(Lewis 2007 ) and are largely responsible for the high tolerance of bacterial biofilms
to antimicrobial drugs.
Persister cells are not identical to the non-growing cells within a biofilm, and
drug indifference is not the same as persistence. While the lack of response to
antimicrobials by dormant/slow growing cells occurs with no specific mechanistic
basis, persistence is restricted to a very small subpopulation of cells whose toler-
ance occurs through some mechanism that as yet remains poorly understood (Lewis
2008 ; Jayaraman 2008 ).
In a typical acute infection, the initial treatment kills sensitive cells, but the
persister cells are protected from the host defences and are not affected by the
antimicrobial agents. It is for this reason that the recent modelling efforts support
prolonged but periodic treatment protocols that address the heterogeneity in
bacterial populations, rather than the continuous administration of the antibiotic
typical of conventional clinical practise (De Leenheer and Cogan 2008 ). In other
words, therapy occurs repeatedly, with each dosing period being of a short
duration. This is reminiscent of the “duration” issue discussed earlier in this
chapter.
Currently, it is believed that persister cells can occur both within and outside the
biofilm matrix. Those that are outside the biofilm matrix (including planktonic
persister cells) can potentially be killed by the host’s immune system. However,
persisters sometimes embed themselves in a manner that shields them from the
host’s immune defence system, such as those that reside in the central nervous system
(Treponema pallidum), macrophages or granulomas (Mycobacterium tuberculosis)
stomach (Helicobacter pylori), and gallbladder (Salmonella typhi) (Harrison et al.
2005 ; Jayaraman 2008 ). How these cells “recognise” places to hide is not known
but, as discussed below, some investigators have suggested that pathogens can
sense environmental conditions and communicate with other cells in a manner that
maximises their likelihood of survival (Nadell et al. 2009 ).
Inter-communication between invading bacterial cells appears to be an impor-
tant component of many infectious diseases. For example, the signalling system
associated withPseudomonas aeruginosacontrols the production of factors impli-
cated in virulence, and drugs that interfere with this system (e.g. azithromycin)
seem to exert a significant positive effect on the clinical outcome ofP. aeruginosa
infections in cystic fibrosis patients (Winstanley and Fothergill 2009 ). Such
cell-to-cell communication occurs via the secretion of a signalling molecule that
is sensed by the overall bacterial population, leading to altered bacterial gene
expression and thereby triggering the expression of virulence determinants. It has
been suggested that this intercellular signalling network is responsible for coordi-
nating the range of bacterial activities associated with the development and main-
tenance of biofilms (Nadell et al. 2009 ).
Studies to date have suggested that the communication molecules reach a critical
concentration at a specific cell density (or “quorum”). Thus the term “quorum
sensing” (QS) has been used to describe this signalling system (Horswill and
Nauseef 2008 ). This sensing allows for the development of organised bacterial
communities within the biofilm, which is reminiscent of a multicellular organism
Antimicrobial Drug Resistance 253