AAC Accepts, published online ahead of print on 27 May 2014 Antimicrob. Agents Chemother. doi:10.1128/AAC.00099-14 Copyright © 2014, American Society for Microbiology. All Rights Reserved.
1
Carbapenem-resistant Klebsiella pneumoniae strains exhibit diversity in aminoglycoside
2
modifying enzymes, which exert varying effects on plazomicin and other agents
3 4
Reem Almaghrabi,1 Cornelius J. Clancy,1-3 Yohei Doi,1 Binghua Hao,1,2 Liang Chen,4 Ryan K.
5
Shields,1,2 Ellen G. Press,1 Nicole M. Iovine,5 Bethany M. Townsend,1 Marilyn M. Wagener,1,3
6
Barry Kreiswirth,4 M. Hong Nguyen1,2
7
1
University of Pittsburgh School of Medicine, Pittsburgh, PA; 2XDR Pathogen Laboratory,
8
University of Pittsburgh Medical Center, Pittsburgh, PA; 3Pittsburgh VA Healthcare System,
9
Pittsburgh, PA; 4Public Health Research Institute, New Jersey Medical School-Rutgers
10
University, Newark, NJ; 5University of Florida College of Medicine, Gainesville, FL.
11
Running title: Plazomicin against carbapenem-resistant K. pneumoniae
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Key words: carbapenem-resistant Klebsiella pneumoniae, plazomicin, aminoglycoside-
13
modifying enzyme
14
Corresponding Author:
Cornelius J Clancy, M.D.
15
University of Pittsburgh School of Medicine
16
Scaife Hall, Suite 871
17
3550 Terrace Street, Pittsburgh, PA 15261
18
[email protected]
19
(412)-383-5193
20
21
ABSTRACT
22
We measured in vitro activity of plazomicin, a next generation aminoglycoside, and other
23
aminoglycosides against 50 carbapenem-resistant Klebsiella pneumoniae strains from two
24
centers, and correlated results with the presence of various aminoglycoside modifying enzymes
25
(AMEs). Ninety-four percent of strains were ST258 clones, which exhibited 5 ompK36
26
genotypes; 80% and 10% of strains produced Klebsiella pneumoniae carbapenemase (KPC)-2
27
and KPC-3, respectively. Ninety-eight percent of strains possessed AMEs, including AAC(6’)-
28
Ib (98%), APH(3’)-Ia (56%), AAC(3)-IV (38%), and ANT(2”)-Ia (2%). Gentamicin,
29
tobramycin and amikacin non-susceptibility rates were 40%, 98% and 16%, respectively.
30
Plazomicin minimum inhibitory concentrations (MICs) ranged from 0.25 to 1 µg/ml.
31
Tobramycin and plazomicin MICs correlated with gentamicin MICs (r=0.75 and 0.57,
32
respectively). Plazomicin exerted bactericidal activity against 17% (1xMIC) and 94% (4xMIC)
33
of strains. All strains with AAC(6’)-Ib were tobramycin-resistant; 16% were non-susceptible to
34
amikacin. AAC(6’)-Ib combined with another AME was associated with higher gentamicin,
35
tobramycin and plazomicin MICs than AAC(6’)-Ib alone (p=0.01, 0.0008, and 0.046,
36
respectively). The presence of AAC(3)-IV in a strain was also associated with higher
37
gentamicin, tobramycin and plazomicin MICs (p=0.0006,
1
Carbapenem-resistant Klebsiella pneumoniae strains exhibit diversity in aminoglycoside
2
modifying enzymes, which exert varying effects on plazomicin and other agents
3 4
Reem Almaghrabi,1 Cornelius J. Clancy,1-3 Yohei Doi,1 Binghua Hao,1,2 Liang Chen,4 Ryan K.
5
Shields,1,2 Ellen G. Press,1 Nicole M. Iovine,5 Bethany M. Townsend,1 Marilyn M. Wagener,1,3
6
Barry Kreiswirth,4 M. Hong Nguyen1,2
7
1
University of Pittsburgh School of Medicine, Pittsburgh, PA; 2XDR Pathogen Laboratory,
8
University of Pittsburgh Medical Center, Pittsburgh, PA; 3Pittsburgh VA Healthcare System,
9
Pittsburgh, PA; 4Public Health Research Institute, New Jersey Medical School-Rutgers
10
University, Newark, NJ; 5University of Florida College of Medicine, Gainesville, FL.
11
Running title: Plazomicin against carbapenem-resistant K. pneumoniae
12
Key words: carbapenem-resistant Klebsiella pneumoniae, plazomicin, aminoglycoside-
13
modifying enzyme
14
Corresponding Author:
Cornelius J Clancy, M.D.
15
University of Pittsburgh School of Medicine
16
Scaife Hall, Suite 871
17
3550 Terrace Street, Pittsburgh, PA 15261
18
[email protected]
19
(412)-383-5193
20
21
ABSTRACT
22
We measured in vitro activity of plazomicin, a next generation aminoglycoside, and other
23
aminoglycosides against 50 carbapenem-resistant Klebsiella pneumoniae strains from two
24
centers, and correlated results with the presence of various aminoglycoside modifying enzymes
25
(AMEs). Ninety-four percent of strains were ST258 clones, which exhibited 5 ompK36
26
genotypes; 80% and 10% of strains produced Klebsiella pneumoniae carbapenemase (KPC)-2
27
and KPC-3, respectively. Ninety-eight percent of strains possessed AMEs, including AAC(6’)-
28
Ib (98%), APH(3’)-Ia (56%), AAC(3)-IV (38%), and ANT(2”)-Ia (2%). Gentamicin,
29
tobramycin and amikacin non-susceptibility rates were 40%, 98% and 16%, respectively.
30
Plazomicin minimum inhibitory concentrations (MICs) ranged from 0.25 to 1 µg/ml.
31
Tobramycin and plazomicin MICs correlated with gentamicin MICs (r=0.75 and 0.57,
32
respectively). Plazomicin exerted bactericidal activity against 17% (1xMIC) and 94% (4xMIC)
33
of strains. All strains with AAC(6’)-Ib were tobramycin-resistant; 16% were non-susceptible to
34
amikacin. AAC(6’)-Ib combined with another AME was associated with higher gentamicin,
35
tobramycin and plazomicin MICs than AAC(6’)-Ib alone (p=0.01, 0.0008, and 0.046,
36
respectively). The presence of AAC(3)-IV in a strain was also associated with higher
37
gentamicin, tobramycin and plazomicin MICs (p=0.0006,
