title: Carbapenem-resistant Klebsiella pneumoniae strains exhibit diversity in aminoglycoside-modifying enzymes, which exert differing effects on plazomicin and other agents.
abstract: We measured in vitro activity of plazomicin, a next-generation aminoglycoside, and other aminoglycosides against 50 carbapenem-resistant Klebsiella pneumoniae strains from two centers and correlated the results with the presence of various aminoglycoside-modifying enzymes (AMEs). Ninety-four percent of strains were sequence type 258 (ST258) clones, which exhibited 5 ompK36 genotypes; 80% and 10% of strains produced Klebsiella pneumoniae carbapenemase 2 (KPC-2) and KPC-3, respectively. Ninety-eight percent of strains possessed AMEs, including AAC(6')-Ib (98%), APH(3')-Ia (56%), AAC(3)-IV (38%), and ANT(2")-Ia (2%). Gentamicin, tobramycin, and amikacin nonsusceptibility rates were 40, 98, and 16%, respectively. Plazomicin MICs ranged from 0.25 to 1 μg/ml. Tobramycin and plazomicin MICs correlated with gentamicin MICs (r = 0.75 and 0.57, respectively). Plazomicin exerted bactericidal activity against 17% (1× MIC) and 94% (4× MIC) of strains. All strains with AAC(6')-Ib were tobramycin-resistant; 16% were nonsusceptible to amikacin. AAC(6')-Ib combined with another AME was associated with higher gentamicin, tobramycin, and plazomicin MICs than AAC(6')-Ib alone (P = 0.01, 0.0008, and 0.046, respectively). The presence of AAC(3)-IV in a strain was also associated with higher gentamicin, tobramycin, and plazomicin MICs (P = 0.0006, P < 0.0001, and P = 0.01, respectively). The combination of AAC(6')-Ib and another AME, the presence of AAC(3)-IV, and the presence of APH(3')-Ia were each associated with gentamicin resistance (P = 0.0002, 0.003, and 0.01, respectively). In conclusion, carbapenem-resistant K. pneumoniae strains (including ST258 clones) exhibit highly diverse antimicrobial resistance genotypes and phenotypes. Plazomicin may offer a treatment option against strains resistant to other aminoglycosides. The development of molecular assays that predict antimicrobial responses among carbapenem-resistant K. pneumoniae strains should be a research priority.
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Reem
authors.initials: R
authors.lastname: Almaghrabi
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA Pittsburgh VA Healthcare System, Pittsburgh, Pennsylvania, USA cjc76@pitt.edu.
authors.forename: Cornelius J
authors.initials: CJ
authors.lastname: Clancy
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Doi
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA XDR Pathogen Laboratory, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
authors.forename: Binghua
authors.initials: B
authors.lastname: Hao
authors.affiliation: Public Health Research Institute, New Jersey Medical School-Rutgers University, Newark, New Jersey, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA XDR Pathogen Laboratory, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
authors.forename: Ryan K
authors.initials: RK
authors.lastname: Shields
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Ellen G
authors.initials: EG
authors.lastname: Press
authors.affiliation: University of Florida College of Medicine, Gainesville, Florida, USA.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Iovine
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Bethany M
authors.initials: BM
authors.lastname: Townsend
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA Pittsburgh VA Healthcare System, Pittsburgh, Pennsylvania, USA.
authors.forename: Marilyn M
authors.initials: MM
authors.lastname: Wagener
authors.affiliation: Public Health Research Institute, New Jersey Medical School-Rutgers University, Newark, New Jersey, USA.
authors.forename: Barry
authors.initials: B
authors.lastname: Kreiswirth
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA XDR Pathogen Laboratory, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
authors.forename: M Hong
authors.initials: MH
authors.lastname: Nguyen
mesh_terms: D000583:Amikacin / Q000378:metabolism / Q000494:pharmacology; D000617:Aminoglycosides / Q000378:metabolism / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D004338:Drug Combinations; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D057075:Enzyme Assays; D015870:Gene Expression; D005839:Gentamicins / Q000378:metabolism / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D012853:Sisomicin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D018440:beta-Lactam Resistance / Q000235:genetics; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism; D047090:beta-Lactams / Q000494:pharmacology
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004338:Drug Combinations; D005839:Gentamicins; D007527:Isoenzymes; D047090:beta-Lactams; D000583:Amikacin; D001618:beta-Lactamases; C063912:carbapenemase; C550938:plazomicin; D012853:Sisomicin