title: Pharmacodynamic modelling of in vitro activity of tetracycline against a representative, naturally occurring population of porcine Escherichia coli.
abstract: BACKGROUND
  The 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 E max model with three parameters: maximum net growth rate (amax); concentration for a half-maximal response (E max); and the Hill coefficient (γ).
  
  
  RESULTS
  The 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 αmax between susceptible and resistant strains in the absence of a drug was not different. EC 50 increased linearly with MIC on a log-log scale, and γ was different between susceptible and resistant strains.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark. amaisahmad@gmail.com.
authors.forename: Amais
authors.initials: A
authors.lastname: Ahmad
authors.affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark. caza@sund.ku.dk.
authors.forename: Camilla
authors.initials: C
authors.lastname: Zachariasen
authors.affiliation: Department of Applied Mathematics and Computer Science, Technical University of Denmark, Lyngby, Denmark. laec@dtu.dk.
authors.forename: Lasse Engbo
authors.initials: LE
authors.lastname: Christiansen
authors.affiliation: Department of Applied Mathematics and Computer Science, Technical University of Denmark, Lyngby, Denmark. kagr@dtu.dk.
authors.forename: Kaare
authors.initials: K
authors.lastname: Græsbøll
authors.affiliation: National Veterinary Institute, Section of Epidemiology, Technical University of Denmark, Frederiksberg C, Denmark. ntoft@vet.dtu.dk.
authors.forename: Nils
authors.initials: N
authors.lastname: Toft
authors.affiliation: Boyd Orr Centre for Population and Ecosystem Health, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. louise.matthews@glasgow.ac.uk.
authors.forename: Louise
authors.initials: L
authors.lastname: Matthews
authors.affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark. pedam@sund.ku.dk.
authors.forename: Peter
authors.initials: P
authors.lastname: Damborg
authors.affiliation: Department of Epidemiology and Microbial Genomics, Technical University of Denmark, Lyngby, Denmark. yvoa@food.dtu.dk.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Agersø
authors.affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark. jeo@sund.ku.dk.
authors.forename: John Elmerdahl
authors.initials: JE
authors.lastname: Olsen
authors.affiliation: Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark. saxmose@sund.ku.dk.
authors.forename: Søren Saxmose
authors.initials: SS
authors.lastname: Nielsen
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects*; D008954:Models, Biological; D013552:Swine / Q000382:microbiology; D013752:Tetracycline / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D013752:Tetracycline