Comparative and Veterinary Pharmacology

resistance mutations have a much larger effect on MPC than on MIC values (Zhao
and Drlica 2008 ).
An illustration of a MSW is provided in Fig. 2.
With recognition of MSW concepts, there is an ongoing effort within human
medicine to explore alternative dosing strategies that will minimise the emer-
gence of resistant microbes. For example, Zhao and Drlica ( 2008 ) recommended
the use of escalating dosing strategies to kill susceptible cells while preventing the
amplification of resistant mutant subpopulations. Alternatively, others suggest that
for difficult (severe) infections, aggressive therapy should be employed. This
includes high dose – short duration (HDSD) therapies (Stein 2008 ; Schrag et al.
2001 ) or the administration of large doses of potent and highly efficacious anti-
microbials for short periods of time followed by dose de-escalation (Siegel 2008 ).

4.3 Duration of Dosing

Relatively little experimental work has focused on the duration of therapy. In this
regard, the choice of dose and duration of therapy will generally have the greatest
influence in circumstances where resistance develops as a point mutation. In those
situations, resistance can develop when the size of the bacterial population exceeds
the inverse of the mutational frequency to resistance (Tam et al. 2007 ). For
quinolones, target site mutations and/or efflux-pump overexpression occurs with a
frequency of ~1/10^6 –1/10^8.
In a study designed to examine the relationship between the duration of drug
exposure and the emergence of drug resistance, Tam et al. ( 2007 ) employed in vitro
infection models. In comparison with traditional rodent models, such in vitro
models allow for longer therapy durations and the generation of exposure profiles

Mutation Selection Window

MPC

MIC

Time

plasma free drug concentrations

Fig. 2Diagrammatic representation of the MSW, as defined by the upper and lower bounds, MPC
and MIC, respectively

Antimicrobial Drug Resistance 245