A mechanism-based pharmacokinetic/pharmacodynamic model allows prediction of antibiotic killing from MIC values for WT and mutants.
OBJECTIVE
In silico pharmacokinetic/pharmacodynamic (PK/PD) models can be developed based on data from in vitro time-kill experiments and can provide valuable information to guide dosing of antibiotics. The aim was to develop a mechanism-based in silico model that can describe in vitro time-kill experiments of Escherichia coli MG1655 WT and six isogenic mutants exposed to ciprofloxacin and to identify relationships that may be used to simplify future characterizations in a similar setting.


METHODS
In this study, we developed a mechanism-based PK/PD model describing killing kinetics for E. coli following exposure to ciprofloxacin. WT and six well-characterized mutants, with one to four clinically relevant resistance mutations each, were exposed to a wide range of static ciprofloxacin concentrations.


RESULTS
The developed model includes susceptible growing bacteria, less susceptible (pre-existing resistant) growing bacteria, non-susceptible non-growing bacteria and non-colony-forming non-growing bacteria. The non-colony-forming state was likely due to formation of filaments and was needed to describe data close to the MIC. A common model structure with different potency for bacterial killing (EC50) for each strain successfully characterized the time-kill curves for both WT and the six E. coli mutants.


CONCLUSIONS
The model-derived mutant-specific EC50 estimates were highly correlated (r(2) = 0.99) with the experimentally determined MICs, implying that the in vitro time-kill profile of a mutant strain is reasonably well predictable by the MIC alone based on the model.
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden david.khan@farmbio.uu.se.
David D
DD
Khan
Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Pernilla
P
Lagerbäck
Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Sha
S
Cao
Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Ulrika
U
Lustig
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Elisabet I
EI
Nielsen
Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Otto
O
Cars
Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Diarmaid
D
Hughes
Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Dan I
DI
Andersson
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Lena E
LE
Friberg
D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002939:Ciprofloxacin / Q000493:pharmacokinetics / Q000494:pharmacology*; D003198:Computer Simulation; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects* / Q000502:physiology; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects*; D012641:Selection, Genetic
D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin