Novel Targets for Treatment of Pseudomonas aeruginosa Biofilms - Antibiofilm Agents: From Diagnosis to Treatment and Prevention - page 251

a detrimental role. In this respect, the increased tolerance of biofilms has strength-
ened the belief that a chronic infection equals the biofilm state of growth (Burmølle
et al. 2010 ; Høiby et al. 2010 ). Once a mature biofilm has formed, it is almost
impossible to eradicate it with antimicrobials and a chronic inflammation will
occur. The best option is to remove or debride the infected tissue or implant, and
if that is not an option chronic suppressive therapy seems to be the only alternative
(Høiby et al. 2010 ).
The tolerance of biofilms has been linked to its slow growth since both in vitro
aggregates in suspension and flow-cell biofilms have the same slow growth rate as
stationary phase shaking cultures (Alhede et al. 2011 ). Interestingly, a recent study
showed that the growth rate of biofilms is independent of age, but that the tolerance
to antibiotics increases with age. It was found that the tolerance towards antibiotics
was reversible by physical disruption, suggesting that internal structures of the
matrix components plays the major role in surviving otherwise lethal treatments
with antibiotics and resistance to phagocytes (Alhede et al. 2011 ).
In addition to the inherent tolerance of the biofilm, traditional resistance mech-
anisms (e.g., efflux pumps and other adaptive resistance systems) are also promi-
nent players in biofilm infections (Ciofu 2003 ; Haagensen et al. 2007 ; Pamp
et al. 2008 ). The implication of adaptive resistance in metabolically active biofilm
cells has led to the effective combination therapy for early eradication of
P. aeruginosa in cystic fibrosis patients (Hansen et al. 2008 ). However, due to the
rise in multi-resistant strains, and the fact that mature biofilms are close to impos-
sible to eradicate, new and alternative targets are needed in order to treat chronic
biofilm infections.
3 Novel Treatments
As stated by (Høiby et al. 2010 ), the first and preferred strategy against biofilm
infection would be to prevent invading bacteria from forming aggregates. Since the
aggregates show increased tolerance to both antibiotics and the immune system,
development of drugs that impede surface attachment or other specific events in the
early stages of aggregation may keep infecting bacteria in a planktonic, susceptible
state (Bjarnsholt et al. 2005a , b ). Killing infecting bacteria has long been the
preferred strategy. This has been achieved by conventional antimicrobials targeting
basal life processes of the bacteria. But the dissemination of resistance and the lack
of new antimicrobials have initiated the search for new strategies. It is generally
accepted that the application of lethal or growth inhibiting compounds will impose
a selective pressure upon the bacteria resulting in resistance genes and hence a
purification in the population (Nnis System 2004 ; Clatworthy et al. 2007 ; Hawkey
2008 ; Spellberg et al. 2008 ; Boucher et al. 2009 ). Therefore, a constant develop-
ment of new drugs is essential, as drugs already in use become obsolete.