Biomedical Engineering Reference
In-Depth Information
4.1 Conventional Antifungal Agents
As mentioned before, fungal cells within biofilms display dramatically reduced
susceptibility to most conventional antifungals, perhaps with the exception of
echinocandins. They are up to 1,000 times more resistant to azole derivatives,
and they also showed decreased susceptibility to polyenes as compared to their
planktonic counterparts (Chanda and Caldwell
2003
; Ramage et al.
2001a
). In truth,
polyenes such as amphotericin B and nystatin exhibit biofilm activity; but unfortu-
nately they do so at concentrations which are exceedingly high and generally
considered unsafe due to their intrinsic toxicity (Ramage et al.
2002c
). However,
liposomal formulations of amphotericin B display unique efficacy against
Candida
biofilms (Kuhn et al.
2002
), most likely due to their improved safety profile and
perhaps enhanced penetration due to encapsulation. Very importantly,
echinocandins display excellent anti-biofilm activity at therapeutic concentrations
(Bachmann et al.
2002
; Kuhn et al.
2002
; Ramage et al.
2002c
). Initial experiments
with caspofungin (the first echinocandin to reach the market) demonstrated its
excellent in vitro activity against
C. albicans
biofilms, and soon after was corrob-
orated for micafungin, anidulafungin, and non-
albicans Candida
spp. (Kucharikova
et al.
2011
). These observations were further extended to in vivo animal models and
to clinical experience with patients (Kucharikova et al.
2010
,
2013
; Tumbarello
et al.
2012
). Thus, the excellent anti-biofilm activity of echinocandins has been one
of the main factors for them to become first line therapy against candidiasis,
particularly when a biofilm etiology (i.e., catheter-related candidemia) is suspected
(Pappas et al.
2009
; Tumbarello et al.
2012
). Although these three echinocandins
are considered equally effective, a recent report described drug- and species-
specific differences in susceptibility among biofilms of different
Candida
spp.,
with
C. lusitaniae
and
C. guilliermondii
biofilms generally exhibiting reduced
susceptibility (Simitsopoulou et al.
2013
). Also, it is important to note that the
anti-biofilm activity of echinocandins is not universal, as other fungal biofilms,
such as those formed by
A. fumigatus
, are relatively resistant to treatment with this
new class of antifungal agents (Fanning and Mitchell
2012
; Ramage et al.
2012
).
4.2 Combination Therapy
The existence of different classes of antifungal drugs with different molecular
targets opened new possibilities for combination therapy against fungal biofilms.
An in vitro study using fluconazole, amphotericin B and caspofungin against
Candida
biofilms pointed towards indifference for all antifungal combinations
tested (Bachmann et al.
2003
). However, the combination between amphotericin
B and caspofungin may benefit from a rapid initial killing by the polyene followed
by a more sustained effect by the echinocandin (Bachmann et al.
2003
; Ramage
et al.
2002c
). In contrast,
there was a trend towards antagonism with the
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