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.

FIG 1

In vitro susceptibility to various aminoglycosides, stratified by gentamicin susceptibility.

FIG 2

Time-kill curves of plazomicin against representative strains. Note the regrowth of the last two strains. The regrowth of strain 115 was eliminated when tested with plazomicin concentrations of 4× and 16× MIC. The regrowth of strain 743 was eliminated when tested with plazomicin at 16× MIC.

FIG 3

Distribution of aminoglycoside MICs according to the presence or absence of additional AMEs [ANT(2″)-Ib, AAC(3)-IV, or APH(3′)-Ia] on the AAC(6′)-Ib backbone. The horizontal lines represent the mean MIC ± standard error. Note that the combination of AAC(6′)-Ib and ≥1 other AME was associated with significantly higher MICs of gentamicin (P = 0.01), tobramycin (P = 0.0008), and plazomicin (P = 0.046) but not amikacin (P = 0.31).

FIG 4

Distribution of aminoglycoside MICs according to the presence or absence of AAC(3)-IV in combination with AAC(6′)-Ib. The horizontal line represents the mean MIC ± standard error. Note that the presence of AAC(3)-IV was associated with significantly higher MICs of gentamicin (P = 0.0006), tobramycin (P < 0.0001), and plazomicin (P = 0.01) but not amikacin (P = 0.58).

FIG 5

Associations between specific AMEs and gentamicin resistance. Gentamicin-susceptible and -resistant strains are shown as black and gray bars, respectively. The percentages of strains that were gentamicin resistant are shown above the respective bars.