JAC Advance Access published online on October 15, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn425
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Original research |
In vitro pharmacodynamics of colistin against multidrug-resistant Klebsiella pneumoniae
1 Facility for Anti-infective Drug Development and Innovation, Monash Institute of Pharmaceutical Sciences, Monash University, VIC, Australia 2 Infectious Diseases and Microbiology Departments, Austin Health, VIC, Australia 3 Division of Laboratory Medicine, Women’s and Children’s Hospital, North Adelaide, SA, Australia 4 University of Adelaide, SA, Australia
Received 25 July 2008; returned 1 September 2008; revised 5 September 2008; accepted 16 September 2008
* Corresponding author. Tel: +61-3-9903-9702; Fax: +61-3-9903-9629; E-mail: Jian.Li{at}pharm.monash.edu.au
Background: Resistance to colistin is emerging in multidrug-resistant Gram-negative bacteria and no solid pharmacodynamic data are available for colistin against Klebsiella pneumoniae.
Methods: Twenty-one multidrug-resistant clinical K. pneumoniae isolates from 16 different clinical sites worldwide were employed. The genetic relatedness of these isolates was examined with PFGE. In vitro pharmacodynamic properties of colistin (sulphate) were investigated by studying the MICs, mutation prevention concentrations, time–kill kinetics, population analysis profiles and the post-antibiotic effect (PAE). Time–kill was studied with three clinical isolates plus ATCC 13883 at concentrations ranging from 0.5 to 64x MIC. The PAE was examined after 20 min of exposure of these isolates.
Results: The 22 isolates belonged to 18 different PFGE groups. For susceptible isolates, colistin MICs ranged from 0.125 to 1 mg/L. Six isolates were colistin-resistant with MICs of 
32 mg/L. Colistin heteroresistance was observed in 15 of 16 isolates considered colistin-susceptible based on MICs. For susceptible isolates, colistin showed extremely rapid killing; however, regrowth was observed as early as 2 h after treatment and substantial regrowth at 24 h even at concentrations up to 64x MIC for some isolates. Colistin exhibited no or very modest PAE against the isolates tested.
Conclusions: The data suggest that monotherapy with colistin methanesulfonate, the parenteral form of colistin, and long dosage intervals may be problematic for the treatment of infections caused by multidrug-resistant K. pneumoniae, particularly for colistin-heteroresistant strains. Further investigation on combination therapy of colistin with other antibiotics is warranted.
Key Words: heteroresistance , killing kinetics , post-antibiotic effect , mutation prevention concentration , population analysis profile
Joint senior authors, who contributed equally to this study.
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