Pharmacodynamic modelling of in vitro activity of tetracycline against a representative, naturally occurring population of porcine Escherichia coli

Abstract

BackgroundThe complex relationship between drug concentrations and bacterial growth rates require not only the minimum inhibitory concentration but also other parameters to capture the dynamic nature of the relationship. To analyse this relationship between tetracycline concentration and growth of Escherichia coli representative of those found in the Danish pig population, we compared the growth of 50 randomly selected strains. The observed net growth rates were used to describe the in vitro pharmacodynamic relationship between drug concentration and net growth rate based on Emax model with three parameters: maximum net growth rate (αmax); concentration for a half-maximal response (Emax); and the Hill coefficient (γ).ResultsThe net growth rate in the absence of antibiotic did not differ between susceptible and resistant isolates (P = 0.97). The net growth rate decreased with increasing tetracycline concentrations, and this decline was greater in susceptible strains than resistant strains. The lag phase, defined as the time needed for the strain to reach an OD600 value of 0.01, increased exponentially with increasing tetracycline concentration. The pharmacodynamic parameters confirmed that the between susceptible and resistant strains in the absence of a drug was not different. EC50 increased linearly with MIC on a log–log scale, and γ was different between susceptible and resistant strains.ConclusionsThe in vitro model parameters described the inhibition effect of tetracycline on E. coli when strains were exposed to a wide range of tetracycline concentrations. These parameters, along with in vivo pharmacokinetic data, may be useful in mathematical models to predict in vivo competitive growth of many different strains and for development of optimal dosing regimens for preventing selection of resistance.

Limitations of MIC as sole metric of pharmacodynamic response across the range of antimicrobial susceptibilities within a single bacterial species

“…The direction of change in the PD-parameter Hill coefficient among bacterial isolates with different MIC (determined under the standard conditions) of the fluoroquinolone enrofloxacin for zoonotic pathogen P. multocida in this study was similar to that reported for commensal E. coli for tetracycline8. The magnitude of the change was also remarkably similar between the two bacteria-antimicrobial systems.…”

“…Recent experimental evidence confirms this hypothesis for commensal Escherichia coli and a time-dependent antimicrobial tetracycline8. For example, larger values of the PD parameter Hill coefficient are observed for E. coli isolates with higher tetracycline MICs, compared to the isolates with lower MICs8. The value captures the steepness in relationships between an increase in the antimicrobial concentration and an increase in the PD-effect on growth of the exposed bacterial population.…”

“…This can have significant clinical implications for design of antimicrobial treatment regimens, as then not only the MIC but also other PD parameters need to be considered when choosing the dose and dosing interval. Recent experimental evidence confirms this hypothesis for commensal Escherichia coli and a time-dependent antimicrobial tetracycline8. For example, larger values of the PD parameter Hill coefficient are observed for E. coli isolates with higher tetracycline MICs, compared to the isolates with lower MICs8.…”

“…A three to four fold increase in the Hill coefficient value was observed for P. multocida isolates with enrofloxacin MIC of 1.5 or 2 μg/mL, compared to the isolate with the MIC of 0.01 μg/mL (Table 1). Based on the data presented in Ahmad et al 8,. the average value of Hill-coefficient for E. coli isolates with tetracycline MIC above 2 μg/mL was four times that for the isolates with tetracycline MIC below 0.5 μg/mL.…”

Effect of Tetracycline Dose and Treatment Mode on Selection of Resistant Coliform Bacteria in Nursery Pigs

“…Several studies modeling the development of tetracycline resistance in pigs following treatment under different scenarios have recently been published (22,(40)(41)(42). Such models have been fed with data on the growth responses of E. coli to different concentrations of tetracycline.…”