JAC Advance Access originally published online on January 28, 2008
Journal of Antimicrobial Chemotherapy 2008 61(3):636-642; doi:10.1093/jac/dkm511
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Original research |
Comparison of once-, twice- and thrice-daily dosing of colistin on antibacterial effect and emergence of resistance: studies with Pseudomonas aeruginosa in an in vitro pharmacodynamic model
1 Facility for Anti-infective Drug Development and Innovation, Victorian College of Pharmacy, Monash University, Melbourne, Australia 2 Division of Laboratory Medicine, Women's and Children's Hospital, North Adelaide, Australia 3 Department of Pharmacy, Women's and Children's Hospital, North Adelaide, Australia 4 Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia
Received 13 June 2007; returned 24 October 2007; revised 3 October 2007; accepted 4 December 2007
* Corresponding author. Tel: +61-3-9903-9061; Fax: +61-3-9903-9629; E-mail: roger.nation{at}vcp.monash.edu.au
Objectives: The optimal dosing regimen for colistin methanesulphonate (CMS) against Pseudomonas aeruginosa is unknown. CMS is converted in vivo to its active form, colistin. We evaluated three colistin dosage regimens in an in vitro pharmacokinetic/pharmacodynamic model.
Methods: Three intermittent dosage regimens involving 8, 12 and 24 h dosage intervals (Cmax of 3.0, 4.5 or 9.0 mg/L, respectively) were employed. Antibacterial activity and emergence of resistance were investigated over 72 h using two strains of P. aeruginosa: ATCC 27853 and 19056. The areas under the killing curves (AUBC0–72) and population analysis profiles (AUCPAP) were used to compare regimens.
Results: No difference in bacterial killing was observed among different regimens. For ATCC 27853, substantial killing was observed after the first dose with less killing after subsequent doses irrespective of regimen; regrowth to between 5.95 and 7.49 log10 cfu/mL occurred by 72 h (growth control 7.46 log10 cfu/mL). AUCPAPs at 72 h for the 12 hourly (4.08 ± 1.54) and 24 hourly (4.16 ± 2.48) regimens were substantially higher than that for both the growth control (1.63 ± 0.08) and 8 hourly regimen (2.30 ± 0.87). For 19056, bacterial numbers at 72 h with each regimen (1.32–2.75 log10 cfu/mL) were far below that of the growth control (7.79 log10 cfu/mL); AUCPAPs could not be measured effectively due to the substantial killing.
Conclusions: No difference in overall bacterial kill was observed when the recommended maximum daily dose was administered at 8, 12 or 24 h intervals. However, the 8 hourly regimen appeared most effective at minimizing emergence of resistance.
Keywords: colistin methanesulphonate , dosage regimens , pharmacokinetics , pharmacodynamics , multidrug resistance
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