than it was in veterinary pathogens. Although pathogens isolated from both human
and veterinary hosts appeared to have higher incidences of resistance as compared
to those restricted to a single animal host, pathogens expressing the most marked
(broad) drug resistance profile were found to exclusively infect humans. Thus,
differences occurred in the available genetic repertoire of a bacterial species
and were reflected in the observed resistance patterns. Because of these genetic
differences, bacterial species undergoing comparable selection pressures in differ-
ent host species do not automatically result in similarly resistant populations.
Rather, the prevalence of resistance within a bacterial species can differ between
populations isolated from different hosts and, for some species; fluctuations in
dominant subpopulations (for instance particular serotypes) can be the most impor-
tant factor determining resistance.
4 Pharmacokinetic Considerations
4.1 General Considerations
When deriving and applying PK/PD relationships for antimicrobial drugs, it is
important to recognise that it is the free (non-protein bound) drug concentrations
in plasma or serum that most closely reflect active drug concentrations at the site of
infection (Liu et al. 2002 ; Merrikin et al. 1983 ). Therefore, although plasma free
drug concentrations do not necessarily translate directly into the concentration–
time profiles at the site of infection for extracellular infections, concentrations at the
infection site (the biophase) are usually represented (at least proportionally) by
plasma free drug concentrations. Accordingly, it is generally recommended that
PK/PD relationships should be based upon free drug concentrations (Liu et al.
2002 ).
While there are a number of factors that determine and contribute to the PK/PD
indices (e.g. AUC/MIC,Cmax/MIC,T>MIC) and to numerical PK/PD targets (e.g.
AUC/MIC=100 h), there are several crucial factors that the PK/PD approach does
not adequately address. For example, the in vitro MIC, which is the universally used
PD component of these indices, does not provide information on the time to kill, the
time to maximum kill, the log change within a fixed time, or the maximum
reduction in viable bacterial counts (MacGowan and Bowker 2002 ). Moreover,
MICs are normally determined by doubling dilutions and are therefore subject to
considerable inaccuracies. There is the additional consideration, that bacterial
growth and growth inhibition by antimicrobial drugs in vivo may differ consider-
ably between artificial growth media (Illambas et al. 2009 ; Potter et al.2009a,b)
There are also many other drug effects in vivo that are unrelated to the MIC but
which can influence clinical outcome (e.g. anti-inflammatory and immunomodula-
tory effects, the ability to interact with dormant phase bacteria in a biofilm, the
ability to interfere with bacterial colonisation on epithelial surfaces, and the influ-
ence of the drug on toxin production and release). These additional determinants of
Antimicrobial Drug Resistance 241