1874. Assessment of MIC Increases with Meropenem-Vaborbactam and Ceftazidime-Avibactam in TANGO II (a Phase 3 Study of the Treatment of CRE Infections)
Session: Poster Abstract Session: Clinical Study with New Antibiotics and Antifungals
Saturday, October 7, 2017
Room: Poster Hall CD
  • 1874_BacterialResistanceTANGOII_092917 RESIZED 90x45.pdf (461.8 kB)
  • Background: TANGO II is a Phase 3 comparative trial of meropenem-vaborbactam (M-V) given as monotherapy vs. best available therapy (BAT) in patients with bacteremia, cUTIs, cIAI, or HABP/VABP due to CRE. Patients in the BAT arm could receive ceftazidime-avibactam (C-A) as monotherapy. Changes in MIC in bacterial isolates to M-V or C-A recovered during monotherapy were assessed.

    Methods: MICs were conducted on baseline and post-baseline isolates of Enterobacteriaceae (ENT) recovered during treatment. MICs were determined using CLSI reference methods and MIC changes ≥4 were further assessed. Whole genomes of the majority of isolates were sequenced using Illumina MiSeq platform. Transcription level of various genes was determined using RT-PCR.

    Results: 25 patients treated with M-V and 4 treated with C-A had KPC-producing ENT. The mean days of treatment was 8.5 and 8.4 for M-V and C-A, respectively. One patient treated with M-V who carried KPC-3-producing K. pneumoniae (KP) (1/25; 4.0%) had a subsequent clinical isolate with a ≥4-fold change in M-V MIC (0.25 to 1 µg/mL), but remained susceptible after 6 days of therapy for acute pyelonephritis; the MIC increase was associated with overexpression of AcrAB, and no mutations in blaKPC-3 were observed.

    Two of the 4 patients treated with C-A (2/4; 50%) had a post-baseline clinical isolate of KP with ≥4-fold increase in MIC compared to the baseline isolate. In one case, the C-A MIC of the KPC-2-producing isolate increased >128-fold (0.5 to >64 µg/mL) following 7 days of therapy for a complicated intra-abdominal infection (cIAI). Resistance was associated with a point mutation in the blaKPC-2 gene leading to D179Y amino acid substitution in the enzyme, downregulation of genes encoding porins OmpK35 and OmpK36, and upregulation of the efflux operon, acrAB. In the second case, the C-A MIC of the KPC-3 producing isolate increased 8-fold (1 µg/mL to 8 µg/mL) after 14 days of therapy for cIAI; this change in MIC was associated with downregulation of ompK36 and acquisition of a plasmid-containing blaCTX-M-15 and blaOXA-1 genes.

    Conclusion: M-V appears to be associated with a lower incidence of in vitro MIC changes compared to C-A. Based on these findings, M-V may be a viable treatment option for infections due to KPC-producing CRE.

    Olga Lomovskaya, Ph.D.1, Mariana Castanheira, PhD2, Jose Vazquez, MD, FACP, FIDSA3, Keith S. Kaye, MD, MPH4, Kirk Nelson, BS1, Dongxu Sun, PhD1, Elizabeth Alexander, MD, MSc5, Michael N. Dudley, Pharm.D., FIDSA1 and Michael Yin, MD6, (1)The Medicines Company, San Diego, CA, (2)JMI Laboratories, Inc., North Liberty, IA, (3)Henry Ford Hospital, Detroit, MI, (4)University of Michigan Medical School, Ann Arbor, MI, (5)The Medicines Company, Parsippany, NJ, (6)Columbia University Medical Center, New York, NY


    O. Lomovskaya, The Medicine's Company: Employee and Shareholder , Salary

    M. Castanheira, Wockhardt Bio Ag: Research Contractor , Research grant

    J. Vazquez, None

    K. S. Kaye, Xellia: Consultant , Consulting fee
    Merck: Consultant and Grant Investigator , Consulting fee and Research support
    The Medicines Company: Consultant and Grant Investigator , Consulting fee and Research support

    K. Nelson, The Medicines Company: Employee , Salary

    D. Sun, The Medicines Company: Employee , Salary

    E. Alexander, The Medicines Company: Shareholder , Salary

    M. N. Dudley, The Medicine's Company: Employee and Shareholder , Salary

    M. Yin, Gilead Sciences: Consultant , Consulting fee

    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.