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

Abstract

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. 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 (AUBC(0-72)) and population analysis profiles (AUCPAP) were used to compare regimens. 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. 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.