eradicate the remaining bacterial burden. Under such conditions, it is possible to use
a dosing regimen without selecting for resistant strains, if the duration is short
enough to avoid eradicating the susceptible population. When the susceptible
population is eradicated, the resistant population begins to increase and the host
defences can no longer control the infection. Clinically, this would be perceived as
the emergence of resistance with clinical failure. Secondly, Drusano and colleagues
also concluded that, because the growth rate of the susceptible population is always
significantly greater than that of the resistant population, the resistant organisms
tend to be less ‘biologically fit’. The latter may have important implications with
respect to the long-term prevalence of wild type versus resistant strains. Ultimately,
they concluded that even sub-optimal dosing regimens will have minimal long-term
impact on resistance selection pressure if the duration of dosing is short enough to
avoid eradicating the susceptible subpopulation while amplifying the resistant
subpopulation.
4.4 PK/PD is More Than MICs
While numerical values of PK/PD parameters have been proposed for many anti-
bacterial drugs, most studies have evaluated the impact of antibiotic exposure on
clinical efficacy rather than their impact on resistance development. It is only
recently that attention has been focused on resistance prevention (Blondeau et al.
2004 ; Boak et al. 2007 ; Lees et al. 2006 ; Rybak 2006 ). In this regard, criticism has
been levied against the use of MIC as the PD index, although the increasing use of
MPC does help to address this deficiency (Blondeau et al. 2004 ).
Nevertheless, neither the MIC nor the MPC provides a complete explanation of
the responses to antimicrobial agents. For example, as noted by Tam et al. ( 2007 ),
PK/PD proposals relating to the prevention of resistance are difficult to substantiate,
if the prevalent resistance mechanisms are the result of transmissible elements.
Furthermore, MIC values provide no information on the rate of kill. In fact, even for
a single drug and a single pathogen species, there can be marked variations in the
killing activity across bacterial strains, even when the strains share the same MIC
value. Noel et al. ( 2007 ) showed that within a bacterial species, there was strain to
strain variation that impacted on the PK/PD index, and that such variability needed
to be considered when targeting specific therapeutic outcomes. It is important to
recall Zhao and Drlica’s proposal that the PK/PD metrics for avoiding the selection
of resistant strains may be better made on the basis of PK/MPC than on PK/MIC.
Recent in vitro studies on strains of the pathogensM. haemolyticaandP. multocida
isolated from cases of calf pneumonia have also revealed the importance of
recognising inter-strain variabilities in the time–kill relationships for the antimicro-
bial drugs amoxicillin, florfenicol, marbofloxacin, oxytetracycline and tulathromy-
cin (Illambas et al. 2009 ; Potter et al.2009a,b).
It is interesting to speculate on the best surrogate marker for such strain to strain
differences. An example is the response of two bacterial species to a single
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