Minimising the Emergence of Resistance to Antimicrobial Drugs through Rational Dosage Schedule Design Based on Pharmacokinetic-Pharmacodynamic (PK-PD) Modelling and Population PK-PD Modelling

<ol> <LI> To establish in vitro MIC values and microbial growth inhibition/kill curves in broth for each of the drugs, marbofloxacin, amoxycillin, oxytetracycline and tulathromycin against several strains of each of the pathogens, Mannheimia haemolytica, Pasteurella multocida and Mycoplasma bovis.

<LI> To subject the data to PK-PD modelling to derive appropriate indices (such as AUC/MIC)of antimicrobial activity.

<LI> To determine the occurrence and stability of any resistance development to each organism and each drug in the in vitro growth inhibition/kill studies.

<LI> To establish in vitro MIC values and microbial growth inhibition/kill curves in calf serum for each of the drugs and each of the organisms listed in Objective 1, using strains which will grow in this medium.

<LI> To establish microbial growth inhibition/kill curves ex vivo in calf serum, exudate and transudate for each of the drugs and each of the organisms listed in Objective 1, using strains which will grow in each of these matrices.

<LI> To derive PK-PD indices of antimicrobial activity in vivo by PK-PD modelling in a calf model of pneumonia based on the pathogen, Mannheimia haemolytica, for each of the drugs listed in Objective 1.

<LI> To undertake population pharmacokinetic and pharmacodynamic assessments for each of the agents, marbofloxacin, amoxycillin, oxytetracycline and tulathromycin in clinical case of calf pneumonia.

<LI> To undertake PK-PD modelling on the data and to derive by Monte Carlo simulations doses of each drug which will provide at least a 90% successful bacteriological outcome based on (i) an empirical antibiotherapy (MIC unknown) and (ii) a targeted antibiotherapy (MIC known), as demonstrated for doxycycline in piglets by Toutain and co-workers (see Lees et al., 2006).

<LI> To undertake Monte Carlo simulations to determine doses of each drug which avoid the emergence of resistant organisms.

<LI> To monitor the resistance of respiratory tract pathogens and g.i.t. commensal bacteria to each of the agents investigated before and after the courses of treatment.