Giuseppe
Emeritus
[Source: Antimicrobial Agents and Chemotherapy, full text: (LINK). Abstract, edited.]
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Characterization of porin expression in Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae identifies isolates most susceptible to the combination of colistin and carbapenems
Jae H. Hong 1, Cornelius J Clancy 1,2, Shaoji Cheng 1, Ryan K. Shields 1, Liang Chen 3, Yohei Doi 1, Yanan Zhao 3, David S. Perlin 3, Barry N. Kreiswirth 3 and M. Hong Nguyen 1
Author Affiliations: <SUP>1</SUP>University of Pittsburgh, Pittsburgh, PA <SUP>2</SUP>Pittsburgh VA Health System <SUP>3</SUP>Public Health Research Institute, University of Medicine and Dentistry of New Jersey, Newark, NJ
ABSTRACT
We characterized carbapenem resistance mechanisms among 12 Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) clinical isolates, and evaluated their effects on the activity of 2- and 3-drug combinations of colistin, doripenem and ertapenem. All isolates were resistant to ertapenem and doripenem; 75% (9/12) were resistant to colistin. Isolates belonged to ST258 clonal group, and harbored bla<SUB>KPC-2</SUB>, bla<SUB>SHV-12,</SUB> and bla<SUB>TEM-1</SUB>. By time-kills, doripenem (8 μg/ml) and ertapenem (2 μg/ml) were inactive against 92% (11/12) and 100% (12/12) of isolates, respectively. Colistin (2.5 μg/ml) exerted bactericidal effects (range: 0.39-2.5 log<SUB>10</SUB>) against 78% (7/9) of colistin-resistant isolates. Colistin-ertapenem, colistin-doripenem and colistin-doripenem-ertapenem exhibited synergy against 42% (5/12), 50% (6/12) and 67% (8/12) of isolates, respectively. Expression of ompK35 and ompK36 porins correlated with each other (R<SUP>2</SUP> = 0.80). Levels of porin expression did not correlate with colistin-doripenem or colistin?ertapenem synergy. However, synergy with colistin-doripenem-ertapenem was more likely against isolates with high porin expression than low expression (100% (8/8) vs 0% (0/4); p=0.002). Moreover, bactericidal activity (area under the bacterial killing curve) against isolates with high porin expression was greater for colistin-doripenem-ertapenem than colistin-doripenem or colistin-ertapenem (p≤0.049). In conclusion, colistin-carbapenem combinations may provide optimal activity against KPC-Kp, including colistin-resistant isolates. Screening for porin expression may identify isolates that are most likely to respond to a triple combination of colistin-doripenem-ertapenem. In the future, molecular characterization of KPC-Kp isolates may be a practical tool for identifying effective combination regimens.
FOOTNOTES
Corresponding author: Cornelius J Clancy, M.D., University of Pittsburgh, Scaife Hall, Suite 871, Pittsburgh, PA 15261, Email: CJC76@pitt.edu, Phone: 412-383-5193, Fax: 412-648-8455
Copyright ? 2013, American Society for Microbiology. All Rights Reserved.
-Jae H. Hong 1, Cornelius J Clancy 1,2, Shaoji Cheng 1, Ryan K. Shields 1, Liang Chen 3, Yohei Doi 1, Yanan Zhao 3, David S. Perlin 3, Barry N. Kreiswirth 3 and M. Hong Nguyen 1
Author Affiliations: <SUP>1</SUP>University of Pittsburgh, Pittsburgh, PA <SUP>2</SUP>Pittsburgh VA Health System <SUP>3</SUP>Public Health Research Institute, University of Medicine and Dentistry of New Jersey, Newark, NJ
ABSTRACT
We characterized carbapenem resistance mechanisms among 12 Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) clinical isolates, and evaluated their effects on the activity of 2- and 3-drug combinations of colistin, doripenem and ertapenem. All isolates were resistant to ertapenem and doripenem; 75% (9/12) were resistant to colistin. Isolates belonged to ST258 clonal group, and harbored bla<SUB>KPC-2</SUB>, bla<SUB>SHV-12,</SUB> and bla<SUB>TEM-1</SUB>. By time-kills, doripenem (8 μg/ml) and ertapenem (2 μg/ml) were inactive against 92% (11/12) and 100% (12/12) of isolates, respectively. Colistin (2.5 μg/ml) exerted bactericidal effects (range: 0.39-2.5 log<SUB>10</SUB>) against 78% (7/9) of colistin-resistant isolates. Colistin-ertapenem, colistin-doripenem and colistin-doripenem-ertapenem exhibited synergy against 42% (5/12), 50% (6/12) and 67% (8/12) of isolates, respectively. Expression of ompK35 and ompK36 porins correlated with each other (R<SUP>2</SUP> = 0.80). Levels of porin expression did not correlate with colistin-doripenem or colistin?ertapenem synergy. However, synergy with colistin-doripenem-ertapenem was more likely against isolates with high porin expression than low expression (100% (8/8) vs 0% (0/4); p=0.002). Moreover, bactericidal activity (area under the bacterial killing curve) against isolates with high porin expression was greater for colistin-doripenem-ertapenem than colistin-doripenem or colistin-ertapenem (p≤0.049). In conclusion, colistin-carbapenem combinations may provide optimal activity against KPC-Kp, including colistin-resistant isolates. Screening for porin expression may identify isolates that are most likely to respond to a triple combination of colistin-doripenem-ertapenem. In the future, molecular characterization of KPC-Kp isolates may be a practical tool for identifying effective combination regimens.
FOOTNOTES
Corresponding author: Cornelius J Clancy, M.D., University of Pittsburgh, Scaife Hall, Suite 871, Pittsburgh, PA 15261, Email: CJC76@pitt.edu, Phone: 412-383-5193, Fax: 412-648-8455
Copyright ? 2013, American Society for Microbiology. All Rights Reserved.
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