ceftolozane and enhances its spectrum of activity against one of the most difficult-to-treat pathogens in hospitals.

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          Author and article information

          Journal
          Antimicrob Agents Chemother
          Antimicrob. Agents Chemother
          aac
          aac
          AAC
          Antimicrobial Agents and Chemotherapy
          American Society for Microbiology (1752 N St., N.W., Washington, DC )
          0066-4804
          1098-6596
          21 February 2020
          March 2020
          6 January 2020
          : 64
          : 3
          : e02055-19
          Affiliations
          [a ] Department of Chemistry, University of Manitoba, Winnipeg, Manitoba, Canada
          [b ] Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Manitoba, Canada
          Author notes
          Address correspondence to Frank Schweizer, schweize@ 123456cc.umanitoba.ca .

          Citation Idowu T, Zhanel GG, Schweizer F. 2020. A dimer, but not monomer, of tobramycin potentiates ceftolozane against multidrug-resistant and extensively drug-resistant Pseudomonas aeruginosa and delays resistance development. Antimicrob Agents Chemother 64:e02055-19. https://doi.org/10.1128/AAC.02055-19.

          Author information
          https://orcid.org/0000-0003-1583-8562
          https://orcid.org/0000-0001-8697-5519
          Article
          PMC7038263 PMC7038263 7038263 02055-19
          10.1128/AAC.02055-19
          7038263
          31907191
          0492837b-6196-431c-8174-c840b668cafa
          Copyright © 2020 American Society for Microbiology.

          All Rights Reserved.

          History
          : 11 October 2019
          : 3 December 2019
          : 1 January 2020
          Page count
          Figures: 3, Tables: 5, Equations: 0, References: 52, Pages: 11, Words: 7034
          Funding
          Funded by: Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (NSERC), https://doi.org/10.13039/501100000038;
          Award ID: DG 2018-06047
          Award Recipient :
          Categories
          Susceptibility
          Custom metadata
          March 2020

          Pseudomonas ,aminoglycoside,ceftolozane,antimicrobial resistance,tobramycin,synergy

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