700. Identification and Whole Genome Sequencing (WGS) of meropenem-vaborbactam (MV) resistant Klebsiella pneumoniae (MVRKP) among patients without prior exposure to MV: Collateral damage
Session: Poster Abstract Session: Resistance Mechanisms: Gram-Negative
Thursday, October 4, 2018
Room: S Poster Hall
Posters
  • IDweek_Draft_Meropenem_Vaborbactam_9_29_19.pdf (405.1 kB)
  • Background:

    MV is a newly approved β-lactam/β-lactamase inhibitor combination (BLIC) for the treatment of complicated urinary tract infections (cUTI).  Vaborbactam is a cyclic boronic acid BLI that was mainly developed as a potent inhibitor of KPC carbapenemases and other Ambler class A&C enzymes. Vaborbactam is inactive against metallo-β-lactamases (MBL) and certain Class D enzymes (e.g. OXA-2 & OXA-48). We encountered a case of MV resistant Klebsiella pneumoniae (MVRKP) and sought to explore the various mechanisms of MV resistance within KP.   

    Methods:

    A 65-year-old nursing home resident with multiple prior hospitalizations and recent exposure to antibiotics (Timeline) developed sepsis secondary to carbapenem-resistant Klebsiella pneumoniae (CRKP) cUTI. WGS of the patient’s isolate was performed. This was followed by random screening for MV resistance and WGS of other isolates from a historical database.   

    Results:

    Results of WGS are seen in the table below. Sequencing of our patient’s isolate revealed strain ST258 with a premature stop in aa89 of OmpK35 as well as insertions at Gly134 and Asp135 (i.e. the GD repeat) of OmpK36. Furthermore, the KPC plasmid’s copy number was ~5 times higher than the chromosome. No mutations encoding efflux system AcrAB-TolC were found.

    Conclusion:

    Resistance to MV in KP was found in isolates that predate the drug’s availability. Notably, resistance occurred in the absence of MBLs and OXAs. The mechanism seems to involve outer membrane porin mutations in OmpK35 and/or OmpK36. WGS is a useful tool in identifying the mechanism of resistance especially for newer agents.  

    Table: Characterization of MVRKP by WGS

        

         Typing                Enzymes                          Efflux

    Outer membrane porin variant

    Notes

    Strain

    Date

    MV MIC (mg/ml)

    MLST

    β-lactamase

    Multidrug transporters and regulators

     

    OmpK35

    OmpK36

     

    1

    2-1-12

    16

     ST258

    KPC-2 & SHV-160

    Emr, mexk, oqxAB, smeD

    FS 121insG

     

    S to CZA & TGC   

    2

    4-3-12

    16

    ST258

    KPC-2 & SHV-160

    Emr, mexk, oqxAB, smeD

    FS 121insG

     

    S to CZA & TGC   

    3

    2013

    16

    ST258

    KPC-2 & SHV-160

    Emr, mexk, oqxAB, smeD

    FS 121insG

     

    S to CZA & TGC

    4

    2013

    4

    ST258

    KPC-2 & SHV-160

    Emr, mexk, oqxAB, smeD

    FS 121insG

     

    S to CZA & TGC

    5

    2017

        32

         ST258

    KPC-2, SHV-11, SHV-12

    N/A

    STOP aa89

    134-135 GD ins

    CZA MIC 8

                                                               

     

    Mohamad Yasmin, MD1, Liang Chen, PhD2, Steven H. Marshall, MS3, Barry N. Kreiswirth, PhD2, Federico Perez, MD, MS4 and Robert A. Bonomo, MD5, (1)Infectious Diseases, Case Western Reserve University, Cleveland, OH, (2)Public Health Research Institute, Rutgers New Jersey Medical School, Newark, NJ, (3)Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH, (4)Louis Stokes Cleveland VA Medical Center, Cleveland, OH, (5)Department of Pharmacology, Biochemistry, Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, OH

    Disclosures:

    M. Yasmin, None

    L. Chen, None

    S. H. Marshall, None

    B. N. Kreiswirth, None

    F. Perez, None

    R. A. Bonomo, None

    Findings in the abstracts are embargoed until 12:01 a.m. PDT, Wednesday Oct. 3rd with the exception of research findings presented at the IDWeek press conferences.