Pharmacology & Pharmacy, 2011, 2, 354-360
doi:10.4236/pp.2011.24046 Published Online October 2011 (http://www.SciRP.org/journal/pp)
Basic Research―Significance of Detection and
Clinical Impact of Candida albicans in
Non-Immunosuppressed Patients
Petra Heizmann1, Frank Klefisch2, Wolfgang R. Heizmann3
1St. Wolfgang Clinic, Internal Medicine, Bad Griesbach, Germany; 2Paulinenhaus Krankenanstalt e.V., Berlin, Germany; 3Centre for
Medical Microbiology and Infectiology, Berlin, Germany.
Received May 15th, 2011; revised September 14th, 2011; accepted September 30th, 2011.
ABSTRACT
Background: The clinical significance of the detection of Candida albicans on mucous membranes of the respiratory or
intestinal tract from patients in intensive care units is still not finally clarified. Many patients reveal colonization, al-
though, despite increased risk, there are only a few invasive infections detectable. Therefore, antimycotic therapy in this
setting is strongly discouraged. In reality, however, many patients receive antimycotics as a pre-emptive therapy. To
elucidate this point, a literature research was performed. Results: In the light of new results on the pathogenicity of C.
albicans, the recommendation not to treat should be discussed anew. Without becoming invasive, C. albicans influences
the immune system negatively in an anti-inflammatory sense (Th2) by means of at least two distinct mechanisms [action
on toll like receptors (TLR), production of farnesol], which will be discussed. Conclusion: It is believed that patients in
the phase of CARS or MARS can be further endangered by concomitant colonization of mucous membranes by C. albi-
cans, i.e., in the sense of an anti-inflammatory immune response. Treatment with azole preparations, like fluconazole,
which interacts with ergosterol synthesis in this phase of the disease, may trigger an additional effect on the patient,
through increase of farnesol concentration by way of a negative feedback. Results of animal experiments on the immune
system and concomitant therapeutic consequences indicate the need for verification through clinical trials.
Keywords: Candida Albicans, Farnesol, Azole, Echinocandin, TLR, Immune Answer, Th Cell
1. Introduction
“The diagnosis of pulmonary moniliasis (C. albicans-
Infection) is fraught with difficulties … Actually there
are no indisputable criteria for establishing the diagno-
sis…” [1]. Even after 50 years the clinical significance of
a detection of Candida in the respiratory or intestinal
tract is greatly disputed. Based on the results of studies
performed on non-neutropenic patients, the detection of
Candida species in specimen of the deep respiratory tract,
even in high concentrations, is regarded as colonization
of mucous membranes rather than invasive infection [2],
Therefore, in many cases, administration of anti-fungal
drugs is regarded as unwarranted and expensive [3].
On the other hand, colonization of mucous membranes
represents a significant risk factor for invasive Can-
dida-infections [4-6]. For example, in a previous study,
growth of Candida in at least one specimen was positive
in 215 of 357 patients (60.2%) [7]. Candida was mostly
detected in secretions of the respiratory tract (49.8%), in
rectal smears (48.3%) and in wounds (20.1%). The rela-
tive part of Candida albicans was 72%, Candida gla-
brata 16%, Candida tropicalis 5%, Candida parapsilosis
3% and Candida krusei 2%. A colonization—particularly
in several localizations—together with other risk factors
such as loss of skin and mucous membrane barrier func-
tion, major surgical procedures (in particular abdominal),
burns, total parenteral nutrition, acute renal failure and
haemodialysis, high APACHE II scores, antacids and
artificial respiration can contribute to an increased risk of
invasive Candida infections. However, the number of
proven invasive infections (detection in blood cultures,
Candida endophthalmitis, growth from usually sterile
specimen such as pleural or peritoneal fluid) based on the
number of patients with colonization, is rather rare. Of a
total of 1669 patients, 719 patients had no colonization or

Basic Research—Significance of Detection and Clinical Impact of Candida albicans in 355
Non-Immunosuppressed Patients
infection; in 883 patients colonization was detected, but
only 97 patients (5.8%) had an infection [8].
Consequently the conclusion seems obvious: detection
of Candida from the deep respiratory or intestinal tract
has no further significance for affected patients, unless
they have additional risk factors for an invasive infection
e.g. colonization in multiple body sites. Nevertheless,
based on personal experience, a large number of ICU
patients are treated with antifungals without detection of
an invasive infection. The question arises as to whether a
pathogenic correlation does exist that justifies the “em-
pirical therapy” (better: prophylaxis or “pre-emptive the-
rapy”).
2. Material and Methods
A literature review was performed using PubMed and the
following key words: Candida albicans, immune system,
therapy, fluconazole, echinocandin, farnesol, TLR.
3. Results from Basic Research
3.1. An Alternative Way for Pathogenesis
To be clinically relevant, C. albicans would have to pos-
sess virulence factors that can negatively influence the
homeostasis in a patient, independently from an invasion.
A connection between C. albicans and the develop-
ment of an allergic reaction of the respiratory system has
already been postulated over 50 years ago [1]. First pub-
lications of systematic studies on this topic appeared al-
most 20 years ago. In 10 out of 13 children with allergic
asthma and C. albicans specific IgE antibodies a reaction
with Candida antigen of 46 kDa was detected [9]. In an
additional study, sera from 105 patients with C. albicans-
specific IgE antibodies reacted with 42 different candida
antigens in the immunoblot—42% with the 46 kDa anti-
gen and 28% with a 27 kDa antigen [10]. According to
Ito K. et al. [11], the 46 kDa antigen is an enolase; anti-
bodies directed against enolase were detected in 37% of
patients, all positive for C. albicans IgE antibodies.
The detection of C. albicans-specific IgE antibodies
indicates that the immune system reacts to a C. albicans
antigen stimulus with a Th2 (“anti-inflammatory”) re-
sponse. In animal experiments, the administration of IL-4
and IL-10 (Th2) was the reason for a fatal progression
which was linked to the inhibition of IL-12 and a
Th2-dominance [12]. In 1999, Talluri G et al. [13] could
demonstrate, in patients with candiduria and candidemia,
that the production of interleukins of the Th2 cell lineage
(IL-4, IL-10; “anti-inflammatory”) was increased and
that the IL-2 concentration (Th0, Th1, “inflammatory”)
was decreased. The immune system of patients with
symptoms of chronic mucocutaneous candidiasis also
shows a shift of the T-cells towards the Th2-population
[14]. This anti-inflammatory response of the immune
system with a prevalence of the Th2-cell lineage results
in insufficient or no elimination of pathogens, and there-
by in a relative immune weakness.
3.2. Growth Form of C. albicans and Immune
Response
There are two different types of C. albicans growth forms:
yeast cells (blastoconidia) and hyphae, which can alternate
depending on the external conditions (see below). There-
fore, a differentiation between these two forms is signifi-
cant as this controls the interaction between micro- organ-
isms and the immune system.
The production of various interleukins as a reaction to
C. albicans antigen is controlled by toll-like receptors
(TLR) of antigen presenting cells. In animal testing, mice
with and without TLR2 were infected with C. albicans.
In this case, mice without TLR2 (TLR2–) survived longer
than those with TLR2 (TLR2+), the colony counts in the
kidneys of TLR2–-mice was lower by a factor of 100 (p <
0.01). At the same time, the IL-10 production in TLR2–-
mice was reduced, the IFN-γ concentration increased and
the destruction of Candida by macrophages improved
[15]. IL-10 appears to be a key to the immune defence of
C. albicans infections. In the event of a systematic infec-
tion, knockout mice without IL-10 production were able
to eliminate significantly more C. albicans cells in the
kidneys than controls with IL-10 production (p > 0.05).
This phenomenon could be caused by a direct influence of
IL-10 on the function of neutrophilic granulocytes [16].
The stimulation of dendritic cells with zymosan (de-
rivative of yeast cell walls) leads to an induction of
IL-10- and of TGF-β (transforming growth factor beta),
with simultaneous suppression of IL-12, IL-6 and TNF-α
(pro-inflammatory), whereby both TLR-2 (as heterodi-
mers together with TLR-6) and Dectin-1 control the sig-
nal transduction [17,18].
According to the model of Van der Graaf [19], the
growth form of C. albicans significantly influences the
immune response. If the cell grows as blastoconidium
(yeast cell), it interacts with TLR4 of antigen-presenting
cells. This trigger leads to a pro-inflammatory (Th1) re-
sponse with a significant increase of IFN-γ and TNF-α.
However, if C. albicans switches to the hyphal form, the
anti-inflammatory (Th2) response overbalances with an
increase of IL-10 production controlled by TLR2.
3.3. C. albicans and Farnesol Formation—
Impact on the Immune System
C. albicans produces a lipophilic substance called farne-
sol. Farnesol is produced from farnesyl diphosphate, a

Basic Research—Significance of Detection and Clinical Impact of Candida albicans in 356
Non-Immunosuppressed Patients
molecule that interestingly represents a precursor of cho-
lesterol in humans, ergosterol (cell membrane) in yeasts
and staphyloxanthin (yellow pigment, virulence factor) in
Staphylococcus aureus. For C. albicans, the E,E-Isomer
has the function of a “quorum sensing molecule” (QSM),
i.e., it is significant for the communication of yeast cells
amongst each other and, for example, controls the transi-
tion of the blastoconidia to the hyphal form [20], de-
pending on time of exposure. In addition, the lipophilic
farnesol interacts with host cell membranes, i.e., it can
possibly make way for an invasive infection. It also in-
terferes with the immune response and protects C. albi-
cans from the impact of oxygen radicals [21,22]. In
physiological concentrations, farnesol reduces the effect
of H2O2 on the Candida cell, strains with farnesol pro-
duction are ~20 times more resistant than strains without
[23,24].
In an animal model, mice infected with farnesol pre-
treated or farnesol-producing C. albicans strains die
more quickly [25,26]. In the control group with C. albi-
cans knockout strains without farnesol production, the
survival rate was significantly higher (p < 0.0014). Far-
nesol actually suppresses the production of IL-12 and
IFN-γ, both necessary for an adequate defence against C.
albicans infections (Th1) and it also increases the IL-5
level (Th2) [22].
In addition, farnesol modulates the expression of genes
(TUP1, CRK1, PDE2) which regulate the hyphal forma-
tion in terms of an increased formation of hyphae [27].
These experimental data show that C. albicans has a
negative impact on the immune system (growth in hyphal
form and interaction with TLR2; farnesol production)
with a shift of the T-cell response towards Th2 (anti-
inflammatory), independent from invasiveness.
3.4. Factors That Can Impact the Production of
Farnesol through C. albicans
As mentioned previously, farnesol is generated from two
molecules of farnesyl diphosphate. Farnesyl diphosphate
is an early precursor in the synthesis of ergosterol, a sig-
nificant part of the cytoplasmic membrane of yeast cells.
If C. albicans cells are exposed to azoles, the farnesol
production increases significantly. This effect is also
used in the various previously described infection models
[23,25,28]. As azoles, e.g., fluconazole are inhibiting the
ergosterol synthesis through inhibition of the lanosterole
14-α-demethylase, a negative feedback must be pre-
sumed. Clinical isolates of C. albicans strains produce 2
to 4 µM farnesol with a cell density of 108 cells/ml. Un-
der the influence of subinhibitory concentrations of sub-
stances which, like azoles, inhibit the sterol biosynthesis,
the production increases by the factor of 10 - 45 [27]. Abe
et al. (2009) were able to demonstrate that farnesol con-
centrations of ~56 µM and higher suppress the inhibitory
activity of macrophages on hyphae formation of C. albi-
cans and also leads to an apoptosis of the macrophages
[29]. Evidently, farnesol also increases the apoptosis of
cells of an oral squamous epithelial carcinoma cell line
[30].
3.5. Mucous Membranes Intersection—
C. albicans and the Local Immune System
Anaerobic conditions, as they exist in biofilms on mu-
cous membranes, lead to a growth of C. albicans in hy-
phal form, the growth form that controls the anti-in-
flammatory shift of T-cells via TLR2. In experimentally
produced biofilms, antifungal drugs such as amphotericin
B, clotrimazole, fluconazole, miconazole and ketocona-
zole do not inhibit the growth of C. albicans [31]. The
only effect of the azole would therefore be the increase
of farnesol concentration with subsequent suppression of
IL12 and IFN-γ. In fact, in the model of a mucocutaneous
Candida infection, the suppression of inflammatory leu-
kocytes could be observed [32]. This is also true in re-
current vulvovaginal candidosis [33].
Candida cells incorporated in biofilms of mucous
membranes e.g. of the gut are in close contact to the mu-
cous membrane-associated immune system (MALT). The
M-cells of the MALT are situated at the boundary sur-
face both exogenously (gut lumen) and endogenously in
close contact with the micro-organisms existing in the
gut lumen, like hyphae of C. albicans. Without having to
become invasive, C. albicans can control the differentia-
tion of Th0-cells towards Th2-cells via the TLR2 of
M-cells [34] in this situation [19]. Animal testing actu-
ally demonstrates that the immune system of the intestine
is able to influence cytokine levels in lymph nodes and in
the blood [35].
In the model of the gastrointestinal Candida infection,
the administration of IL-10 and IL-4 lead to an induction
of CD4+ cells in the Peyer’s patches with production of
high levels of IL-10 and IL-4 [12]. At the same time, this
negative effect on the immune system is increased
through farnesol (Figure 1).
4. Possible Effects for Patients
The colonization of patients with high C. albicans cell
counts is in most cases an event of a prolonged hospital
stay, often also the result of a previous or existing antibi-
otic treatment [36,37]. However, this means that the af-
fected persons could be in a CARS or MARS condition
[38]. In this phase, multiple organ dysfunctions or organ
failure could occur, the condition of the patient deterio-
rates and the fatalities could increase [39].

Basic Research—Significance of Detection and Clinical Impact of Candida albicans in 357
Non-Immunosuppressed Patients
Blastoconidi
a
TLR 4 TLR 2
Antigen-presenting
cell
Hypha
Th1-answer
inflammatory
IL-10 
Th2-answer
anti-inflammatory
Farnesol-diphosphate
Farnesol
IL-5 IL-12 
Figure 1. Impact of C. albicans on the immune system. Blas-
toconidia cause the stimulation of the inflammatory Th1
response by TLR4 mediated activation of antigen-pre-
senting cells. Hyphae stimulate TLR2 signalling and pro-
duction of IL-10 which promotes an anti-inflammatory Th2
response. Farnesol leads to up-regulation of IL-5 and down-
regulation of IL-12 and IFNγ promoting the Th2 response.
In patients with a colonization of the mucous mem-
branes through C. albicans, the immune system could be
weakened via the above-mentioned mechanisms during
this critical period of illness. If it is now decided—often
also because previous antibiotic treatments have not re-
sulted in an improved clinical condition—to eliminate
the yeasts by administering antifungal drugs, fluconazole
is often selected nowadays.
However, this decision in particular could be associ-
ated with serious disadvantages for the patient, in light of
the illustrated pathogenic processes. In the case of a sep-
sis through a Gram-negative pathogen like Escherichia
coli, the production of IL-12 usually increases via the
release of liopolysaccharides of the cell wall. A Th1-
response develops that leads to an inflammatory response
and therefore to elimination of the pathogen. However,
Navarathna et al. [26] demonstrated in their experiment
that, under the influence of farnesol, this IL-12 stimula-
tion remains absent: therefore, a significant function of
the immune system fails (Table 1).
5. Conclusion and Therapeutic
Consequences
Basic research of previous years has demonstrated how
actively C. albicans can impact the host immune system
via TLR and farnesol production in terms of an anti-in-
Table 1. Changes of the IL-12 production under the influence
of LPS, IFN-γ and farnesol [26].
Average IL-12 production (pg/ml)
Pre-treatment
p40 p70
None 1.5 4.25
Farnesol (100 µM) 0.33 2
IFN-γ + LPS 3215 40.8
Farnesol + IFN-γ + LPS 1.7 7.1
flammatory (Th2) immune response. Thus, the detection
of C. albicans on mucous membranes obtains—at least in
some patients—a completely new, clinically relevant sig-
nificance. Precisely in those patients who are in the phase
of CARS or MARS with reduced cellular defence, an
increase of this process in phases with bacterial translo-
cation could lead to a worsening in the course of the dis-
ease.
Due to the results of basic research, a rational basis
exists nowadays to treat these patients with antifungal
drugs in order to interrupt the pathogenic process of the
immune modulation. Azole should subsequently not be
prescribed for critically ill patients as this would result in
an increase of farnesol formation by a negative feedback
through inhibition of the ergosterol synthesis.
Contrary to azoles, echinocandins like caspofungin or
anidulafungin do not inhibit the ergosterol metabolism of
C. albicans and are effective in biofilms [40]: C. albicans
is eliminated without directly resulting in an increase of
the farnesol concentration through negative feedback.
In addition, echinocandins possess a further significant
property. They interfere with the cell wall of C. albicans,
which mainly consists of β-glucans and that have an im-
pact on the immune system in terms of a pro-inflamma-
tory response. However, this characteristic does not usu-
ally occur as the β-glucans are not accessible to the im-
mune system through an external mannan layer. Only
when C. albicans cells are exposed to sub-inhibitory
concentrations of caspofungin the level of TNFα (Th1-
response) increases three to four times under experimen-
tal conditions, in comparison to untreated Candida cells
[41].
The model presented here—immune modulating effects
of C. albicans—could also explain the debated superior
clinical outcome of anidulafungin in comparison to flu-
conazole in C. albicans infections [42].
Of specific interest are future clinical studies in which
the design is applied such that it can demonstrate which
patients with C. albicans colonization ideally benefit
from an echinocandin therapy.

Basic Research—Significance of Detection and Clinical Impact of Candida albicans in 358
Non-Immunosuppressed Patients
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Abbreviations
CARS Compensatory anti-inflammatory response syn-
drome
GOLD Global Initiative for Chronic Obstructive Lung
Disease
ICU Intensive care unit
Ig Immunoglobulin
IL Interleukin
IFN Interferon
CFU Colony forming units
LPS Lipopolysaccharide
MARS Mixed anti-inflammatory response syndrome
TGF Tumour growth factor
Th T helper cells
TLR Toll like receptor
TNF Tumour necrosis factor