Abstract
The minimum inhibitory concentration (MIC) of an antimicrobial drug for a bacterial pathogen is used as a measure of the bacterial susceptibility to the drug. However, relationships between the antimicrobial concentration, bacterial susceptibility, and the pharmacodynamic (PD) inhibitory effect on the bacterial population are more complex. The relationships can be captured by multi-parameter models such as the Emax model. In this study, time-kill experiments were conducted with a zoonotic pathogen Pasteurella multocida and the fluoroquinolone enrofloxacin. Pasteurella multocida isolates with enrofloxacin MIC of 0.01 μg/mL, 1.5 μg/mL, and 2.0 μg/mL were used. An additive inhibitory Emax model was fitted to the data on bacterial population growth inhibition at different enrofloxacin concentrations. The values of PD parameters such as maximal growth inhibition, concentration achieving a half of the maximal inhibition, and Hill coefficient that captures steepness of the relationships between the concentration and effect, varied between the isolate with low MIC and less susceptible isolates. While enrofloxacin PD against the isolate with low MIC exhibited the expected concentration-dependent characteristics, the PD against the less susceptible isolates demonstrated time-dependent characteristics. The results demonstrate that bacterial antimicrobial susceptibility may need to be described by a combination of parameters rather than a single parameter of the MIC.
Highlights
Relationships between the antimicrobial concentration, bacterial susceptibility, and the PD-effect on the bacterial population are known to be more complex than what can be captured by the minimum inhibitory concentration (MIC) parameter alone
The maximal inhibition of P. multocida population growth (Emax) was statistically significantly higher for the isolate with the lowest enrofloxacin MIC compared to the isolates with higher MIC values
The inhibition of the population growth of the more susceptible isolate was more sensitive to smaller changes in the antimicrobial concentration, and the effect continued to respond to an increase in the concentrations above several multiples of the MIC (Figs 2a,b and 3a,b)
Summary
Relationships between the antimicrobial concentration, bacterial susceptibility, and the PD-effect on the bacterial population are known to be more complex than what can be captured by the MIC parameter alone. Multi-parameter mathematical models have been developed to capture the relationships, such as the maximum effect (Emax) model based on the Hill function[3,4]. Based on our review of experimental literature[7], we hypothesized that this is not the case; the other PD parameters’ values may change between pathogen isolates for which the drug’s MIC differ. This can have significant clinical implications for design of antimicrobial treatment regimens, as the MIC and other PD parameters need to be considered when choosing the dose and dosing interval. The antimicrobial was the fluoroquinolone enrofloxacin, which is thought to exhibit the concentration-dependent activity against this pathogen[14]
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