Carbapenem-resistant Klebsiella pneumoniae strains exhibit diversity in aminoglycoside-modifying enzymes, which exert differing effects on plazomicin and other agents

Reem Almaghrabi, Cornelius J. Clancy, Yohei Doi, Binghua Hao, Liang Chen, Ryan K. Shields, Ellen G. Press, Nicole M. Iovine, Bethany M. Townsend, Marilyn M. Wagener, Barry Kreiswirth, M. Hong Nguyen

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Abstract

We measured in vitro activity of plazomicin, a next-generation aminoglycoside, and other aminoglycosides against 50 carbapenemresistant Klebsiella pneumoniae strains from two centers and correlated the results with the presence of various aminoglycosidemodifying 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.

Original languageEnglish
Pages (from-to)4443-4451
Number of pages9
JournalAntimicrobial agents and chemotherapy
Volume58
Issue number8
DOIs
Publication statusPublished - 08-2014

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Carbapenems
Klebsiella pneumoniae
Aminoglycosides
Tobramycin
Gentamicins
Enzymes
Amikacin
Clone Cells
Genotype
6'-(hydroxylethyl)-1-(haba)-sisomicin
Phenotype
Research
aminoglycoside N(3')-acetyltransferase

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Almaghrabi, Reem ; Clancy, Cornelius J. ; Doi, Yohei ; Hao, Binghua ; Chen, Liang ; Shields, Ryan K. ; Press, Ellen G. ; Iovine, Nicole M. ; Townsend, Bethany M. ; Wagener, Marilyn M. ; Kreiswirth, Barry ; Nguyen, M. Hong. / Carbapenem-resistant Klebsiella pneumoniae strains exhibit diversity in aminoglycoside-modifying enzymes, which exert differing effects on plazomicin and other agents. In: Antimicrobial agents and chemotherapy. 2014 ; Vol. 58, No. 8. pp. 4443-4451.
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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 carbapenemresistant Klebsiella pneumoniae strains from two centers and correlated the results with the presence of various aminoglycosidemodifying 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.",
author = "Reem Almaghrabi and Clancy, {Cornelius J.} and Yohei Doi and Binghua Hao and Liang Chen and Shields, {Ryan K.} and Press, {Ellen G.} and Iovine, {Nicole M.} and Townsend, {Bethany M.} and Wagener, {Marilyn M.} and Barry Kreiswirth and Nguyen, {M. Hong}",
year = "2014",
month = "8",
doi = "10.1128/AAC.00099-14",
language = "English",
volume = "58",
pages = "4443--4451",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
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}

Almaghrabi, R, Clancy, CJ, Doi, Y, Hao, B, Chen, L, Shields, RK, Press, EG, Iovine, NM, Townsend, BM, Wagener, MM, Kreiswirth, B & Nguyen, MH 2014, 'Carbapenem-resistant Klebsiella pneumoniae strains exhibit diversity in aminoglycoside-modifying enzymes, which exert differing effects on plazomicin and other agents', Antimicrobial agents and chemotherapy, vol. 58, no. 8, pp. 4443-4451. https://doi.org/10.1128/AAC.00099-14

Carbapenem-resistant Klebsiella pneumoniae strains exhibit diversity in aminoglycoside-modifying enzymes, which exert differing effects on plazomicin and other agents. / Almaghrabi, Reem; Clancy, Cornelius J.; Doi, Yohei; Hao, Binghua; Chen, Liang; Shields, Ryan K.; Press, Ellen G.; Iovine, Nicole M.; Townsend, Bethany M.; Wagener, Marilyn M.; Kreiswirth, Barry; Nguyen, M. Hong.

In: Antimicrobial agents and chemotherapy, Vol. 58, No. 8, 08.2014, p. 4443-4451.

Research output: Contribution to journalArticle

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T1 - Carbapenem-resistant Klebsiella pneumoniae strains exhibit diversity in aminoglycoside-modifying enzymes, which exert differing effects on plazomicin and other agents

AU - Almaghrabi, Reem

AU - Clancy, Cornelius J.

AU - Doi, Yohei

AU - Hao, Binghua

AU - Chen, Liang

AU - Shields, Ryan K.

AU - Press, Ellen G.

AU - Iovine, Nicole M.

AU - Townsend, Bethany M.

AU - Wagener, Marilyn M.

AU - Kreiswirth, Barry

AU - Nguyen, M. Hong

PY - 2014/8

Y1 - 2014/8

N2 - We measured in vitro activity of plazomicin, a next-generation aminoglycoside, and other aminoglycosides against 50 carbapenemresistant Klebsiella pneumoniae strains from two centers and correlated the results with the presence of various aminoglycosidemodifying 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.

AB - We measured in vitro activity of plazomicin, a next-generation aminoglycoside, and other aminoglycosides against 50 carbapenemresistant Klebsiella pneumoniae strains from two centers and correlated the results with the presence of various aminoglycosidemodifying 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.

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