Prophylaxis, empirical and preemptive treatment of

invasive candidiasis
Elliott Geoffrey Playforda,b, Jeff Lipmanc,d and Tania C. Sorrelle,f
a
Infection Management Services, Princess Alexandra
Hospital, bCentre for Clinical Research, University of
Queensland, cDepartment of Intensive Care, Royal
Brisbane and Womens Hospital, dBurns Trauma
Critical Care Research Centre, University of
Queensland, Brisbane, Queensland, eCentre for
Infectious Diseases and Microbiology and Westmead
Millennium Institute, Westmead and fSydney Medical
School, University of Sydney, Sydney, Australia

Correspondence to Dr Geoffrey Playford, Infection

Management Services, Princess Alexandra Hospital,
Ipswich Road, Woolloongabba, Brisbane, Queensland
4102, Australia
E-mail: [email protected]
Current Opinion in Critical Care 2010,
16:470474

Purpose of review
Invasive candidiasis remains an important infection for ICU patients, associated with
poor clinical outcomes. It has been increasingly recognized that the traditional paradigm
of culture-directed antifungal treatment is unsatisfactory, and that earlier antifungal
intervention strategies, such as prophylaxis, preemptive therapy, and empiric therapy,
are required to improve patient outcomes. The purpose of this review is to summarize
the recent supportive evidence for such strategies and to highlight the current
challenges in their implementation.
Recent findings
Despite new antifungal agents and classes, the mortality from invasive candidiasis
remains high. Antifungal prophylaxis remains the best-studied early antifungal
intervention strategy; however, unless targeted to patients at highest risk, is inefficient.
Recent data suggests that although risk predictive models, using a combination of
clinical risk factors and Candida colonization parameters, may be a relatively simple and
practical approach to guide prophylaxis or preemptive therapy, further validation of
these models is required. A single trial has demonstrated that empiric antifungal therapy
is not of benefit when instituted to patients with antibiotic-refractory fever alone.
Summary
On the basis of current knowledge, it is difficult to universally recommend antifungal
prophylaxis, apart from patient groups with a known very high risk, such as those with
necrotising pancreatitis or recurrent gastrointestinal perforations. Antifungal prophylaxis
may also be reasonable where local incidence rates and epidemiology are compelling.
Among stable patients with multifocal Candida colonization and/or a multitude of
clinical-risk factors, preemptive therapy is currently not indicated, although the
development of better risk predictive models may assist with such patients. Among
patients with refractory fever despite broad-spectrum antibacterial therapy, empiric
antifungal therapy may be reasonable where local incidence rates are high (e.g. >10%);
however, a thorough search for alternate causes must be instituted.
Keywords
candidiasis, fungal infection, preemptive therapy, prophylaxis
Curr Opin Crit Care 16:470474
2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
1070-5295

Introduction
The traditional paradigm of culture-directed antifungal
therapy among critically ill patients in the ICU is increasingly recognized as unsatisfactory, given the high crude
and attributable mortality rates and substantial excess
costs associated with invasive candidiasis, the insensitivity and slow turnaround times of traditional diagnostic
microbiology techniques, and the association between
time to initiation of antifungal therapy and poor outcome.
Early antifungal intervention strategies including prophylaxis, preemptive therapy, and empiric therapy
have, therefore, received increasing attention. Pending
the development, validation, and widespread availability
of the next generation of nonculture-based diagnostic
1070-5295 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins

assays, such early antifungal interventions need to be

based upon clinical and other microbiological parameters.
This review will focus upon the rationale and supporting
evidence for early antifungal intervention strategies.

Rationale for early antifungal intervention

strategies
Invasive candidiasis has long been appreciated as an
important clinical entity, particularly among critically
ill ICU patients, with crude mortality rates of 4060%.
Despite advances in supportive care and the introduction
of new antifungal agents, crude mortality rates, which in
part reflect underlying comorbidities and concurrent
critical illnesses, remain high in contemporary ICU
DOI:10.1097/MCC.0b013e32833e10e8

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Treatment of invasive candidiasis Playford et al. 471

patient cohorts [17]. Although attributing adverse outcomes specifically to a superimposed infection is methodologically difficult, there is agreement that invasive
candidiasis is independently associated with adverse
clinical outcomes and excess economic costs among
ICU patients [811].
With the aim of improving poor clinical outcomes, potentially modifiable treatment-related factors have been
sought. The time to initiation of effective antifungal
therapy has repeatedly been identified as an important
determinant of mortality. Indeed, initiation of antifungal
therapy within 1224 h of the first ultimately positive
blood culture is required to significantly improve
mortality rates [6,7]. However, as modern automated
blood culture techniques generally signal positive only
after 23 days, they are unsuitable for guiding the
initiation of antifungal therapy early enough to influence
patient outcomes. New nonculture-based techniques,
such as the detection of fungal nucleic acids [12,13] or
(1!3)-b-D-glucan [1416] or other fungal antigens may
eventually provide rapid and sensitive diagnostic support
for early antifungal therapy. At present, these are not yet
sufficiently standardized, validated, or available for their
routine clinical adoption. Additionally, the clinical features of invasive candidiasis are nonspecific, mimicking
quantitatively more common aetiologies, such as bacterial infection or noninfective processes.
Although early antifungal intervention strategies may lead
to improved clinical outcomes, their use in patients at low
risk of invasive candidiasis has the potential to increase
costs, toxicity, and generate ecological selection pressure
for antifungal resistance. Hence, there are important and
competing clinical and economic consequences of the
different strategies that must be considered in order to
optimize their benefits and minimize their harms.
Overall, critically ill ICU and surgical patients now
account for at least one-third of all cases of invasive
candidiasis [17]. However, the epidemiology of invasive
candidiasis is complex. In particular, it is characterized by
marked geographic and temporal variations both in incidence and species distribution. Some of this variability
can be explained by differences in patient case mix,
clinical and infection control practices, and, in particular,
utilization of antimicrobial agents. There is contemporary
evidence that the incidence of invasive candidiasis continues to increase and several large, longitudinal epidemiological studies from the United States, Canada,
Europe, and Australia have highlighted the continuing
importance of this infection [1821]. Overall, the ICU
incidence (incidence-density) of candidaemia remains
approximately 2/1000 admissions (510/10 000 patientdays) [22], although in many settings it is considerably
higher. When including other (nonbloodstream) forms of

invasive candidiasis, the overall ICU incidence of invasive candidiasis is estimated to be 12% [17].
The distribution of causative Candida species also shows
geographical variation and has evolved over time. A
dramatic increase in the relative proportion of ICU-associated candidaemia episodes caused by nonalbicans Candida
spp. was documented in the United States through the
1990s [23], but other recent multicentre studies suggest
that Candida albicans remains the predominant invasive
Candida spp. among ICU patient cohorts, accounting for
4060% of candidaemia episodes [24,24]. However,
there is considerable geographic variation, particularly in
the relative proportion of episodes caused by Candida
glabrata (higher in the United States) or Candida parapsilosis (higher in some European centres) [22].
These institutional, regional, and temporal epidemiological trends are highly relevant to the choice of early
antifungal intervention strategies; in particular which
patient populations should be targeted and which antifungals should be used.

Antifungal prophylaxis
Antifungal prophylaxis with fluconazole has been assessed
in at least eight clinical trials, involving a diverse spectrum
of ICU and critically ill surgical patients [2532]. Although
individually relatively underpowered, these seminal studies from the mid-late 1990s and early 2000s collectively
demonstrated that fluconazole reduced the incidence of
invasive candidiasis by around 50% and possibly was
associated with a survival benefit [3336]. However, the
fundamental drawback of antifungal prophylaxis remains
the need for it to be targeted to a patient group expected to
have a high underlying rate of infection. Given an average
incidence of invasive candidiasis among most unselected
ICU cohorts of around 12% [17], a relative risk reduction
of 50% associated with prophylaxis would translate into
100200 patients needing to be treated to prevent one
infection. Clearly, this is an inefficient strategy, and, therefore, tools to target prophylaxis to a higher risk group (e.g. a
group with at least a 10% incidence, where the number
needed to treat is
20) are required. For some patient
groups, such as those with acute necrotising pancreatitis
or recurrent gastrointestinal perforations, prophylaxis
appears reasonable; however, its utility for the majority
of ICU patients is unclear. Although risk factors for invasive candidiasis are well documented, they occur almost
ubiquitously among ICU patients and hence these risk
factors cannot be simply used to define a high-risk cohort.
However, combinations of these risk factors can potentially be integrated into risk predictive models. In this
regard, a United States group has developed several variants of a clinical prediction rule using clinical risk factors
that occur soon before or soon after ICU admission from

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472 Infectious diseases

retrospective North and South American ICU cohorts.

Although these rules were reported to be able to identify
subsets of patients with an approximate 10% incidence of
invasive candidiasis (i.e. a 10% positive predictive value)
they differed in the proportions of all invasive candidiasis
cases captured (i.e. variable sensitivities) [3739]. Nevertheless, using one of these rules, this group recently
reported that in a beforeafter study from a single US
centre, a significant reduction in the incidence-density of
candidaemia among a 12-month prospective cohort that
received oral or intravenous fluconazole where the prediction rule was met (0.79 episodes/1000 line-days) compared
with a 12-month historical cohort not given prophylaxis
(3.4 episodes/1000 line-days) [40]. Importantly, only 2.6%
of patients in the prospective cohort met the rule and were
administered prophylaxis, suggesting that the rule was
both sensitive and specific. However, in this particular
ICU setting, Candida spp. historically accounted for 50% of
all nosocomial bloodstream infections, a proportion that
may be substantially greater than expected in many other
ICU settings. Nevertheless, these findings are entirely
consistent with the recommendation in the recent IDSA
guidelines, that in settings with a high incidence of invasive candidiasis, antifungal prophylaxis may be a reasonable approach, in conjunction with a thorough review of
infection control procedures [41].
Another logical approach to risk stratification has been to
integrate Candida colonization parameters, a well established risk factor for invasive candidiasis, together with
clinical risk factors [42]. This approach has been investigated by a Spanish group, which from a retrospective large
multicentre cohort derived a Candida score weighting the
independently significant variables associated with invasive candidiasis, severe sepsis (2 points), surgery, total
parenteral nutrition, and multifocal Candida colonization
(1 point each). With a threshold value of 2.5 points,
potentially clinically relevant performance characteristics
of this model were reported (positive predictive value, 16%
and sensitivity, 81%). However, it should be recognized
that this scores derivation cohort included only patients
with a length of ICU stay of at least 7 days; this may be
somewhat problematic, given that the median time to
invasive candidiasis following ICU admission is regularly
reported to be 810 days [1]. Hence the applicability of
this rule to the considerable proportion of patients who
develop ICU-acquired invasive candidiasis prior to 7 days
is unknown. Notwithstanding this important issue, the
same group has recently reported a prospective validation
of the Candida score, with overall similar performance
characteristics [43]. It is particularly important that such
prospective validation studies are performed on independent cohorts, as the generalizability of risk-predictive
models in other settings cannot be assumed. Potential
confounders include differences in case mix, clinical practice, and antimicrobial utilization. This issue was high-

lighted recently in a prospective multicentre Australian

ICU cohort where published clinical risk factor-only
models performed significantly less well than among the
American derivation cohorts [44].
A significant and plausible concern remains the selection
pressure for resistance that may be exerted by the widespread adoption of antifungal prophylaxis in ICU settings. However, the relationship between fluconazole
usage at institutional, hospital unit, or individual levels,
and the emergence of C. glabrata, or other nonalbicans
Candida spp. appears complex, with seemingly conflicting results reported in published studies. Recently a US
group who published one of the original prophylaxis
randomized controlled trials (in 1998) [31], examined
the epidemiology of C. glabrata colonization and infection
in a unit where fluconazole prophylaxis was routinely
given to patients with an expected length of stay of at
least 3 days (in practice 50% of all admissions). The
second cohort (from 2003, 3 years after introduction of the
prophylaxis protocol) did not demonstrate a greater likelihood of colonization or infection with C. glabrata,
although there were important differences in case mix
and performance of surveillance cultures between the
two cohorts [45]. Whether these findings are generalizable to other settings where prophylaxis is used or over
longer time periods remains unknown.
Finally, given the significant differences in epidemiology
of invasive candidiasis, particularly in respect to species
distribution, the choice of antifungal for prophylaxis must
be informed by local epidemiological surveillance. In
situations where azole resistant Candida spp. are prevalent and newer agents, such as the echinocandins, are
considered for prophylaxis, this choice would be greatly
assisted by use of an accurate risk prediction model. This
approach would both contain costs and reduce selection
pressure for resistance to additional antifungal classes.

Preemptive antifungal therapy

Conceptually, preemptive therapy includes therapy
initiated in response to one or more biological markers
of infection risk. In the context of invasive candidiasis,
these biomarkers might include Candida colonization
parameters or fungal antigens, such as (1!3)-b-D-glucan. Hence, prophylaxis and preemptive therapy, particularly where Candida colonization parameters are used,
represent conceptually overlapping paradigms.
The association between Candida colonization and subsequent infection has long been established. However,
two measures, the colonization index (a ratio of number of
body sites yielding Candida spp. and the number of body
sites sampled) and the corrected colonization index (colonization index corrected for the density of growth), have

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Treatment of invasive candidiasis Playford et al. 473

been derived to quantify this association [42]. Use of the

corrected colonization index (0.4) to trigger initiation of
preemptive fluconazole therapy in a beforeafter study in
a single institution, was associated with a significant
reduction in ICU-acquired invasive candidiasis [46].
For such an approach to be implemented repeated
surveillance cultures would be required; these have considerable logistical and financial implications. Unfortunately, few additional published data are available to
assess the utility of this approach.

Empiric antifungal therapy

Empiric therapy is generally defined as antifungal therapy
administered to patients with clinical features of the
inflammatory response consistent with a fungal aetiology,
but without microbiological confirmation. As with all early
antifungal strategies, this assumes that outcomes will be
improved in patients who would otherwise have delayed
definitive antifungal treatment. Although the use of
empiric therapy is relatively common in practice [47],
few supportive data are available. The fundamental problem with this approach remains that the clinical manifestations of invasive candidiasis overlap considerably with
those associated with other nonfungal infective and inflammatory processes [48].
Recently, a multicentre double blind randomized controlled clinical trial comparing empiric fluconazole therapy
with placebo in critically ill ICU patients was reported [49].
In this trial 270 patients with antibacterial refractory fever
were randomized to receive fluconazole 800 mg intravenously or placebo. There was no difference in a composite
endpoint for success (encompassing fever resolution,
absence of invasive fungal infection, no toxicity-related
discontinuations, and no need for a nonstudy systemic
antifungal medication). However, certain aspects of this
study may limit its practical relevance: the inclusion
criteria required only antibacterial refractory fever without
any other marker of invasive candidiasis risk and the composite primary outcome measure was relatively nonspecific. Indeed the inclusion criteria would capture many
patients with diverse infective and inflammatory processes, as indicated by the relatively low overall infection
rate (7%) and the low Candida colonization rate (20%).
Hence, this study indicates that empiric antifungal therapy
instituted solely on the basis of nonspecific clinical features, but without other markers of risk and without an
extensive search for other causes, is unlikely to be
of benefit.

treatment paradigms. Pending the availability of the next

generation of sensitive and rapid diagnostic tests, clinical
and colonization parameters are needed to guide targeted
early institution of antifungal therapies to patients at
greatest risk. Although much work has been performed
in stratifying patient risk, much remains, particularly
given the variable and evolving epidemiology of invasive
candidiasis in critically ill patients.
On the basis of current knowledge, it is difficult to universally recommend antifungal prophylaxis, apart from
patient groups with a known very high risk (such as those
with gastrointestinal dehiscence and multiple abdominal
surgical procedures). Antifungal prophylaxis may also be
reasonable where local incidence rates and epidemiology
are compelling, however, in such circumstances, a
thorough review of infection control and other clinical
practices should be prompted. Among stable patients with
multifocal Candida colonization and/or clinical risk factors
for infection, preemptive therapy is currently not indicated, although the development of better risk predictive
models may assist with such patients in the future. Finally,
among patients with refractory fever despite broad-spectrum antibacterial therapy, empiric antifungal therapy may
be reasonable, where local incidence rates are high,
together with a thorough search for alternate causes.

Acknowledgement
This work was supported by Centre of Clinical Research Excellence
grant (264625) and project grant (512307) from the National Health
and Medical Research Council of Australia.

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Conclusion
The ongoing poor clinical and economic outcomes associated with invasive candidiasis among ICU patients
demand reconsideration of traditional culture-directed

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