PHARMACOKINETIC, PHARMACODYNAMIC AND CLINICAL CORRELATIONS RELATING TO THE THERAPY OF COLONIC INFECTIONS IN THE PIG AND BREAKPOINT DETERMINATIONS

Summary The colonic contents concentrations (CCCs) of valnemulin, tiamulin, lincomycin, tylosin and acetylisovaleryl tylosin were related to their pharmacodynamic effect on Brachyspira hyodysenteriae and B. pilosicoli from a variety of published minimum inhibitory concentration (MIC) surveys and, where possible, these findings were correlated with clinical data to determine suitable clinical breakpoints. There were limited data available for CCC determinations and some results had to be estimated. Determinations of MICs also varied, depending on the method. The micro-broth method gave figures, on average, one dilution lower than agar plate tests; but doubling dilutions of antibiotic used in the tests also limit precision. Tests on large numbers of isolates of B. hyodysenteriae with the micro-broth test demonstrated MIC patterns where possible mutations occurred and reduced susceptibility or tolerance occurred. In the case of tylosin, there was a large jump in MICs to complete resistance development. The other antibiotics seemed to develop resistance in a more gradual stepwise way and these dips were thought to demonstrate where the effective bio-concentrations of the antibiotics reached in the colon to stimulate the mutations. When these results were compared with clinical challenge study results, with isolates of known MICs, or field experience reports, in general, a confirmatory picture evolved. Breakpoints for the antibiotics at their normal upper usage levels were derived for brachyspiras. Valnemulin at 75ppm had an estimated breakpoint at >0.125 and >0.25µg/ml for micro-broth test and agar plate test respectively and similarly for 100ppm tiamulin >0.5 and >1.0µg/ml, lincomycin 110ppm >50 and >100µg/ml, tylosin 100ppm >16 and >32µg/ml and 100ppm acetylisovaleryltylosin >16 and >32µg/ml.