326. β-lactamase Characterization of Baseline Pseudomonas aeruginosa (PSA) from Five Ceftazidime-avibactam (CAZ-AVI) Phase 3 Clinical Trials
Session: Poster Abstract Session: Emerging Resistance - Epidemiology and Mechanisms
Thursday, October 5, 2017
Room: Poster Hall CD
Posters
  • IDWeek2017-CAZ-AVI-PSA-trials.pdf (702.6 kB)
  • Background: CAZ-AVI has been evaluated in Phase 3 trials for the treatment of complicated urinary tract infections, complicated intra-abdominal infections, and hospital-acquired pneumonia, including ventilator-associated pneumonia. This study presents the β-lactamase characterization of baseline PSA recovered from patients enrolled in 5 Phase 3 trials of CAZ-AVI.

    Methods: 189 baseline PSA isolates (one per patient) were included (19 countries). Isolates met the β-lactamase MIC screening criteria, and displayed CAZ MIC ≥16 µg/mL and/or carbapenem MIC ≥8 µg/mL. Susceptibility (S) testing was centrally performed by CLSI methods. Isolates underwent microarray-based assay, PCR/sequencing for screening of ESBL and carbapenemases (CARB), and qRT-PCR for determination of chromosomal AmpC expression.

    Results: Isolates showed low S rates for CAZ (30.7%S; MIC50/90, 32/>64 µg/mL), meropenem (30.2%S; MIC50/90, 8/>8 µg/mL) and piperacillin-tazobactam (28.8%S; MIC50/90, 64/>128 µg/mL). In all, 27.5% (52/189) of isolates were CAZ-AVI resistant (R) and 36.5% (19/52) of these carried metallo-β-lactamases; 12 isolates carried IMP alleles, which were detected in China (blaIMP-25), Czech Republic (blaIMP-7), Mexico (blaIMP-18 and -56), Ukraine (blaIMP-1) and Vietnam (blaIMP-26), while 2 blaVIM-1-carrying PSA were found in Ukraine and 5 blaVIM-2 in Romania and Russia. Among CAZ-nonS PSA (69.3%; 131/189), 45.8% (60/131) showed overexpression of AmpC with or without blaOXA-like (OXA-2, -10 or -17), PSE-1, PER-1, IMP-56 or VIM-like (VIM-1 or -2) enzymes, 31.3% (41/131) had numerous combinations of CARB and ESBL enzymes, and 22.9% (30/131) had no β-lactamase genes detected. A total of 58/189 (30.7%) CAZ-S PSA were selected due to high MIC results for carbapenems. Among these 58 isolates, only 5 carried ESBL genes (blaOXA-2, blaPSE-1 and blaOXA-74).

    Conclusion: A great proportion (45.8%) of CAZ-nonS PSA were hyper-producers of the chromosomal AmpC enzyme. CAZ-nonS isolates also carried various combinations of CARB and ESBL genes, while CAZ-S and carbapenem-R PSA likely had non-enzymatic β-lactam resistance mechanisms.

    Funding: This study was sponsored by AstraZeneca (AZ). The AZ product ceftazidime-avibactam was acquired by Pfizer in December 2016.

    Rodrigo E. Mendes, Ph.D.1, Mariana Castanheira, PhD1, Leah N. Woosley, B.S.1, Gregory G. Stone, Ph.D.2, Robert Mclaughlin, PhD3, Patricia Bradford, PhD2 and Robert K. Flamm, PhD4, (1)JMI Laboratories, Inc., North Liberty, IA, (2)Formerly of AstraZeneca Pharmaceuticals LP, Waltham, MA, (3)AstraZeneca, Waltham, MA, (4)United States Committee on Antimicrobial Susceptibility Testing, Silverton, OR

    Disclosures:

    R. E. Mendes, AstraZeneca: Research Contractor , Research grant

    M. Castanheira, AstraZeneca: Research Contractor , Research grant

    L. N. Woosley, AstraZeneca: Research Contractor , Research grant

    G. G. Stone, AstraZeneca: Formerly an employee and shareholder at time of study , salary and shareholder
    Pfizer Inc.: Employee , Salary

    R. Mclaughlin, AstraZeneca: Employee , Salary

    P. Bradford, AstraZeneca: Formerly an employee and shareholder at time of study , salary and shareholder

    R. K. Flamm, AstraZeneca: Research Contractor , Research grant

    Findings in the abstracts are embargoed until 12:01 a.m. PDT, Wednesday Oct. 4th with the exception of research findings presented at the IDWeek press conferences.