The combination of colistin and doripenem is synergistic against Klebsiella pneumoniae at multiple inocula and suppresses colistin resistance in an in vitro pharmacokinetic/pharmacodynamic model

Deris, Zakuan Z., Yu, Heidi H., Davis, Kathryn, Soon, Rachel L., Jacob, Jovan, Ku, Caron K., Poudyal, Anima, Bergen, Phillip J., Tsuji, Brian T., Bulitta, Jurgen B., Forrest, Alan, Paterson, David L., Velkov, Tony, Li, Jian and Nation, Roger L. (2012) The combination of colistin and doripenem is synergistic against Klebsiella pneumoniae at multiple inocula and suppresses colistin resistance in an in vitro pharmacokinetic/pharmacodynamic model. Antimicrobial Agents and Chemotherapy, 56 10: 5103-5112. doi:10.1128/AAC.01064-12

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Author Deris, Zakuan Z.
Yu, Heidi H.
Davis, Kathryn
Soon, Rachel L.
Jacob, Jovan
Ku, Caron K.
Poudyal, Anima
Bergen, Phillip J.
Tsuji, Brian T.
Bulitta, Jurgen B.
Forrest, Alan
Paterson, David L.
Velkov, Tony
Li, Jian
Nation, Roger L.
Title The combination of colistin and doripenem is synergistic against Klebsiella pneumoniae at multiple inocula and suppresses colistin resistance in an in vitro pharmacokinetic/pharmacodynamic model
Formatted title
The combination of colistin and doripenem is synergistic against Klebsiella pneumoniae at multiple inocula and suppresses colistin resistance in an in vitro pharmacokinetic/pharmacodynamic model
Journal name Antimicrobial Agents and Chemotherapy   Check publisher's open access policy
ISSN 0066-4804
1098-6596
Publication date 2012-10
Sub-type Article (original research)
DOI 10.1128/AAC.01064-12
Open Access Status File (Publisher version)
Volume 56
Issue 10
Start page 5103
End page 5112
Total pages 10
Place of publication Washington, DC, United States
Publisher American Society for Microbiology
Collection year 2013
Language eng
Formatted abstract
Multidrug-resistant (MDR) Klebsiella pneumoniae may require combination therapy. We systematically investigated bacterial killing with colistin and doripenem mono- and combination therapy against MDR K. pneumoniae and emergence of colistin resistance. A one-compartment in vitro pharmacokinetic/pharmacodynamic model was employed over a 72-h period with two inocula (∼106 and ∼108 CFU/ml); a colistin-heteroresistant reference strain (ATCC 13883) and three clinical isolates (colistin-susceptible FADDI-KP032 [doripenem resistant], colistin-heteroresistant FADDI-KP033, and colistin-resistant FADDI-KP035) were included. Four combinations utilizing clinically achievable concentrations were investigated. Microbiological responses were examined by determining log changes and population analysis profiles (for emergence of colistin resistance) over 72 h. Against colistin-susceptible and -heteroresistant isolates, combinations of colistin (constant concentration regimens of 0.5 or 2 mg/liter) plus doripenem (steady-state peak concentration [Cmax] of 2.5 or 25 mg/liter over 8 h; half-life, 1.5 h) generally resulted in substantial improvements in bacterial killing at both inocula. Combinations were additive or synergistic against ATCC 13883, FADDI-KP032, and FADDI-KP033 in 9, 9, and 14 of 16 cases (4 combinations at 6, 24, 48, and 72 h) at the 106-CFU/ml inoculum and 14, 11, and 12 of 16 cases at the 108-CFU/ml inoculum, respectively. Combinations at the highest dosage regimens resulted in undetectable bacterial counts at 72 h in 5 of 8 cases (4 isolates at 2 inocula). Emergence of colistin-resistant subpopulations in colistin-susceptible and -heteroresistant isolates was virtually eliminated with combination therapy. Against the colistin-resistant isolate, colistin at 2 mg/liter plus doripenem (Cmax, 25 mg/liter) at the low inoculum improved bacterial killing. This investigation provides important information for optimization of colistin-doripenem combinations.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
Official 2013 Collection
School of Medicine Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 33 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 39 times in Scopus Article | Citations
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Created: Thu, 08 Nov 2012, 13:50:20 EST by Roheen Gill on behalf of UQ Centre for Clinical Research