mycoses

Diagnosis,Therapy and Prophylaxis of Fungal Diseases

Review article

Practical considerations on current guidelines for the management of

non-neutropenic adult patients with candidaemia
A. Glockner1 and O. A. Cornely2
1

BDH-Klinik Greifswald, Germany and 2Department I of Internal Medicine, Clinical Trials Centre Cologne, ZKS Koln, BMBF, Center for Integrated Oncology CIO
KolnBonn, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), German Centre for Infection Research, University of
Cologne, Cologne, Germany

Summary

Recent guideline recommendations on the management of candidaemia provide

valuable treatment guidance for routine clinical practice, but need to be interpreted in
the light of the actual situation of the patient and the local epidemiology of fungal
infections. Echinocandins emerge as the generally preferred primary treatment.
Treatment should be initiated immediately after notification of a Candida-positive blood
culture in all patients. Ambiguous issues include the definition of optimum duration of
treatment, the indication and time point to step down to oral azoles, catheter
management, and the appropriate approach in critically ill patients at high risk for
candidaemia in the absence of definitive proof of infection. Patients with clinical
suspicion of antifungal treatment failure need prompt workup for adequacy of
treatment, focal sources of sustained infection and potential superinfection.

Key words: candidaemia, treatment, guideline, echinocandin, azole.

Introduction
Candidaemia is a potentially devastating bloodstream
infection with Candida spp. predominantly affecting
hospitalised, severely ill patients. Candida spp. has been
implicated in up to 9% of cases in a large survey of over
24000 blood stream infections.1 Major risk factors for
candidaemia in non-neutropenic patients include gastrointestinal perforation, recent abdominal surgery,
prolonged stay on intensive care units, compromised
immune system, treatment with broad spectrum antibacterial agents, malignant diseases, organ dysfunction,
the extremes of age, central venous catheters and
Candida colonisation. Despite substantial advances in
antifungal agents and treatment strategies, candidaemia remains associated with high mortality. The
overall mortality is reported at 3060% and attributable
mortality rates of 2540% have been estimated.16
Correspondence: A. Glockner, BDH-Klinik Greifswald, Karl-Liebknecht-Ring
26a, 17491 Greifswald, Germany.
Tel.: +4 938 348 71231. Fax: +4 938 348 71226.
E-mail: a.gloeckner@bdh-klinik-greifswald.de

Submitted for publication 16 December 2011

Revised 28 March 2012
Accepted for publication 4 April 2012

 2012 Blackwell Verlag GmbH

Candidaemia may cause severe sepsis and septic shock

leading to multiorgan failure and death.7 Other complications include deep organ invasion, endocarditis and
septic thrombosis. Optimising the outcomes of candidaemia, particularly in critically ill patients, requires the
timely initiation of adequate antifungal therapy.8
Four international expert panels of medical societies
have recently issued guidelines that include recommendations on the management of candidaemia in nonneutropenic non-haematological adult patients. The
Infectious Diseases Society of America (IDSA) practical
management guidelines of 20099; the guidelines of the
4th European Conference on Infections in Leukemia
(ECIL-4) of 2011,10 the recent candidiasis guidelines
presented in 2011 by the European Fungal Infections
Study Group (EFISG)11 of the European Society of
Microbiology and Infectious Diseases (ESCMID), and the
joint candidiasis guidelines of the German-speaking
Mycological Society and the Paul Ehrlich Society
(DMYKG PEG)12 (Table 1). Note that the EFISG guidelines and the latest version of the ECIL guidelines are not
yet published as full papers and may be subject to
changes. These four guidelines are useful because of
their evidence-based approach that involves comprehensive appraisal of the available data supporting the
recommendations.

doi:10.1111/j.1439-0507.2012.02208.x

A. Glockner and O. A. Cornely

Table 1 Therapeutic recommendations for candidaemia in non-neutropenic adult patients without upfront information on Candida species
and or susceptibility.

IDSA [9]

ECIL-4 (for overall

population) [10]

EFISG (ESCMID) [11]

DMYKG PEG [12]

All pts with Candida-positive
blood culture
EC or FLC
L-AMB alternative in
critically ill pts
FLC: avoid after azole
prophylaxis and in critically
ill pts
14 d after first negative
blood culture
AND
complete resolution of all
signs and symptoms
attributable to
candidaemia

Indication for
antifungal therapy
Preferred first line
therapy

All pts with Candidapositive blood culture

EC or FLC

All pts with Candidapositive blood culture

EC or L-AMB or FLC or
VORI

All pts with Candidapositive blood culture

EC

Criteria for choice

of drug

EC: moderately to severely

ill, recent azole exposure
FLC: less severely ill
2 weeks after
documented clearance
of Candida from
bloodstream
AND
resolution of symptoms
attributable to
candidaemia
Recommended, with
daily or every other
day sampling
May step down to oral
FLC (or VORI) after
35 days of EC in
stable pts

FLC and VORI: avoid

after azole prophylaxis
FLC: avoid if severely ill
14 d after last positive
blood culture
AND
resolution of signs and
symptoms

Only EC as
recommended first
line therapy
14 d after end of
candidaemia

No statement

Recommended, with
daily sampling

No statement

After 10 d of IV therapy if
FLC-susceptible species
oral therapy tolerated
patient stable

Recommended in pts
receiving azoles or
AMB-D
Not recommended for
pts treated with EC
or L-AMB
Recommended

Duration of
therapy

Blood culture
monitoring on
therapy
Step down therapy
to oral fluconazole

Catheter
removal

Strongly
recommended

Recommended (always
if C. parapsilosis
detected)

Fundoscopy

Recommended; within
the first week of therapy

No statement

Recommended
No statement on
frequency
Optional after 10 d of IV
therapy if
negative blood cultures
proven susceptibility of
isolate
clinical stabilisation
ability to take oral
medication
unrestricted GI absorption
Recommended for all pts

Recommended; Prior to end

of therapy

pts, patients; EC, echinocandin; FLC, fluconazole; VORI, voriconazole; L-AMB, liposomal amphotericin B; IV, intravenous.

This article reviews important aspects of these current

guidelines for the management of candidaemia in
non-neutropenic adult patients from the clinicians
perspective, trying to (i) bridge gaps between the
evidence-based recommendations and their implementation in routine clinical practice, and (ii) discuss
feasible approaches and their limitations in areas where
guidance is currently inconclusive due to lack of
evidence.

Time of antifungal treatment initiation

Several analyses performed in the past years have
shown a dramatic effect of delays in the initiation of

adequate antifungal treatment on the mortality of

candidaemia patients, with extreme effects of even short
delays in those with Candida septic shock.1316
As a performance criterion of candidaemia management, the IDSA expert panel requests the initiation of
antifungal therapy in all candidemic patients within
24 h after a blood culture positive for yeast.9 This
suggestion appears clearly inadequate if it refers to the
time of the actual detection of Candida in the incubating
blood sample.
Rather, an immediate start of therapy after notification of Candida-positivity in a blood culture appears
necessary, since early treatment initiation increases
the probability of survival. Actually, this approach is

 2012 Blackwell Verlag GmbH

Practical considerations on current guidelines

recommended by the EFISG and the DMYKG PEG

guidelines.11,12
However, the median time to Candida positivity in
blood cultures is 32 h according to a recent analysis.17
This raises the issue of pre-emptive antifungal therapy
i.e. treatment initiation in the absence of culture positive
samples in non-neutropenic critically ill patients with
signs of severe sepsis and presence of risk factors for
invasive fungal infection.
Although the EFISG guideline panel voted against the
use of fluconazole in non-neutropenic adult patients
with APACHE II score >16 and fever despite broadspectrum antibiotics, it still argues that antifungal
therapy of high-risk patients with persistent fever of
unknown origin may be an option in patients at high
risk.11 This approach appears particularly appropriate if
such a patient develops severe sepsis or septic shock.
Risk scores based on clinical characteristics and
fungal colonisation insufficiently identified patients
who may benefit from early antifungal therapy based
on clinical features or surrogate fungal markers,
respectively, in the absence of positive fungal blood
culture.
The use of molecular markers of infection, i.e.
detection of fungal cell wall components (1,3-beta-Dglucan) or Candida nucleic acids (via PCR), is an
attractive approach to identify patients who might
benefit from early antifungal therapy. As far as beta-Dglucan is concerned this approach is only marginally
supported by the EFISG guidelines because of issues in
test performance, mostly false positivity due to difficultto-control confounding factors.11 Although generally
highly sensitive, PCR still lacks the degree of standardisation and validation required for its use in treatment
decisions for early antifungal therapy.
For the time being, initiation of a risk-based antifungal therapy while awaiting a blood culture result should
be considered for non-haematological patient groups
who have been shown to benefit from antifungal
prophylaxis, i.e. predominantly those with gastrointestinal anastomotic leakage or relapsed gastrointestinal
perforation.18
As Kumar et al. [15] impressively demonstrated in a
retrospective analysis of patients with septic shock, the
dismal survival rates of the subpopulation with fungal
sepsis were predominantly due to delays in treatment for
more than 26 h after onset of hypotension. Initiating
pre-emptive antifungal therapy within this window of
opportunity may thus be life saving for some patients
and may be used to buy time while additional
exploration of the causes of exacerbating sepsis is
undertaken.

 2012 Blackwell Verlag GmbH

Factors determining the initial choice of

therapy
Severity of illness

The current IDSA guidelines9 favour the use of echinocandins in moderately to severely ill patients without
giving a closer definition of these terms besides hemodynamic instability. Similarly, the ECIL-3 guidelines
discourage the use of fluconazole in severely ill
patients.11 The rationale behind these recommendations is recent data showing improved outcomes of
candidaemia in patients with early adequate therapy,
particularly in those with severe sepsis. As echinocandins have a broader spectrum of antifungal activity and
are considered fungicidal against many Candida isolates,
this class of antifungals should be preferred in critically
ill patients.
Traditionally, patients with hemodynamic instability,
i.e. those requiring vasopressors were considered as
being at highest risk for unfavourable outcomes of
candidaemia invasive candidiasis. However, this approach may be too narrow as it focuses on one single
systemic hallmark of severe infection. Rather the full
clinical picture and organ dysfunction pattern should be
considered.
Candidaemia patients with acute failure of one or
more organs should generally be considered as being
severely ill. Consequently, all patients treated on
intensive care units should be included into this
category and thus receive an echinocandin as the
primary treatment.
A randomised study comparing anidulafungin vs.
fluconazole for candidaemia showed a significantly
higher global success rate in the total population for
the echinocandin.19 In subgroup analyses, patients with
organ dysfunction (lung, kidney, liver or cardiovascular) had consistently higher global success rates in the
anidulafungin group.20 The difference was significant
for patients with APACHE II scores >15 and those with
severe sepsis and multiorgan dysfunction.20
On the basis of the results of this study 19 and the
cumulative experience with this class of antifungals
the EFISG panel chose to recommend echinocandins as
the class of choice (recommendation grade A; evidence
grade I) for primary targeted therapy of candidaemia in
all patients.11 We agree with the recommendation of
the EFISG, where fluconazole is no longer considered a
preferred option for the targeted initial treatment
of candidaemia. Its use is only marginally recommended (grade CI) due to its therapeutic inferiority to
anidulafungin.11

A. Glockner and O. A. Cornely

Pre-exposure to azole antifungals

Azole antifungals are commonly used as prophylactic

agents in patients at risk for invasive fungal infection or
as antifungal therapy for suspected mycosis. As the
widespread use of azoles may select for Candida strains
or species with reduced susceptibility to azoles,21
current guidelines recommend echinocandins for primary treatment in patients with recent history of
exposure (IDSA) or previous prophylaxis (ECIL-3)10
with azole antifungals, without giving a precise definition of these terms. The EFISG circumvents this issue as
it does not support primary use of azoles at all.11
Evidently, candidaemia after immediately preceding
prophylaxis, i.e. a breakthrough infection, requires the
use of a non-azole antifungal. But what about patients
who received azoles some time ago? As there are no data
available on the evolution of the species distribution of
colonising Candida after previous exposure to azoles in
individual patients, no inferences can be made regarding a safe interval between the previous azole use and
the current candidaemia episode.
It thus appears that all candidaemia patients ever
having received prophylactic azoles may be excluded
from primary therapy with an azole antifungal. The
term recent exposure to an azole used by the IDSA
panel is poorly defined and requires interpretation.9 A
recently published multicentre analysis of 2441 yeast
bloodstream infections in France revealed a significant
association of infection with isolates of reduced fluconazole-susceptibility and pre-exposure to fluconazole
within 30 days before the current episode.22 Thus, it is
reasonable to exclude at least those patients from
primary treatment with fluconazole who received any
amount of azoles in the preceding month.
Other factors predisposing for infection with
fluconazole-resistant Candida

According to the IDSA guidelines, elderly patients, those

with malignant disease and patients with diabetes
mellitus should not receive fluconazole initially, as these
factors favour infection with C. glabrata.9 This recommendation may be extended to include patients with
previous hospitalisation because they are at increased
risk of being colonised by C. glabrata.23
Candida species

As of the reasons for the downgrading of fluconazole as

an option for first-line therapy of candidaemia, the
EFISG cited the limited spectrum of antifungal activity

and a high likelihood of insufficient susceptibility of

C. glabrata and C. krusei, in particular.11 With respect to
the infecting Candida species, the IDSA as well recommends to prefer an echinocandin in patients with
C. glabrata (or C. krusei) infection.9 Thus, using echinocandins in blood stream infections with these species
appears to be a general consensus.
On the basis of low-level evidence the IDSA panel
states that C. parapsilosis infections should preferably be
treated with fluconazole. This notion is not supported by
the EFISG experts who generally prefer echinocandins
for initial therapy, and only marginally consider the use
of fluconazole as an option for documented C. parapsilosis candidaemia (grade of recommendation C; evidence
level I).11
According to the IDSA guidelines, candidaemia due to
C. albicans, C. tropicalis and C. parapsilosis may be
treated with fluconazole in less critically ill patients.9
However, it should be kept in mind that Candida
speciation is not absolutely predictive of fluconazole
susceptibility. Firstly, while isolates of C. albicans,
C. tropicalis and C. parapsilosis are susceptible to fluconazole in the majority of cases, this is not always the
case. In a recent survey, Oxman et al. [24] found that
these species comprised 36% of the isolates with reduced
fluconazole susceptibility and 48% of the resistant
isolates. Eight per cent of C. albicans showed reduced
susceptibility to fluconazole. Therefore, the local fungal
epidemiology with respect to resistance must be monitored and considered in treatment decisions. While in
microbiological surveys the great majority of C. albicans
isolates are susceptible to fluconazole it should be kept in
mind that also in candidaemia with fluconazole-susceptible fungal species, data from the phase III trial of
anidulafungin vs. fluconazole19 indicate that an echinocandin appears to be the superior choice even in less
critically ill patients, as in the subpopulation with
APACHE II scores <20, the anidulafungin group had a
20% higher global success rate at the end of intravenous therapy (81% vs. 61%).
Regarding C. parapsilosis, the IDSA guidelines argue
that this species has less in vitro susceptibility to
echinocandins.9 However, clinical studies including
the recent ICE trial25 of anidulafungin in intensive care
patients with invasive candidiasis do not support the
notion that infections with C. parapsilosis are less
effectively treated by echinocandins than those with
other species. Moreover, Pfaller et al. did not find any
C. parapsilosis isolates resistant against echinocandins in
analyses blood stream isolates from a large surveillance
programme.26,27 Therefore, using echinocandins in
known C. parapsilosis infections may be a valid option

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Practical considerations on current guidelines

given the fact that C. parapsilosis causes 13% of all

candidaemias in Europe28 and echinocandins are recommended by the IDSA and EFISG as first-line therapy
in severely ill patients in the absence of species
information. As resistance of clinical Candida isolates of
different species is being described for echinocandins as
well,29 susceptibility testing appears prudent if therapeutic failure is suspected.
When interpreting susceptibility data, the recently
revised breakpoints for fluconazole and echinocandins of
the European Committee on Antimicrobial Susceptibility
Testing (EUCAST) and the US Clinical Laboratory
Standards Institute (CLSI) for antifungal susceptibility
testing should be considered.3032 The new values are
based on epidemiological data on susceptibility distributions of wild-type isolates. Fluconazole breakpoints
issued by the EUCAST are now considerably lower than
the former values without changes in the underlying
testing methodology. This fact may lead to reduced rates
of isolates classified as susceptible to fluconazole and
may further restrict its usefulness in clinical practice.
Due to the generally low and inconsistent activity of
fluconazole against C. glabrata, the EUCAST generally
discourages the use of fluconazole for infection with this
species and therefore did not issue a breakpoint for
C. glabrata. The CLSI breakpoints for echinocandins now
reflect species- and drug-specific differences in wild-type
distributions that should be respected when interpreting
susceptibility data. The EUCAST has not completed the
process of breakpoint definition for echinocandins yet.
The available values for anidulafungin are speciesspecific as well.

Catheter management
As stated in the IDSA guidelines and confirmed by
similar recommendations of ECIL and DMYKG PEG a
central venous catheter (CVC) should be removed in
patients with candidaemia whenever possible, given the
role of catheters as a reservoir for Candida spp. in
biofilms33,34 and a potential source for persistent
candidaemia.35
Analyses of data from recent studies and several older
investigations suggested more favourable outcomes;
lower mortality and shorter duration of candidaemia
in patients who have their CVC removed early, i.e.
72 h after onset of candidaemia.3640 On the basis of
this evidence, the EFISG as well recommends the
removal of indwelling vascular access lines at least for
patients receiving azoles or amphotericin B deoxycholate (grade BII).11 For patients receiving echinocandins
this may not be as crucial as removal of indwelling

 2012 Blackwell Verlag GmbH

lines within 48 h after treatment initiation was not

associated with a higher survival rate.
However, some studies that attempted to adjust their
analyses for potential confounders4144 and particularly
a recent multivariate analysis of data from two phase III
trials performed by Nucci et al. [45] did not find any
benefit of early catheter removal. This somewhat
unexpected result may actually relate to the fact that
both trials underlying the analysis by Nucci and
colleagues involved drugs with known activity against
biofilm-associated sessile Candida cells (echinocandins
or liposomal amphotericin B),4649 potentially making
catheter removal a less critical factor. Nonetheless, as
prospective studies on the benefits of catheter removal
are lacking and probably may not be feasible at all it
appears prudent to remove CVCs in candidaemia
patients whenever possible.
It may be argued that patients with CVCs usually
have their catheters for a reason. Early replacement
rather than omission of the catheter will therefore be
required in many situations. Catheter replacement in
situ via a guide wire is inadequate due to the risk of
reseeding the new catheter with Candida. The following
approach appears reasonable: after removal of the
indwelling catheter, the new catheter should be inserted
via de-novo puncture at a different body site, avoiding
the groin if possible. To further reduce the risk of
recolonisation of the new catheter, it may be preferable
to do the replacement after administration of the first
dose(s) of the antifungal via the old catheter, allowing
for reduction of the overall fungal load. In patients who
can be managed by peripheral venous access for a short
interval, a hiatus of one day between CVC removal and
reinsertion may add to the protection of the new
catheter. It should be evident that patients who require
reinsertion of a new catheter and those in whom an
indwelling CVC or other implanted devices cannot be
removed at all should be treated with antifungals active
against biofilm-associated Candida, i.e. an echinocandin
or liposomal amphotericin B, a notion that is consistent
with the current EFISG guidelines.
In routine clinical practice, the fate of a central
venous catheter will often be determined before the
causative pathogen of a developing clinical sepsis can be
identified, making the considerations discussed above
less critical.
As a bottom line it may be concluded that catheters
and other indwelling devices should be removed or
replaced whenever possible and as early as feasible. An
echinocandin or liposomal amphotericin B should be
used if a catheter or other device in the blood stream
must absolutely be left in place. To avoid creating a safe

A. Glockner and O. A. Cornely

haven for fungi in biofilms, the antifungal should then

in theory be administered through all lumina which
appears challenging from a practical point of view.

Blood culture monitoring on antifungal

treatment
In the absence of sufficiently validated reliable molecular or surrogate markers positive blood culture
remains the diagnostic tool in Candida blood stream
infection and blood culture monitoring is a major factor
guiding treatment decisions after initiating antifungal
therapy, particularly with respect to treatment response
and duration. The IDSA expert panel recommends
drawing blood samples for follow-up blood cultures
daily or every other day, whereas the EFISG prefers daily
sampling.11
In our view, the frequency of sampling may be
reduced after 5 days, as 80% of patients had negative
cultures after this treatment period in the randomised
trials. However, as blood culture negativity is a
requirement for treatment discontinuation and or step
down to oral therapy, it may still be cost-effective to
have high-frequency sampling in the whole time period
up to the first negative blood culture.

Duration of therapy
On the basis of the treatment duration defined in the
protocols of clinical trials, the guidelines recommend
duration of therapy of two weeks (14 days) after (i) the
resolution of symptoms and (ii) the end of candidaemia
whereas the latter is not uniformly defined. The most
unequivocal definition is the first negative blood
culture as stated in the guidelines of IDSA and
DMykG PEG.12 The criterion of the last positive blood
culture is less robust as it depends in the frequency of
blood culture sampling. We therefore prefer using the
time of blood sampling for the first negative blood
culture as the starting point for the residual 2 weeks of
therapy.

Step-down therapy
According to the IDSA guidelines it is reasonable to
switch (step down) patients from an echinocandin to
oral fluconazole if they have an initial fungal isolate
likely to be susceptible to fluconazole (e.g. C. albicans,
C. parapsilosis, C. tropicalis) and if they clinically improved after initial intravenous echinocandin therapy.9
Similarly, the EFISG considers a step down to oral
fluconazole feasible after 10 days of intravenous anti-

fungal therapy adequate if (i) the species is susceptible to

fluconazole (ii) the patient is clinically stable and (iii)
tolerates oral medication.11
These recommendations aim at (i) a reduction of the
overall exposure to echinocandins, thus minimising the
selective pressure on fungal isolates with reduced
echinocandin susceptibility, (ii) the reduction of health
resource consumption (iii) simplification of therapy.11
Although the last two effects are undisputed, the effect
of shortening the echinocandin exposure on the risk of
emergence of resistant strains is less clearly established.
The step-down concept is based on several randomised trials50 which allowed for a switch to oral
fluconazole after at least 10 days of intravenous treatment with the respective study drugs if this was
clinically and microbiologically appropriate. The trial
protocols stated somewhat divergent requirements for
the switch that generally included the following:
ability to tolerate oral medication,
afebrile body temperature for at least 24 h,
most recent blood culture remaining negative for
Candida species (for at least 48 h in one study 50),
clinical improvement,
initial fungal isolate which is not C. glabrata or
C. krusei and tested fully susceptible to fluconazole.
It should be noted as a caveat that the evidence base
supporting the step-down concept is limited, as only 15
35% of the patients were actually switched to oral
therapy in these trials.19,50,51
As discussed above, Candida species determination is
not sufficiently predictive of fluconazole susceptibility.
Thus, susceptibility testing of the initial isolate is
explicitly recommended by the ECIL-3 before stepping
down to fluconazole.10
Besides the requirements listed above, signs of
improvement should additionally include the following:
reduced or resolved need of vasopressors (if initially
present), improvement of organ function and regression
of infection markers in the lab. The patient must have
adequate enteral absorption capacity. This will usually
be the case in those who mainly receive oral or enteral
nutrition and have no clinically relevant diarrhoea,
recurrent vomiting or evidence of ileus. In addition,
patients should not receive renal replacement therapies
to avoid the need of complex dose adjustments associated with fluconazole use in this setting. In addition,
hepatic dysfunction, potentially interacting concomitant medications and unremovable CVCs or devices may
limit the usability of azoles.
Although in the randomised trials, the step-down
option was limited to oral fluconazole, and the guidelines only mention this approach, a switch to an

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Practical considerations on current guidelines

intravenous azole may well be an option for patients

fulfilling the above-listed requirements with the exception of reliable enteral absorption. Both approaches
appear to be supported by the randomised trial conducted by Kullberg et al. [52], who compared voriconazole vs. amphotericin B followed by fluconazole for
candidaemia. In the comparator arm, patients switched
from amphotericin B to either intravenous or oral
fluconazole after a median of 4 days with evidence of
adequate treatment efficacy. Since the exposure of
intravenous fluconazole is at least equivalent to the
oral formulation, this approach appears adequate
regardless of the drug used for previous primary
therapy.
This finding relates to the unresolved issue of the
required minimal duration of initial echinocandin
therapy before the transition to oral fluconazole. The
above-mentioned echinocandin phase III trials required
10 days of randomised intravenous therapy. However
indicating the scarcity of data supporting this approach
the IDSA guideline panel discusses the possibility of
reducing the initial intravenous echinocandin treatment to 35 days in stable patients, thus restricting
this approach to less critically ill patients.
Davis et al. [53] recently presented a two-period
single-centre study comparing a retrospective period
one with unrestricted use of echinocandins (caspofungin or micafungin) for invasive candidiasis vs. an
interventional period two involving formal in-house
recommendations for a step down by day 5 from
intravenous anidulafungin to an oral azole (fluconazole;
or voriconazole for patients with C. glabrata or unknown
species) if certain criteria for oral treatment had been
met (negative blood cultures, functional gastrointestinal
tract, hemodynamic stability and improved clinical
profile including leucocyte counts and body temperature). The rate of patients receiving oral step-down
therapy was significantly increased in period two, the
duration of intravenous therapy and the total duration
of therapy were decreased, whereas the clinical success
rate remained unchanged, and hospital mortality
showed no significant difference. While the use of
historical controls and potential educative effects of the
intervention may have biased the results, these data
suggest that an early step down to an oral azole may be
feasible in certain patients without jeopardising outcomes.
The feasibility of an early intravenous-to-oral switch
strategy largely depends on the question if it requires a
negative blood culture, since it is a matter of debate after
which incubation time blood cultures should be
regarded as negative. Strictly speaking, this may require

 2012 Blackwell Verlag GmbH

a full week of no detectable growth. Negativity after

48 h of incubation as required in the randomised trial of
caspofungin vs. amphotericin B does not safely exclude
persistent candidaemia: in an analysis of fungal blood
culture dynamics, Taur et al. [17] reported incubation
times to Candida positivity >50 h in 14% of patients.
Based on these data, a switch to oral fluconazole after
less than 10 days (as required in the randomised trials)
would be feasible only in a minority of patients with
early clearance of the blood stream as the median time
to the first blood sample that remained culture negative
was 23 days in randomised trials.51,54
Therefore it may be questioned if documented blood
culture negativity is absolutely required for an early (i.e.
after <10 days of echinocandin therapy) switch to (oral)
fluconazole in patients fulfilling all the other criteria
mentioned above. Fluconazole may be regarded as
sufficiently effective in candidaemia patients after clinical
improvement on initial treatment with an echinocandin
if the initial isolate is fully fluconazole-susceptible.
However, no current comparative data support this
approach.

Differential use of echinocandins

In their therapeutic recommendations, the IDSA, ECIL3, EFISG and DMYKG PEG guidelines treat the individual echinocandins as largely interchangeable.912 However, there are some pharmacological differences that
may lead to a preference for the one or the other
echinocandin agent in individual patients.
Regarding the choice of initial therapy, the IDSA
recommendations largely focus on the distinction of
echinocandins vs. fluconazole.9 It therefore should be
kept in mind that only anidulafungin was studied in
direct head-to-head comparison vs. fluconazole.19
The European Medicines Agency recommended that
micafungin should only be used if other antifungals are
not appropriate due to a possible risk of liver tumours,
based on preclinical results seen in rats.55
Since anidulafungin has no known drug interactions57 it may be a preferred option for patients receiving
immunosuppressants that have been observed to interact with caspofungin (tacrolimus, cyclosporine) and
micafungin (sirolimus) or other potentially interacting
drugs (inducers of hepatic metabolism in the case of
caspofungin).36 Lastly, caspofungin and micafungin
have not been adequately studied in patients with severe
hepatic impairment (Child Pugh C cirrhosis) and their
use is discouraged for this population in the prescribing
information. Therefore anidulafungin may be preferred
in patients with high-grade hepatic cirrhosis.5557

A. Glockner and O. A. Cornely

No adequate study data are available for the preemptive use of echinocandins in non-neutropenic
patients at high-risk of candidaemia before positive
blood culture results are available. Therefore no distinctions between the individual agents can be made for
this treatment situation.

Clinical therapeutic failure persistent

candidaemia
The issue of therapeutic failure and persistent candidaemia is only addressed by the current guideline of
DMykG PEG. Given the considerable time lag between
blood sampling and culture positivity, assessing therapeutic failure should rely primarily on clinical rather
than microbiological criteria in critically ill patients. In
accordance with the DMYG PEG guidelines, we consider it appropriate to assess treatment response for
clinical failure after 72 h of treatment.
When pondering the decision to switch treatment
particularly if definite evidence of failure of the first lineagent to clear Candida from the bloodstream has not
been obtained yet clinicians should consider the
following questions: Is the primary therapy adequate in
terms of antifungal coverage and dosage? Was a central
venous catheter or another potentially infected device
left in place? Is there evidence of endocarditis, septic
thrombosis or an abscess that may continue seeding
fungal cells into the bloodstream? Is there evidence of
superinfection with other pathogens that may explain
the lack of clinical improvement? Is there an urgent
need of action due to increasingly severe sepsis?
While ensuring effective therapy is vital to prevent
deep organ dissemination, a premature switch may
expose the patient to unnecessary drug toxicity, as in
patients receiving primary treatment with an echinocandin, the most likely secondary option will be
liposomal amphotericin B.

Conclusions
Several recently published guidelines address the management of candidaemia in non-neutropenic adult
patients. While giving valuable guidance, the recommendations need to be interpreted in the light of the
actual clinical situation of a given patient.
Factors influencing the choice of initial therapy include
severity of illness, previous exposure to antifungals,
patient age, species of the initial isolate (if available) and
catheter issues. Antifungal therapy should be started
immediately after notification of positive blood cultures.
Pre-emptive antifungal therapy while awaiting a positive

blood culture result may be needed in severely ill high-risk

patients. In general, echinocandins emerge as the
preferred primary treatment option and should definitely
be used in more severely ill patients. Close blood culture
monitoring is advisable to inform on microbiological
efficacy and guide treatment duration. Treatment should
be continued for 14 days after the first negative blood
culture and resolution of signs and symptoms of infection.
To limit a selection pressure and reduce cost of treatment,
step-down therapy from an intravenous echinocandin to
an oral azole is desirable. The optimum time point
although remains unknown. Clinical suspicion of therapeutic failure should prompt early reconsideration of
treatment adequacy, search for a potential fungal focus,
and frequently a switch in antifungal class to prevent
persistence of infection and deep organ dissemination.

Disclosure
The authors were involved in the preparation of the
following guidelines: OAC: EFISG, DMykG PEG; AG:
DMykG PEG. AG is a consultant to Astellas, MSD, Pfizer
and served at the speakers bureau of Astellas, MSD,
Pfizer.
OAC is supported by the German Federal Ministry of
Research and Education (BMBF grant 01KN1106), has
received research grants from Actelion, Astellas, Basilea, Bayer, Biocryst, Celgene, F2G, Genzyme, Gilead,
Merck/Schering, Miltenyi, Optimer, Pfizer, Quintiles,
and Viropharma, is a consultant to Astellas, Basilea,
F2G, Gilead, Merck/Schering, Optimer, and Pfizer, and
received lecture honoraria from Astellas, Gilead, Merck/
Schering, and Pfizer.

References
1 Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP,
Edmond MB. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide
surveillance study. Clin Infect Dis 2004; 39: 30917.
2 Wey SB, Mori M, Pfaller MA, Woolson RF, Wenzel RP.
Hospital-acquired candidemia. The attributable mortality
and excess length of stay. Arch Intern Med 1988; 148:
26425.
3 Blot SI, Vandewoude KH, Hoste EA, Colardyn FA. Effects of
nosocomial candidemia on outcomes of critically ill patients.
Am J Med 2002; 113: 4805.
4 Voss A, le Noble JL, Verduyn Lunel FM, Foudraine NA, Meis
JF. Candidemia in intensive care unit patients: risk factors for
mortality. Infection 1997; 25: 811.
5 Zaoutis TE, Argon J, Chu J, Berlin JA, Walsh TJ, Feudtner C.
The epidemiology and attributable outcomes of candidemia in
adults and children hospitalized in the United States: a propensity analysis. Clin Infect Dis 2005; 41: 12329.

 2012 Blackwell Verlag GmbH

Practical considerations on current guidelines

6 Gudlaugsson O, Gillespie S, Lee K et al. Attributable mortality

of nosocomial candidemia, revisited. Clin Infect Dis 2003; 37:
11727.
7 Guzman JA, Tchokonte R, Sobel JD. Septic shock due to
candidemia: outcomes and predictors of shock development.
J Clin Med Res 2011; 3: 6571.
8 Allou N, Allyn J, Montravers P. When and how to cover for
fungal infections in patients with severe sepsis and septic
shock. Curr Infect Dis Rep 2011; 13: 42632.
9 Pappas PG, Kauffman CA, Andes D et al. Clinical practice
guidelines for the management of candidiasis: 2009 update by
the Infectious Diseases Society of America. Clin Infect Dis
2009;48:50335.
10 Herbrecht R, Fluckinger U, Gachot B, Ribaud P, Thiebaut A,
Cordonnier C. Antifungal therapy in leukemia patients
guidelines update ECIL-4. http://www.ebmt.org/Contents/
Resources/Library/ECIL/Documents/ECIL%204Update%
202011%20Antifungal%20therapy.pdf [accessed on 2 May
2012].
11 Ullmann AJ, Cuenca-Estrella M, Lortholary O, Cornely OA,
Roilides E. Presentation of the ESCMID diagnostic and management guidelines for Candida diseases 2011. Educational
workshop EW 16; ECCMID 2011.
12 Ruhnke M, Rickerts V, Cornely OA et al. Diagnosis and therapy of Candida infections: joint recommendations of the German Speaking Mycological Society and the Paul-EhrlichSociety for Chemotherapy. Mycoses 2011; 54: 279310.
13 Morrell M, Fraser VJ, Kollef MH. Delaying the empiric
treatment of candida bloodstream infection until positive
blood culture results are obtained: a potential risk factor for
hospital mortality. Antimicrob Agents Chemother 2005; 49:
36405.
14 Garey KW, Rege M, Pai MP et al. Time to initiation of fluconazole therapy impacts mortality in patients with candidemia:
a multi-institutional study. Clin Infect Dis 2006; 43: 2531.
15 Kumar A, Skrobik I, Guzman J et al. The high mortality of
Candida septic shock is explained by excessive delays in
initiation of antifungal therapy. ICAAC 2007; abstract
K-2174.
16 Patel GP, Simon D, Scheetz M, Crank CW, Lodise T, Patel N.
The effect of time to antifungal therapy on mortality in Candidemia associated septic shock. Am J Ther 2009; 16: 50811.
17 Taur Y, Cohen N, Dubnow S, Paskovaty A, Seo SK. Effect of
antifungal therapy timing on mortality in cancer patients
with candidemia. Antimicrob Agents Chemother 2010; 54:
18490.
18 Eggimann P, Francioli P, Bille J et al. Fluconazole prophylaxis
prevents intra-abdominal candidiasis in high-risk surgical
patients. Crit Care Med 1999; 27: 106672.
19 Reboli AC, Rotstein C, Pappas PG et al. Anidulafungin versus
fluconazole for invasive candidiasis. N Engl J Med 2007; 356:
247282.
20 Kett DH, Shorr AF, Reboli AC, Reisman AL, Biswas P, Schlamm HT. Anidulafungin compared with fluconazole therapy
incritically ill patients. ISICEM 2010; Poster A75.
21 Mann PA, McNicholas PM, Chau AS et al. Impact of antifungal prophylaxis on colonization and azole susceptibility of
Candida species. Antimicrob Agents Chemother 2009; 53:
502634.
22 Lortholary O, Desnos-Ollivier M, Sitbon K et al. Recent exposure to caspofungin or fluconazole influences the epidemiology of candidemia: a prospective multicenter study involving

 2012 Blackwell Verlag GmbH

23

24

25

26

27

28

29

30

31

32

33

34

35
36

37

2,441 patients. Antimicrob Agents Chemother 2011; 55: 532

8.
Glockner A, Abel P, Bernhardt H, Zimmermann K, Wiersbitzly
M. Mycological findings upon Admission to A non-surgical
ICU. ICAAC 2002; Poster M-874.
Oxman DA, Chow JK, Frendl G et al. Candidaemia associated
with decreased in vitro fluconazole susceptibility: is Candida
speciation predictive of the susceptibility pattern? J Antimicrob
Chemother 2010; 65: 14605.
Paiva JA, Ruhnke M, Meersseman W. Anidulafungin for
treatment of candidemia invasive candidiasis in selected
intensive care unit populations. SCCM Annual Meeting 2010;
Abstract 297.
Pfaller MA, Castanheira M, Messer SA, Moet GJ, Jones RN.
Variation in Candida spp. distribution and antifungal resistance rates among bloodstream infection isolates by patient
age: report from the SENTRY Antimicrobial Surveillance
Program (2008-2009). Diagn Microbiol Infect Dis 2010; 68:
27883.
Pfaller MA, Messer SA, Moet GJ, Jones RN, Castanheira M.
Candida bloodstream infections: comparison of species distribution and resistance to echinocandin and azole antifungal
agents in Intensive Care Unit (ICU) and non-ICU settings in
the SENTRY Antimicrobial Surveillance Program (20082009). Int J Antimicrob Agents 2011; 38: 659.
Tortorano AM, Dho G, Prigitano A et al. Invasive fungal
infections in the intensive care unit: a multicentre, prospective, observational study in Italy (2006-2008). Mycoses 2012;
55: 739.
Pfaller MA. Antifungal drug resistance: mechanisms, epidemiology, and consequences for treatment. Am J Med 2012;
125(1 Suppl): S313.
Arendrup MC. Susceptibility breakpoints and resistance to
antifungals among Candida species - where are we in 2011?
ECCMID 2011; presentation S428.
European Commitee on Antimicrobial Susceptibility Testing.
Antimicrobials for Candida infections EUCAST clinical MIC
breakpoints v.3.0 2011-04-27. http://www.srga.org/eucastwt/MICTAB/EUCAST clinical MIC breakpoints - antimicrobials for Candida infections.htm [accessed on 2 May
2012].
Pfaller MA, Diekema DJ, Andes D et al. Clinical breakpoints for
the echinocandins and Candida revisited: integration of
molecular, clinical, and microbiological data to arrive at
species-specific interpretive criteria. Drug Resist Updat 2011;
14: 16476.
Estivill D, Arias A, Torres-Lana A, Carrillo-Munoz AJ, Arevalo
MP. Biofilm formation by five species of Candida on three
clinical materials. J Microbiol Methods 2011; 86: 23842.
Krcmery V, Barnes AJ. Non-albicans Candida spp. causing
fungaemia: pathogenicity and antifungal resistance. J Hosp
Infect 2002; 50: 24360.
Kojic EM, Darouiche RO. Candida infections of medical devices. Clin Microbiol Rev 2004; 17: 25567.
Andes DR, Safdar N, Baddley J et al. Impact Of Therapy On
Mortality Across Candida spp In Patients With Invasive
Candidiasis From Randomized Clinical Trials: A Patient Level
Analysis. Presentation M-1312; 50th ICAAC, Boston, MA,
USA, September 11-15, 2010.
Labelle AJ, Micek ST, Roubinian N, Kollef MH. Treatmentrelated risk factors for hospital mortality in Candida bloodstream infections. Crit Care Med 2008; 36: 296772.

A. Glockner and O. A. Cornely

38 Asmundsdottir LR, Erlendsdottir H, Gottfredsson M. Improving survival of patients with candidaemia: analysis of prognostic factors from a long-term, nationwide study in Iceland.
Scand J Infect Dis 2005; 37: 11120.
39 Stamos JK, Rowley AH. Candidemia in a pediatric population.
Clin Infect Dis 1995; 20: 571.
40 Rex JH, Bennett JE, Sugar AM et al. Intravascular catheter
exchange and duration of candidemia. NIAID Mycoses Study
Group and the Candidemia Study Group. Clin Infect Dis 1995;
21: 9946.
41 Nucci M, Silveira MI, Spector N et al. Risk factors for death
among cancer patients with fungemia. Clin Infect Dis 1998;
27: 10711.
42 Rodriguez D, Park BJ, Almirante B et al. Impact of early central venous catheter removal on outcome in patients with
candidaemia. Clin Microbiol Infect 2007; 13: 78893.
43 Velasco E, Bigni R. A prospective cohort study evaluating the
prognostic impact of clinical characteristics and comorbid
conditions of hospitalized adult and pediatric cancer patients
with candidemia. Eur J Clin Microbiol Infect Dis 2008; 27:
10718.
44 Weinberger M, Leibovici L, Perez S et al. Characteristics of
candidaemia with Candida-albicans compared with non-albicans Candida species and predictors of mortality. J Hosp Infect
2005; 61: 14654.
45 Nucci M, Anaissie E, Betts RF et al. Early removal of central
venous catheter in patients with candidemia does not improve
outcome: analysis of 842 patients from 2 randomized clinical
trials. Clin Infect Dis 2010; 51: 295303.
46 DiDone L, Oga D, Krysan DJ. A novel assay of biofilm antifungal activity reveals that amphotericin B and caspofungin
lyse Candida albicans cells in biofilms. Yeast 2011; 28: 5618.
47 Fiori B, Posteraro B, Torelli R et al. In vitro activities of anidulafungin and other antifungal agents against biofilms

10

48

49

50

51

52

53

54

55
56
57

formed by clinical isolates of different Candida and Aspergillus

species. Antimicrob Agents Chemother 2011; 55: 30315.
Kucharkova S, Tournu H, Holtappels M, Van Dijck P,
Lagrou K. In vivo efficacy of anidulafungin against mature
Candida albicans biofilms in a novel rat model of catheterassociated Candidiasis. Antimicrob Agents Chemother 2010;
54: 44745.
Seidler M, Salvenmoser S, Muller FM. Liposomal amphotericin
B eradicates Candida albicans biofilm in a continuous catheter
flow model. FEMS Yeast Res. 2010; 10: 4925. Epub 2010
Mar 5.
Mora-Duarte J, Betts R, Rotstein C et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl
J Med 2002; 347: 20209.
Pappas PG, Rotstein CM, Betts RF et al. Micafungin versus
caspofungin for treatment of candidemia and other forms of
invasive candidiasis. Clin Infect Dis 2007; 45: 88393.
Kullberg BJ, Sobel JD, Ruhnke M et al. Voriconazole versus a
regimen of amphotericin B followed by fluconazole for candidaemia in non-neutropenic patients: a randomised noninferiority trial. Lancet 2005; 366: 143542.
Davis S, Kouza A, Wiegand T, Vazquez J Conversion of
intravenous echinocandins to oral azoles for invasive candidiasis: impact on outcomes and resource utilisation. ECCMID
2008; Abstract O458.
Analysis of data from the randomized trial of anidulafungin
vs. fluconazole for invasive candidiasis (Reboli et al. [19];
Pfizer data on file).
Micafungin (Mycamine) summary of product characteristics;
August 2011.
Anidulafungin (Ecalta) summary of product characteristics;
July 2011.
Caspofungin (Cancidas) summary of product characteristics;
November 2010.

 2012 Blackwell Verlag GmbH