[Source: Antimicrobial Agents and Chemotherapy, full text: (LINK). Abstract, edited.]
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: 1University of Pittsburgh, Pittsburgh, PA 2Pittsburgh VA Health System 3Public Health Research Institute, University of Medicine and Dentistry of New Jersey, Newark, NJ
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 blaKPC-2, blaSHV-12, and blaTEM-1. 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 log10) 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 (R2 = 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.
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
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