mechanism of drug action, the pharmacokinetics (PK) of the antimicrobial agent in
the targeted patient population, the pharmacodynamics (PD) of the bacterial
response to the antimicrobial agent, the PK/PD relationship that will influence
dose selection, and the integrity of the host immune system. Finally, the differences
between bacterial tolerance and bacterial resistance are considered, and the poten-
tial for non-traditional anti-infective therapies is discussed.
KeywordsAntimicrobial resistancePK/PDDose selectionAntimicrobial
tolerance
1 Introduction
Bacteria are incredibly resilient life-forms that have proven their ability to survive
across a variety of environmental conditions. There are examples of bacterial
species that can survive temperatures below freezing and above the boiling point
of water, species that can survive in highly acidic environments or in alkaline
conditions with pH values greater than 12, and others that thrive in aqueous
media containing 30% NaCl.Deinococcus radioduransis a species of bacteria
that can survive in the presence of a thousand times more radiation than can be
tolerated by humans (Benitez de Cruz 2008 ).
Facilitated by their potential for rapid growth, bacterial populations evolve over
short periods of time, promoting their survival under adverse conditions. Typical of
this survival capability is their adaptation to life in the presence of antimicrobial
agents, where, the expression of resistance mechanisms helps to ensure their
continued growth (Epstein et al. 2004 ). Furthermore, bacteria can communicate
with each other through elaborate signalling systems that facilitate their survival in
hostile environments. These communication systems promote synchronised
changes in community structure and composition under adverse conditions (e.g.
the formation of biofilms) or signal the presence of environmental conditions
favourable for colony growth.
Given their multitude of potential survival mechanisms, can we use drugs in a
manner that will prevent the development of antimicrobial resistance? The answer
is NO. However, we can minimise the risk of selecting for resistant microbial
strains by carefully choosing the antimicrobial agent, the product formulation, the
dosage regimen, and the duration of dosing. Therapeutic strategies should be
grounded in pathogen identification, an understanding of the susceptibility char-
acteristics of that pathogen, and knowledge of the relationship between drug dose,
PD, and effect. The relationship between PK and PD and the corresponding PK/PD
target for dose selection is a function of the mechanism(s) of drug action, specific
drug–bug interactions, the natural growth rate of the pathogen, and the mechanisms
through which resistance (or tolerance) can occur.
228 M. Martinez and P. Silley