of potential therapeutic agents. The classification of “susceptible” may not take full
account of the ability of the antimicrobial agent to inhibit the pathogen. The PK of
the drug, the formulation, the dosage regimen, and the likelihood of therapeutic
success at that dosage regimen are all factors which should be considered when the
susceptible (S), intermediate (I) and resistant (R) breakpoints are established for a
drug. Based upon these S, I, R ratings, the clinical laboratory provides information
on drugs that minimise the likelihood of therapeutic failure. Breakpoints arenot
intended as an assurance of therapeutic success.
The Veterinary Antimicrobial Susceptibility Testing Subcommittee (VAST)
of the Clinical and Laboratory Standards Institute (CLSI) has recently published
their M37 guidance, which describes the data and data interpretation used to
establish veterinary susceptibility criteria (Clinical Laboratories Standards 2007 ).
In veterinary medicine, these susceptibility breakpoints are disease-indication and
target-animal-species specific, thereby allowing for potential differences in the
susceptibility breakpoints across target animal species and within a target animal
species across indications. By establishing the criteria correlating the required
levels of drug exposure and the probability of success of therapy, clinically derived
susceptibility breakpoints can minimise the risk of repeated exposure to suboptimal
antimicrobial drug concentrations, which is a major factor contributing to the
development of resistant bacterial strains.
5 Tolerance Versus Resistance
Traditionally, clonal bacterial populations have been considered to be both geno-
typically and phenotypically identical. However, newer techniques have caused this
view to be challenged. It is now well established that phenotypic heterogeneity can
exist within a clonal population due to “noise” in gene expression. This “noise” can
arise as a result of stochastic variations in gene expression or in response to
environmental perturbations (Jayaraman 2008 ). These variations cause drugs to
lose, either partially or totally, their ability to fight infection (drug tolerance).
Drug resistance and drug tolerance differ, in that resistance mechanisms prevent
the antibiotic from hitting a target, whereas tolerance works by shutting down the
targets (Lewis 2008 ). Unlike resistance, which frequently involves genotypic
changes, tolerance is the result of phenotypic changes. Moreover, in contrast to
resistance, which is a function of individual cells, tolerance reflects a community-
based synchronisation of gene expression that changes the bacteria from a growing
to a slow or non-growing state (the biofilm). This conversion facilitates bacterial
survival despite the presence of antimicrobial agents or adverse environmental
factors without necessitating an expression of resistance mechanisms (Jefferson
2004 ; Keren et al. 2004 ).
Biofilms are densely packed communities of microbial cells that grow on
surfaces and surround themselves with secreted polymers (reviewed by Nadell
et al. 2009 ). Individual biofilms are also heterogeneous. Although the bacteria
250 M. Martinez and P. Silley