Review
Management of Candida species infections in
critically ill patients
Philippe Eggimann, Jorge Garbino, and Didier Pittet
Invasive candidiasis is a feared infection with mortality
similar to that of septic shock (40–60%). Improved
knowledge of its pathophysiology and the availability of new
compounds for antifungal therapy and prophylaxis have
contributed to improving the prognosis of severe candidal
infections among immunosuppressed patients at the
possible cost of the emergence of non-albicans strains of
candida with lower susceptibility to azoles. This review
focuses on the management of invasive deep-seated
candidiasis in critically ill, non-immunocompromised
patients. We discuss antifungal use, indications, potential
benefit, and main secondary effects. Prevention strategies
include pre-emptive antifungal therapy and azole-based
prophylaxis. For patients at lower initial risk, pre-emptive
therapy should be based on a management strategy that
takes into account the presence of definite risk factors and
the dynamics of candida colonisation. Among critically ill
patients, azole prophylaxis is effective and is not associated
with acquisition of resistance; it must be restricted to highly
selected groups of patients at high risk only.
Lancet Infect Dis 2003; 3: 772–85
Candidiasis most frequently occurs in immunocompromised
hosts.1 Invasive candidiasis is particularly feared in recipients
of bone-marrow transplants and among patients undergoing
intensive chemotherapy, in whom crude mortality is higher
than 80%.2–4 This high rate justifies the use of aggressive
strategies based on systematic prophylaxis with triazole
derivatives and early empirical pre-emptive antifungal
therapy when candidiasis is suspected.5 Antifungal therapy
can rarely be avoided in immunocompromised patients, and
use of these agents has been implicated in the occurrence of a
shift in the epidemiology of candida infections.6–10
We reviewed the epidemiology of invasive candidiasis in
non-neutropenic, critically ill patients in the November
issue of The Lancet Infectious Diseases.11 In this paper, the
focus is on the management of these infections. Although
many patients are colonised by Candida spp, only a minority
subsequently develop infection. Thus, specific diagnostic
strategies and adapted management preventive strategies are
needed.
Antifungal agents
Delay in initiating antifungal treatment in critically ill patients
is associated with a worse outcome.3,8,12,13 Because no accurate
tools for early diagnosis are yet available, many researchers
recommend early empirical antifungal therapy in non-
772 THE LANCET Infectious Diseases Vol 3 December 2003
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Management of candidiasis
neutropenic patients when candidiasis is suspected.14–19 For
three decades, amphotericin B was the only systemic
antifungal agent available. Azoles, developed in the 1980s,
allow early empirical and pre-emptive treatment.15,17,18 New
prospects for the near future have been opened up by the
introduction of second-generation triazole derivatives and
new classes of agents with very broad ranges of antifungal
activity and better safety profiles. Antifungal spectrum and
pharmacokinetics, including usual dose and relevant side-
effects, are summarised in tables 1 and 2.14–18,20–35
Amphotericin B
Amphotericin B deoxycholate, extracted from Streptomyces
nodosus, is a polyene with a very broad spectrum including
almost all yeasts and filamentous fungi (table 1). Resistant
species (Candida lusitaniae, Candida guilliermondii) have
been described, but the clinical relevance of this resistance is
not clear.36,37 Fungicidal at high concentrations, amphotericin
B is deemed to be fungistatic against most strains at
conventional doses. A cumulative dose of 1–2 g is necessary
for full antifungal efficacy.
Side-effects, mainly related to the infusion and
nephrotoxicity, occur in 50–90% of patients. These adverse
effects have made clinicians reluctant to use the drug.21
Continuous administration over 24 h can greatly reduce
these complications without loss of efficacy;20 this approach,
however, necessitates an individual line, which may not be
easy to achieve in some patients. Other options to decrease
amphotericin B toxicity are to give treatment on alternate
days or in combination with flucytosine to allow use of lower
doses.14,15,17,19
Lipid complexes (Abelcet, ALBC), cholesteryl
sulphate (Amphocin, Amphotec), and lipososomal forms
(AmBisome) are less toxic, and some can be administered
more rapidly and at higher doses than the conventional
formulation (Amphicin, FungizoneV). Lower renal toxicity
may be due to the binding with lipids, which could act as a
storage reservoir from which amphotericin can be released
PE is at the Medical Clinic II and Intensive Care Unit,
and the Infection Control Programme, JG is at the Division
of Infectious Diseases, and DP is at the Division of Infectious
Diseases and the Infection Control Programme, Department of
Internal Medicine, University of Geneva Hospitals, Geneva,
Switzerland.
Correspondence: Professor Didier Pittet, Infection Control
Programme, Department of Internal Medicine, University of Geneva
Hospitals, CH-1211 Geneva 14, Switzerland. Tel +41 22 372 9828;
fax +41 22 372 3987; email didier.pittet@hcuge.ch
http://infection.thelancet.com
 Management of candidiasis
Review

Table 1. Characteristics of polyene antifungal drugs20–26

Amphotericin B Liposomal nystatin Amphotericin B lipid Amphotericin B Liposomal

deoxycholate complex colloidal dispersion amphotericin B
Spectrum of antifungal activity
C albicans +++ ++ +++ +++ +++
C tropicalis +++ ++ +++ +++ +++
C parapsillosis +++ ++ +++ +++ +++
C glabrata +++ ++ +++ +++ +++
C krusei +++ ++ +++ +++ +++
Aspergillus spp +++* ++ +++ +++ +++
Cryptoccus spp +++ ++ +++ +++ +++
Coccidioides spp +++ ++ +++ +++ +++
Histoplasma spp +++ ++ +++ +++ +++
Fusarium spp ++ ++ ++ ++ ++
Mucor spp + + + + +
Side-effects
Total frequency (%) 70–90† 15–30 20–40 20–40 15–30
Chills +++ + ++ ++ ++
Digestive + + + + +
Hepatic + + + + +
Renal +++ + ++ ++ +
Other Anaphylaxis 1% ·· ·· ·· +/⫺
Pharmacokinetics
Morphology Colloidal dispersion Unilamellar liposomes Lipid-drug complex Colloidal particle Unilamellar liposomes
in suspension
Loading dose No No No No No
Daily dose (mg/kg)‡ 0·5–1·5 in 1–6 h 0·24–4·00 in 0·5–1·0 h 5 in 1–2 h 3–4 in 1–2 h 3–6 in 0·5–1·0 h
Route Intravenous Intravenous Intravenous Intravenous Intravenous
Half-life (h) 15–24§ 5 24 28 174
Elimination route In situ Unknown Unknown Unknown Unknown
Peak plasma concentration (g/L) 0·5–2·0 4–9 1·0–2·0 1·0–2·0 7–57
Protein binding (%) 91–95 90 90 90 90
Volume of distribution (L/kg) 4 10 173 4 131
CNS penetration (%) <10 <10 <10 <10 <10
For antifungal activity: +++=excellent, ++=good, +=moderate, +/⫺=poor, ⫺=no activity. For side-effects: +++=very common, ++=frequently reported, +=reported;
+/⫺=uncommon. CNS=central nervous system. *Limited antifungal activity against A terreus. †Infusion-related symptoms are reported in 70–90% of cases. They include nausea,
vomiting, fever, chills, pain at the injection site, gastrointestinal disorder, thrombophlebitis, bronchospasm, hypotension, and cardiac arrhythmias. Pretreatment with paracetamol,
diphenhydramine, chlorpheniramine, meperidine, nephopam, or corticoids helps to reduce the frequency and severity of these events. Slowing of the perfusion rate and increasing
the perfusion time to over 6 h may also be useful. Renal toxicity develops in 25–80% of patients, mostly related to renal vasoconstriction and consequent decrease in the
glomerular filtration rate. It manifests as severe tubulopathy with loss of potassium and magnesium, which inevitably progresses to acute renal failure if the dose is not lowered. A
loading dose of sodium chloride (up to 150 mmol/day) limits the severity of tubulopathy.21;27 ‡No dose adjustments are needed for any of these drugs in relation to abnormal
creatinine clearance, haemodialysis, peritoneal dialysis, continuous venovenous haemofiltration, or liver insufficiency. §Elimination half-life from the body is about 15 days.

gradually. However, this mechanism has not been well
explored at tissue level. Animal studies have suggested that
higher doses are required than of the non-lipid formulation,
which may explain conflicting efficacy results reported in
clinical trials.22,23,38,39 Recent experimental findings suggest that
amphotericin B is active against Candida spp embedded in
biofilm, but the clinical relevance of this finding remains
unclear.40
Amphotericin B lipid formulations are ten to 100 times
more expensive than conventional formulations, so most
institutions restrict their use. Expert consensus generally
recommends that lipid formulations are restricted to patients
who are refractory to treatment, intolerant of other forms,
or at high risk of severe side-effects of conventional
treatment.15–18,23
Some investigators have suggested the administration of
conventional amphotericin B emulsified in a 20% lipid
solution, but the pharmacokinetics and resulting plasma
concentrations of this mixture are not reproducible, and their
use cannot be recommended.24,25
Liposomal nystatin
Nystatin is an established antifungal agent restricted to topical
applications. It has also been used for prophylaxis of fungal
infections in immunocompromised patients. However, in a
meta-analysis of 12 studies,41 the effect did not differ from that
of placebo on fungal colonisation (relative risk 0·85 [95% CI
0·65–1·13]) and overall mortality (0·76 [0·49–1·18]).
Fluconazole was more effective in preventing colonisation
(0·49 [0·34–0·70]) and invasive fungal infection (0·37
[0·15–0·91]). Thus, oral nystatin cannot be recommended for
prophylaxis or treatment of severe candidal infections.
The development of a liposomal form to reduce the
toxicity of nystatin is in phase III.26,42 Similarly to other
polyenes, it binds to ergosterol in the fungal membrane,
resulting in leakage of intracellular electrolytes and cell death.
Nystatin shows good activity against all Candida spp.
Furthermore, liposomal nystatin might be active against some
amphotericin-B-resistant isolates (table 1).43,44 As with other
polyenes, the most common side-effects are hypokalaemia and
nephrotoxicity.

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 Review Management of candidiasis

Table 2. Characteristics of azole and echinocandin antifungal drugs14–18,28–35

Flucytosine Ketoconazole Itraconazole Fluconazole Voriconazole
Spectrum of antifungal activity
C albicans +++ + +++ +++ +++
C tropicalis +++ + +++ +++ +++
C parapsillosis +++ + +++ +++ +++
C glabrata +++ + +/⫺ +/⫺ +++
C krusei +++ ⫺ ⫺ ⫺ +++
Aspergillus spp ++ ⫺ ++ ⫺ +++
Cryptoccus spp +++ ⫺ + ++ +++
Coccidioides spp ++ ++ ++ ⫺ +++
Histoplasma spp ++ ++ ++ ⫺ +++
Fusarium spp ++ + +/⫺ ⫺ ++
Mucor spp ⫺ ⫺ ⫺ ⫺ +
Side-effects
Total frequency (%) 30–50 15–20 10–15 10–15 10–20*
Chills ⫺ ⫺ ⫺ ⫺ Fever
Digestive + ++ + + +
Hepatic ++ + ⫺ ⫺ ⫺
Renal + ⫺ ⫺ ⫺ ⫺
Other Myelotoxicity; rash (rare) Endocrinological; rash (10%) Arrhythmias Cutaneous Vision*
Pharmacokinetics
Loading dose No No 400 mg 10 mg/kg 6 mg/kg
Daily dose 100 mg/kg 200–400 mg 200 mg 5 mg/kg 100–800 mg
in 3–4 doses† in 1 h 4 mg/kg
Route IV or oral Oral IV or oral IV or oral IV or oral
Half-life (h) 3–6 6–9 19–22 24–30 6–9
Elimination route Renal Hepatic Hepatic Hepatic Hepatic
(CYP3A inhibitor) (CYP3A inhibitor)
Peak plasma 50–100 1·5–3·1 0·2–0·4 10·2 2–3
concentration mg/L
Bioavailability (%) 95 80 Variable 95 90
Protein binding (%) Low >90 99 10 60
CNS penetration (%) >75 <10 <10 80 90
Dose adjustments‡
CrCl 40–60 mL/min 500 mg/12 h None None None None
CrCl 10–39 mL/min 500 mg/18 h None None None Do not use IV
CrCl <10 mL/min 500 mg/24 h 200 mg/48 h 200 mg/48 h 5 mg/kg/48 h Do not use IV
Post-HD 500 mg 200 mg 200 mg 5 mg/kg None
Post-PD 500 mg 200 mg 200 mg 5 mg/kg No information
CVVH 500 mg/18 h None None None No information
Moderate liver insufficiency None None None§ None§ None§
Severe liver insufficency None None None§ None§ No information
Interactions
Increases concentrations NA Cyclosporin, phenytoin, Cyclosporin, digoxin, Cyclosporin, Cyclosporin,
rifampicin, warfarin, phenytoin, rifampicin, phenytoin, sirolimus,
antiproteases warfarin, antiproteases, rifampicin, warfarin, quinine, cisapride
antihistamines, statins antiproteases
(continues on next page)

Flucytosine treatment with other antifungal drugs is therefore highly

A fungal deaminase converts this fluorinated pyrimidine
into fluorouracil, which competes with uracil for
incorporation into fungal RNA after phosphorylation, thus
blocking protein synthesis. The antifungal spectrum
includes yeasts and some filamentous fungi (table 2).45,46 Not
bound by plasma proteins, it disperses well and shows
excellent diffusion capability, including the cerebrospinal
fluid. The half-life is around 4–6 h, so it has to be given in
four daily doses.33 Many failures related to the rapid
emergence of resistance have been reported in the treatment
of candidaemia with flucytosine monotherapy; combined
recommended.21 Acute liver failure and potentially lethal
myelotoxicity have been reported.31,47 These features and the
absence of evidence from randomised clinical trials explain
why only marginal use has been reported.48,49 However, many
researchers recommend that flucytosine is combined with
other antifungal agents in cases of severe candidiasis,
particularly of the central nervous system or in other
sanctuaries such as the eye or cardiac valves.15–18 Most
recommendations state that blood concentrations should be
monitored as frequently as once a week; dose adjustment is
necessary in renal impairment.

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 Management of candidiasis
Review

Table 2. Characteristics of azole and echinocandin antifungal drugs14–18,28–35 (continued)

Posaconazole Ravuconazole Caspofungin Micafungin Andinulafungin
Spectrum of antifungal activity
C albicans +++ +++ +++ +++ +++
C tropicalis +++ +++ +++ +++ +++
C parapsillosis +++ +++ +++ +++ +++
C glabrata +++ +++ +++ +++ +++
C krusei +++ +++ +++ +++ +++
Aspergillus spp +++ +++ +++ +++ +++
Cryptoccus spp +++ +++ +++ +++ ⫺
Coccidioides spp +++ +++ +++ +++ NA
Histoplasma spp +++ +++ +++ +++ ⫺
Fusarium spp + ++ + + ⫺
Mucor spp +/⫺ +/⫺ +/⫺ +/⫺ ++
Side-effects
Total frequency (%) 10–20 10–20 10–15 10–15 10–15
Chills ⫺ ⫺ + + NA
Digestive + + + NA +
Hepatic ⫺ ⫺ ⫺ ⫺ NA
Renal ⫺ ⫺ ⫺ ⫺ NA
Other NA NA Rash NA NA
Pharmacokinetics
Loading dose NA NA 70 mg NA NA
Daily dose 400 mg 50 mg 50–200 mg 200 mg
Route Oral Oral IV IV IV
Half-life (h) 15–20 113 9–11 12–15 28
Elimination route Hepatic Hepatic Hepatic Hepatic Hepatic
Peak plasma 1 NA 10 NA 8·7
concentration mg/L
Bioavailability (%) NA NA <5 NA NA
Protein binding (%) 90 95 96 99 80
CNS penetration (%) <10 NA NA NA NA
Dose adjustments‡
CrCl 40–60 mL/min NA NA None NA NA
CrCl 10–39 mL/min NA NA None NA NA
CrCl <10 mL/min NA NA None NA NA
Post-HD NA NA None NA NA
Post-PD NA NA None NA NA
CVVH NA NA None NA NA
Moderate liver insufficiency NA NA 35 mg/24 h NA NA
Severe liver insufficency NA NA No information NA NA
Interactions
Increases concentrations NA NA Cyclosporin NA NA
For antifungal activity: +++=excellent, ++=good, +=moderate, +/⫺=poor, ⫺=no activity. For side-effects: ++=frequently reported, +=reported; ⫺=not reported. NA=not available;
CrCl=creatinine clearance; HD=haemodialysis; PD=peritoneal dialysis; CVVH=continuous venovenous haemofiltration; IV=intravenously. *Transient visual disturbances, rash, and
dose-dependent rises in serum concentrations of hepatic enzymes have been reported in up to 20% of patients. Visual disturbances could be due to blockage of receptor d-
excitation and can take various forms: brightness, blurring, light sensitivity, or some changes in colour vision. Typically, they are seen in around 30% of patients, occurring 30 min
after intravenous administration, and lasting about 30 min. †Some researchers recommended 150 mg/kg daily. In any case, serum concentrations should be below 100 mg/L and
the target range 40–60 mg/L.32–35 §Consider dose reduction if other drugs metabolised by P450 isoenzymes are being given concomitantly.

Azoles P450 that brings about sterol C-14 a-demethylation, resulting

The introduction of the imidazole derivatives heralded a new
era in the treatment of fungal infections. Miconazole, the first
such drug introduced, is no longer used because treatment
failures occurred.50 Ketoconazole, which can be taken orally,
has very low toxicity and is useful in various disorders, such as
chronic mucocutaneous candidiasis. Bioavailability is erratic
and depends on gastric acidity; this feature has contributed to
clinical failures. Accordingly, ketoconazole is not used to treat
haematogenous candidiasis.51,52
The next generation of azoles appeared in the early 1980s.
Triazole derivatives selectively inhibit the fungal cytochrome
in decreased ergosterol synthesis and further inhibition of cell-
membrane formation. Triazoles have narrower ranges of
antifungal activity than polyenes, and the spectrum is drug
dependent for many species (table 2). The drugs are available
for oral use and are well tolerated.53,54
Itraconazole has a broad spectrum of activity (table 2).
Because of the unpredictable bioavailability of the original
capsule formulation, the treatment of severe infections
requires the monitoring of individual blood concentrations to
ensure that the drug is sufficiently absorbed,55 which may
explain why the efficacy of itraconazole has not been studied

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 Review
in large prospective series of invasive candidiasis. The
development of new formulations for oral use has much
improved bioavailability and absorption, which is near
complete when itraconazole is combined with the lipophilic
molecule cyclodextrin. In addition to a recently introduced
intravenous formulation, this oral solution has increased
therapeutic options.56 The administration of high intravenous
doses of itraconazole has been associated with cardiac failure
and requires strict surveillance.
Fluconazole has high oral bioavailability independent of
gastric acidity and is also available for intravenous
administration. It is distributed evenly in body tissues,
including the central nervous system. In non-neutropenic
patients, the efficacy of fluconazole (400 mg/day) was
equivalent to that of amphotericin B in the treatment of
candidaemia in two large randomised trials and two
observational studies.57–60 The excellent tolerability and limited
number of drug interactions rapidly made fluconazole the
first-choice agent for almost all candidiasis in non-
immunocompromised hosts, including the critically ill.14–18
In non-neutropenic and HIV-infected patients with life-
threatening candidiasis, some studies showed dose-dependent
responses.58,61 In a prospective study, 65 critically ill patients
with C albicans candidaemia were given fluconazole 5 mg/kg
or 10 mg/kg daily; the clinical response rates were 60% and
80%, respectively.62 Eight patients receiving 5 mg/kg daily and
one patient receiving 10 mg/kg daily died from the fungal
infection. These findings and those on the species-related
differences in fluconazole susceptibility of C glabrata led
investigators to propose a higher initial dose of 800 mg/day
followed by maintenance doses of 400 mg/day.63 Doses of up
to 1600 mg/day have been reported without additional side-
effects.15–18,63 Fluconazole is also beneficial in the treatment of
hepatosplenic candidiasis.64,65
Voriconazole is a new triazole structurally related to
fluconazole, but with improved potency and spectrum of
activity that includes fluconazole-resistant strains of
candida66,67 and most emerging fungal pathogens such as
Blastomyces dermatitidis, Fusarium spp, and Penicillium
spp.66–68 Parenteral administration can be followed by oral
therapy. Voriconazole is currently approved in many countries
for primary treatment of acute invasive aspergillosis69 and
salvage therapy for rare but serious fungal infections. Clinical
trials on treatment of candidaemia are under way. Transient
visual disturbance is one of the secondary effects that is worth
mentioning (table 2).
Ravuconazole is structurally related to fluconazole and
voriconazole. Its potency to inhibit sterol C-14 demethylation
is similar to that of itraconazole. The antifungal spectrum is
similar to that of voriconazole.66,70 Results of a current phase III
clinical trial have not yet been reported.71
Posaconazole is structurally related to itraconazole and has
a broad spectrum of activity, at least as good as voriconazole. It
is currently under assessment in phase III clinical trials and has
been formulated only in oral tablet and suspension
preparations. Compared with itraconazole, posaconazole is a
significantly more potent inhibitor of sterol C-14
demethylation, particularly in Aspergillus spp.46,66,67 Case reports
of rescue treatment for rare pathogens have been reported.53,72
776 THE LANCET Infectious Diseases Vol 3 December 2003
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Management of candidiasis
Echinocandins
Echinocandins are a new class of antifungal agents that inhibit
the synthesis of 1,3-ß-glucan of the cell wall of many fungi,
resulting in osmotic instability and cell death. The lack of
glucan synthesis enzymes in mammalian tissue explains their
selective antifungal activity.
Echinocandins are fungicidal against a large variety of
organisms, including triazole-resistant strains of candida
(table 2).30 They are also active against Candida spp embedded
in biofilms.40 Caspofungin, micafungin, and amphotericin B
showed a postantifungal effect for longer than 12 h against
Candida spp when tested at concentrations above the
minimum inhibitory concentration; fluconazole showed no
such effect.73 Thus, echinocandins could be especially useful in
the treatment of severe candidiasis.
Caspofungin is a water-soluble, semisynthetic, amine-
derivative polypeptide. In vitro, it shows antifungal activity
against a wide array of clinically important fungi, including
Candida and Aspergillus spp.74,75 It is generally well tolerated
with negligible side-effects.30,76 Caspofungin is currently
approved as rescue treatment for refractory aspergillosis.77 In a
double-blind trial, caspofungin was as effective as
amphotericin B in patients with candidaemia, with a
favourable response in 72% and 63% of patients, respectively
(difference 10·0% [95% CI –4·5 to 24·5]).75 Further analysis
showed that caspofungin was superior even in a subgroup of
patients who met prespecified criteria for assessment (81% vs
65%; difference 15·4% [1·1 to 29·7]). There were significantly
fewer drug-related adverse events in the caspofungin group.
These results and the low toxicity of caspofungin could help to
make it first choice in primary therapy of candidiasis,
particularly in cases of documented or suspected non-albicans
candidal infection, or in patients previously exposed to triazole
prophylaxis or treatment.
Of the other echinocandins, anidulafungin has been
investigated in treatment of diseases caused by Candida spp.78
Its activity in vitro was superior to that of triazoles against C
albicans, C tropicalis, C glabrata, and C krusei.79 Combinations
of fluconazole and caspofungin or anidulafungin did not show
synergy or antagonism against some isolates of candida and
Cryptococcus neoformans in models in vitro.80 However, these
findings warrant future clinical evaluation.
Micafungin is under development.78 It has potent in-vitro
and in-vivo activity against various pathogenic Candida and
Aspergillus spp. In-vitro studies showed greater potency than
triazoles or polyenes against most fungi.81 Micafungin is also
active against azole-resistant C albicans and shows no cross-
resistance with azoles.82
Combination therapy
The results of combination studies strongly depend on the
methods used. Published in-vitro data show great variability,
are rather controversial, and may not be predictive of results
obtained with animal models or in clinical studies.83
Antagonism between azoles and amphotericin B is
commonly reported.14–16 Azoles inhibit biosynthesis of
ergosterol, which is no longer incorporated into the
membrane; thus, the main target of amphotericin B is
restricted. In some experimental models, this antagonism was
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 Management of candidiasis
Review

Table 3. Recommendations for treatment of severe candidiasis in non-immunocompromised patients14-19,28,29,75,85,86

Type of candidiasis Key recommendations Antifungal agents Comments
Candidaemia and All episodes should be treated Amphotericin B 0·6 mg/kg daily* Blood cultures should be done
haematogenous Therapy should be continued at least 2 weeks Fluconazole 12 mg/kg daily initially, during and after therapy
candidiasis after the last positive blood culture and followed by 6 mg/kg daily* IV–oral switch The choice of antifungal agents
resolution of clinical signs of infection Lipid formulation of amphotericin B should be based on
Combined treatments (mostly 1–5 mg/kg daily† species identification and
amphotericin B and flucytosine) are Caspofungin 70 mg initially followed susceptibility testing
recommended by some authors in by 50 mg/daily‡
unstable patients Voriconazole 6 mg/kg daily initially, followed
by 4 mg/kg daily,§ IV–oral switch
Catheter-related Removal of all vascular access lines As above The level of evidence is higher for
candidaemia should be systematically considered immunocompromised patients
All vascular access devices should be Surgically implanted devices are
removed and replaced at another site in also concerned by these
patients with breakthrough candidaemia recommendations
Catheter exit-site All vascular access lines concerned should As above ··
infection be removed and replaced at another site
Local debridement should be considered
Hepatosplenic Generally necessitates long-term Fluconazole 6 mg/kg daily with early Limited experience reported
candidiasis therapy (up to several months) IV–oral switch More common after marrow
Amphotericin B 0·6 mg/kg daily recovery from aplastic periods
Other antifungals
Candidal pneumonia Candida spp isolated from respiratory tract, Amphotericin B 0·6 mg/kg daily ··
including by bronchoscopic techniques, should Lipid formulation of amphotericin B
not be automatically considered pathogenic 1-5 mg/kg daily
Definitive diagnosis relies on Fluconazole 12 mg/kg daily initially,
histopathological confirmation followed by 6 mg/kg daily IV–oral switch
Meningitis Combined therapy (amphotericin B and Amphotericin B 0·6 mg/kg daily ··
flucytosine) recommended by many authors Lipid formulation of amphotericin
B 1–5 mg/kg daily
Other antifungals¶
Endophthalmitis Antifungals combined with surgical Amphotericin B 0·6 mg/kg daily Confirms the diagnosis of
debridement should be considered in every case Lipid formulation of amphotericin B disseminated candidiasis
Combined treatment (amphotericin B and 1–5 mg/kg daily A source of candidaemia should
flucytosine) recommended by many authors Other antifungals be actively sought
Abdominal candidiasis Pathogenicity of Candida spp may be difficult Amphotericin B 0·6 mg/kg daily Candida spp may not be
(peritoneum, pancreas, to establish, but attempts should be made Lipid formulation of amphotericin B considered pathogenic if isolated
gallbladder) A surgical approach should be considered in 1–5 mg/kg daily† in low or moderate amounts or if
combination with antifungals for abscesses Fluconazole 12 mg/kg daily initially, a prompt repair of the initial
and peritonitis followed by 6 mg/kg daily IV–oral switch bowel damage could be achieved
Drainage should be done for candidiasis Other antifungals** Candida spp should be
of the biliary tree suspected to be pathogenic in
Patients with recurrent perforation may cases of pancreatitis
benefit from antifungal prophylaxis
Candiduria Pathogenicity of Candida spp may be Amphotericin B 0·3–1·0 mg/kg daily Short course treatment (7–14
difficult to establish for 1–7 days* days) is generally effective
Treatment is generally not required for Fluconazole 3 mg/kg daily* with rapid If complete removal of foreign
asymptomatic catheter-associated candiduria IV–oral switch material is not possible,
Removal of urinary-tract instruments/devices Amphotericin-B bladder irrigation may placement of new devices may
is helpful and commonly successful be successful for short periods only be beneficial
Short treatment or prophylaxis should be Other antifungals** May represent an early
considered in low-birthweight neonates, manifestation of colonisation and
immunocompromised patients, and those should stimulate an active search
scheduled for urological manipulations at other locations
Non-genital Severe oropharyngeal and oesophageal Amphotericin B 0·6 mg/kg daily Topical antifungals are of limited
mucocutaneous candidiasis commonly requires Fluconazole 12 mg/kg daily initially, efficacy in many cases
candidiasis systemic therapy followed by 6 mg/kg daily* Liquid formulations of
IV-oral switch itraconazole can help to
Itraconazole 5 mg/kg oral cure clinically resistant
Other antifungals†† forms of oesophagitis
Disseminated Should be considered a disseminated See candidaemia ··
cutaneous candidiasis disease
in neonates
*Currently approved for use in this indication by regulatory authorities in many countries. †Restricted use: only for patients with severe side-effects (infusion-related and/or
nephrotoxicity). ‡Registration procedure in progress in many countries. §Multicentre clinical studies in progress. ||Case reports of cure with other antifungals (lipid forms of
amphotericin B; voriconazole; caspofungin). ¶Case reports of cure with voriconazole. **Limited experience with other antifungals. ††Excellent cure rate obtained with voriconazole
and with caspofungin.29,86

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 Review
1␮m
Figure 1. Catheter-related candidaemia in a critically ill patient. Internal
lumen of the infected central venous catheter obtained by scanning
electronic microscopy shows C albicans (hyphae) and coagulase-
negative staphylococci embedded in the biofilm.
not observed and recent clinical findings suggest an additive
effect.84 The development of new classes of antifungal agents
will clearly allow testing of combination therapies, but this
will require better standardisation for in-vitro testing.
Furthermore, the real effect of such strategies can only be
assessed through well-designed, large clinical trials. The
simultaneous availability of new antifungal drugs should be
viewed as an opportunity to test more complex strategies,
including prophylactic or decolonisation regimens among
selected subgroups of patients.
Management of specific clinical conditions
The management of different forms of severe candidiasis is
summarised in table 3.14–19,28,29,75,85,86
Candidaemia and haematogenous candidiasis
The lack of antifungal treatment or a delayed onset
of therapy are independent predictors of death from
candidaemia.3,8,11–13,87,88 Without prompt initiation of adequate
antifungal therapy, endophthalmitis, endocarditis and other
severe disseminated forms of candidiasis can complicate
candidaemia.89–91 Accordingly, systematic treatment of all
episodes of candidaemia is recommended by investigators
and consensus conferences.14 On the basis of the results of
therapeutic studies in critically ill patients, antifungal
treatment should be continued for at least 2 weeks after the last
positive blood culture and resolution of clinical signs of
infection. Short-term treatment (7–14 days) can be considered
in stable patients, with candidaemia duration of less than 48 h
and no complications 15–19,85
Catheter-related candidaemia
Intravenous catheters are the commonest sources of
candidemia (figure 1).92 Removal of catheters without systemic
antifungal therapy has been associated with a high rate of
778 THE LANCET Infectious Diseases Vol 3 December 2003
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Management of candidiasis
complications.93 Nevertheless, many candidaemic patients are
still treated without removal of vascular access. To date, no
randomised controlled study has been specifically designed to
assess the benefit of systematic access removal, which remains
a controversial issue.14,15,17–19,28 Of 15 studies that assessed
outcome of candidaemia in relation to vascular-access
management, only seven included multivariate analyses with
complete information and control for confounding
variables.94
In a retrospective series of 363 episodes of candidaemia in
patients with cancer, changing the central venous catheter was
associated with a good outcome in 80% (97/121) of patients
compared with 54% (131/243) without device removal or
changing.88 An earlier change had a greater effect, and the
benefit persisted until 2 days after the start of antifungal
treatment. Severity of illness (odds ratio 1·05 per additional
point [95% CI 1·03–1·07]), persistent neutropenia (11·0
[4·6–24·0]), and visceral dissemination (6·0 [3·3–11·0])
independently predicted death. After correction for illness
severity, the lack of catheter change had only a marginal effect
(2·0 [1·4–2·9]) compared with antifungal treatment (0·21
[0·09–0·50]). In a prospective observational study of 54 cases
of candidiasis in cancer patients, including 43 of candidaemia,
Nucci and colleagues recorded higher mortality for patients in
whom a central venous catheter was retained.95 Severity of
illness (46·6 [6·3–861]), persistent neutropenia (33·1
[2·2–498]), and age (1·06 for each additional year [1·01–1·11])
independently predicted death. In another prospective
observational study of 145 patients from six tertiary hospitals
in Brazil, catheter retention was independently associated with
an increased risk of death (4·22 [2·0–11·6]).96 Further analysis
revealed that mortality was lower only in the subgroup of 21
patients with neutropenia.94
In a retrospective series of 173 non-neutropenic adults
with candidaemia, mortality was significantly lower, after
adjustment for disease severity, for patients in whom the
catheter was removed (0·62 [0·38–0·99]).12 Other significant
predictors of death were the duration of fungaemia (1·06 per
day [1·02–1·12]) and the adequacy of antifungal treatment
(0·52 [0·32–0·84]).
In a retrospective review of 171 episodes of invasive
candidiasis among recipients of bone-marrow transplants,
including 104 cases of candidaemia, disseminated infections
occurred in 62% (21/34) of patients from whom the central
venous access was removed compared with 55% (36/66) of
those in whom it was maintained.8 No adjustment for disease
severity was reported, but catheter maintenance was associated
with a longer duration of candidaemia.
Nguyen and co-workers investigated risk factors for
mortality in a large prospective series of 407 episodes of
candidaemia.60 Mortality among patients with catheter-related
candidaemia was significantly higher for those whose lines
were retained (41%) than for those from whom they were
removed (21%); the difference remained significant after
adjustment for severity of illness. Among 118 candidaemic
patients, higher severity scores, absence of catheter removal,
persistent candidaemia, and lack of antifungal treatment were
significantly associated with fatal outcome. Finally, in a post-
hoc analysis of 206 episodes of candidaemia, withdrawal or
http://infection.thelancet.com
 Management of candidiasis
change of vascular access at the time of diagnosis was
associated with a significant decrease in the duration of
candidaemia (5·5 vs 4·2 days), suggesting that the delay before
withdrawal or change of vascular access should be taken into
account in outcome assessement.57,97
Further studies have explored the influence of vascular-
access management on the outcome of patients with
candidaemia.84,98–103 However, these did not use multivariate
techniques to adjust for important confounders. Some
suggested that mortality was influenced by the maintenance of
vascular access.98–100
In summary, despite continuing controversy,28,94 and as
currently proposed by most commentators,8,12,57,88,95–103 we
recommend that all vascular access should be systematically
removed at the time of clinical sepsis,104 in particular in the
presence of candidaemia, and especially for unstable, critically
ill patients or when a persistent focus of infection is
suspected.14–19
Peritonitis
Postsurgical candidiasis is characterised by mortality rates
above 50%.105–111 There is no real consensus on diagnostic
criteria for peritonitis. Some researchers judge that the
presence of candida in any abdominal specimen justifies
empirical antifungal treatment,112 whereas others view it as a
contaminant in most cases. Among 206 non-neutropenic
patients with candidaemia, Rex and colleagues found that
abdominal surgery was a risk factor in 61 (31%), but
peritonitis as the source of candidaemia was identified in only
nine.57 In a series of consecutive patients followed up after
abdominal surgery, candida was deemed a contaminant in
most cases.107 Candida spp were pathogenic in the presence of
pancreatitis and in all patients with anastomic leakage or
recurrent perforation of the digestive tract. Candida spp were
also pathogenic when recovered in large amounts in the initial
surgical specimen or isolated in increasing amounts over
sequential cultures. At least three other studies have had
similar findings.108,110,111 The management of postsurgical
candidiasis should combine optimum antifungal therapy and
an adequate surgical approach (table 3).105,107,108,110,111
Urinary-tract infections
Urine is normally a sterile biological fluid; candiduria can be
detected in 0·2–6·0% of the general population, in 1·3–11·0%
of patients in hospital, and in 20–30% of critically ill patients
with urinary catheters.113 Candida spp are the cause of 10–30%
of nosocomial urinary-tract infections.114,115 Fungus ball of the
upper urinary tract is a rare complication and requires
surgical management.116
Candiduria can remain asymptomatic and disappear
spontaneously, or lead to pyelonephritis, or manifest as an
early marker of candidaemia. Asymptomatic candiduria in
patients without urinary catheters can be managed similarly to
disorders associated with bacteriuria.113,117,118 Candiduria
preceded bloodstream infection in only 8% of a consecutive
series of 70 children with candidaemia.99 Thus, its clinical
importance remains uncertain. Many researchers recommend
that risk factors and underlying conditions should be taken
into account before decisions on treatment are made.15,17,119
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Review
A high mortality rate has been reported among candiduric
critically ill patients, but it is probably related to the severity
of comorbid and underlying diseases.120 In a series of
861 episodes of candiduria, in which only 10% of patients
presented without comorbidity, 170 (19·8%) patients died.121
Candidaemia developed in seven (1·4%) but death was
directly attributable to candidaemia in only two (0·4%).
Candiduria resolved in 288 (33%) patients; 117 (41%) did not
receive any antifungal treatment. Withdrawal of the urinary
catheter alone was successful in 41 (14%) patients. The efficacy
of fluconazole was investigated in a double-blind placebo-
controlled randomised study in a subset of these patients.122
Candiduria resolved in 79 (50%) of 159 in the fluconazole
group and 46 (29%) of 157 in the placebo group (p<0·001).
However, urine cultures done 2 weeks later did not show a
significant difference in the eradication rates between the
groups (68% vs 65%), which suggests that systematic
antifungal treatment of asymptomatic candiduria may not be
beneficial.123
Antiseptic-coated urinary catheters were effective in the
prevention of catheter-associated urinary-tract infections,124,125
but did not significantly influence the rate of candiduria.126
Pneumonia
Upper-airway colonisation by candida is commonly reported
in critically ill patients, particularly in those mechanically
ventilated, and the organism figures regularly among
pathogens causing nosocomial pneumonia.127 However,
candida has very low affinity for alveolar pneumocytes,
and histologically proven candidal pneumonia is rare.13,128
The clinical importance of candidal isolates from airway
specimens is difficult to assess,129 even when the samples
are obtained by bronchoalveolar lavage or protected
brushing.130,131 Apart from rare primary candidal pneumonia,
haematogenous dissemination of candida may be a cause of
multiple pulmonary abscesses and should be viewed as a
distinct entity (figure 2).17,131 The existence of true candidal
pneumonia is generally doubted, and definitive diagnosis
requires histological demonstration of invasive disease.132
Thus, recovery of candida from the respiratory tract is
generally deemed colonisation and does not require
antifungal therapy.15–17,19
Figure 2. Open lung biopsy from a 45-year-old patient with persistent
acute respiratory distress syndrome 3 weeks after recurrent anastomotic
leakage of the jejunum. Haematoxylin-eosin staining showing hyphae (in
red) originating from a pulmonary capillary vessel (courtesy of J C Pache,
Clinical Pathology, University of Geneva Hospitals).
779
 Review
Figure 3. White cotton-wool exudates of candida on opthalmoscopy. One
lesion shows haemorrhagic transformation. Reproduced with permission
from ref 133.
Endophthalmitis
The presence of white cotton-wool exudates with vitreal
extension on ophthalmological examination is traditionally
considered a sign of present or recent candidaemia
(figure 3).89,133–135 However, as reviewed by Rodriguez-Adrian
and colleagues,136 although non-specific retinal lesions
(cotton-wool spots, superficial retinal haemorrhages, Roth
spots, diabetic retinopathy) were reported in 74 of 414
candidaemic patients (18% [range 15–78]) included in seven
prospective studies in which the investigators reported
systematic ophthalmological examination, true retinal
chorioretinis or endophthalmitis was identified in only 39
of 335 patients (11% [0–26]) in whom detailed information
about the nature of the lesions was available.136–141 Rodriguez-
Adrian and co-workers reported 15 retinal lesions among
77 surgical critically ill patients (19%) in whom repeated
ophthalmoscopy was done prospectively.136 Of these patients,
only one developed sepsis-related cotton-wool spots and
retinal haemorrhage after Candida spp and staphylococcal
catheter-related infections. A large variety of non-specific
retinal lesions developed in the 14 other patients, and at least
one systemic disease that could potentially cause these lesions
was found in 13. These findings confirmed those of other
prospective studies in which retinal lesions were reported in 66
of 372 (19% [12–26]) of patients with bacteraemic sepsis.142–144
Despite the evidence that opthalmoscopy in critically ill
patients has limited value for the diagnosis of candidal
infection, it should be done systematically when disseminated
candidiasis is suspected. Candidal endophthalmitis requires
antifungal therapy; the recommended dose and treatment
duration vary according to the species identified in cases of
candidaemia and to the clinical evolution of the lesion, but the
780 THE LANCET Infectious Diseases Vol 3 December 2003
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Management of candidiasis
duration should be at least 2 weeks. Most patients require
longer treatment.57,75,140,145 Some reports suggest combination of
azoles and flucytosine in severe cases.14–19,28
Prevention of severe candidiasis
Improvement of quality of care
Recommendations for preventive measures should primarily
target a reduction of exposure to risk factors.146 These
strategies should be based on the general improvement of the
quality of care through implementation of education-based
strategies, including basic infection-control measures such as
hand hygiene practices,147,148 guidelines for catheter insertion
and use,104,149 and antibiotic control.150
Pre-emptive therapy or antifungal prophylaxis
There have been specific attempts to lower the incidence of
candidiasis since the early 1980s.3,105,106,151 Research was essential
to elucidate the pathophysiology of candidiasis and was the
origin of the concept of early pre-emptive and prophylactic
approaches (panel).16 Sequential spread of candidal
colonisation from the abdominal cavity to other body sites
before candidaemia occurred was described by Solomkin and
colleagues,105 who also demonstrated the role of early
antifungal therapy,106 the pre-emptive aproach, in the presence
of risk factors for infection and substantial colonisation. Pre-
emptive therapy defines early antifungal treatment given to
patients with several risk factors for infection and evidence of
significant candidal colonisation, and prophylaxis refers to the
use of antifungal agents in subgroups of patients at high risk of
candidal infection and for whom such an approach has been
demonstrated to be beneficial.152
Azole-based prophylaxis
Triazole-based prophylaxis to prevent severe candidiasis is
nowadays routine in patients with persistent neutropenia after
chemotherapy for haematological malignant disorders or after
bone-marrow transplantation.5 This strategy reduces the need
for parenteral antifungal therapy for superficial and invasive
fungal infections and infection-related mortality.153–155
Similarly, benefit has been proven among recipients of solid
organ transplants.156,157 Azole prophylaxis also prevents severe
morbidity associated with oropharyngeal or oesophageal
candidiasis in HIV-infected patients.158,159 The use of
extended-spectrum antifungals could be particularly useful
in neutropenic patients.160 However, as discussed earlier, this
strategy is one of the causes of the observed epidemiological
Antifungal strategies–operational definitions
Pre-emptive therapy
Early antifungal treatment administered to patients with
evidence of substantial colonisation in the presence of
multiple risk factors for candidal infection (figure 4)
Prophylaxis
Antifungals prescribed to patients in groups at high risk of
candidal infection: organ-transplant recipients; immuno-
compromised patients with expected or current long-term
neutropenia; defined groups of non-immunocompromised
patients in whom prophylaxis is known to be effective (table 4)
http://infection.thelancet.com
 Management of candidiasis
Review

Table 4. Published trials on antifungal prophylaxis in critically ill non-immunosuppressed patients

Ref Year Design Patients Drug used for Duration n Colonisation Invasive Mortality Comments
prophylaxis candidiasis

Positive studies
151 1987 P, R, DB, Surgical ICU with Ketoconazole ND 27 8 (30%) 0 7 (26%) ICU costs
PC at least 3 risk 200 mg/day orally ND 30 18 (60%)* 5 (17%)* 11 (37%)† US$4800 vs 10 000;
factors Placebo *length of ICU stay
6·0 vs 12·5 days
164 1992 P, R, DB, Surgical ICU with Nystatin/norfloxacin 13 days 25 13 (52%) 6 (24%) 13 (40%) Nosocomial
PC hypermetabolism orally 20 days† 21 18 (85%)† 13 (62%)† 10 (48%)† infections per patient:
Placebo 0·9 vs 2·0†
165 1992 Cohort, Burn patients Nystatin/polymyxin ND 1042 219 (16%) 34 (3·3%) ND Wound infections 59
retrospective orally/topically (21%) vs 22 (10%)*
No antifungal ND 1439 277 (27%)* 0* ND
prophylaxis
110 1999 P, R, DB, Surgical with Fluconazole 15 days 23 2/13 (15%) 2 7 (30%) Candidal peritonitis
PC anastomotic 400 mg/day IV 17 days† 20 8/13 (62%)* 7† 10 (59%)† 1 (4%) vs 7 (35%)*
leakage Placebo
166 2001 P, R, DB, Surgical ICU Fluconazole ND 130 ND 11 (8%) 14 (11%) 78% and 89% of
PC >3 days 400 mg/day orally patients were
Placebo ND 130 ND 20 (15%)* 16 (12%)† colonised at entry†
167 2001 P, R, DB, Preterm neonates Fluconazole 6 weeks 50 11 (22%) 0 4 ( 8%) First prophylactic
PC <1000 g 3 mg/kg IV‡ study showing a
Placebo 6 weeks 50 30 (60%)* 10 (20%)* 10 (20%)† significant effect on
mortality
92 2002 P, R, DB, Mechanically Fluconazole 100 mg 8 days 103 29/55 (53%) 4 (4%) 40 (39%) Candidaemia 9 (9%)
PC ventilated >96 h IV and SDD vs 1 (1%)§
Placebo and SDD 8 days 101 40/51 (78%)* 10 (10%)† 41 (41%)†
168 2003 P, R, DB, Early septic shock Fluconazole 200 mg IV 32 0 0 7 (22%) First prophylactic
PC (within 24 h) Placebo 39 1 (3%)† 0 21 (54%)* study showing
Due to pneumonia Fluconazole 200 mg IV 10 days 18 ND 0 5 (28%) significant effect on
Placebo 7 days† 19 ND 0 8 (42%)† mortality in adults;
Due to peritonitis Fluconazole 200 mg IV 9 days 14 ND 0 2 (14%) septic shock was of
Placebo 7 days† 20 ND 0 13 (65%)* bacterial origin in all
but one placebo
case, who were
admitted with
disseminated
candidaemia

Negative studies
169 1994 P, R Surgical ICU Nystatin 2 x 106 ND 75 11 (15%) 5 (7%) 14 (19%)† ··
>2 days 4 x daily orally
Ketoconazole ND 65 8 (12%)† 1 (2%)† 5 ( 6%)†
200 mg/day orally
Clotrimazole 10 mg ND 80 14 (18%)† 1 (1%)† 10 (13%)†
3 x daily orally
All prophylaxis ND 220 33 (15%)† 7 (3%)† 29 (13%)†
No prophylaxis ND 72 17 (23%)† 2 (3%)† 12 (17%)†
170 2000 P, R, DB, Surgical ICU Fluconazole¶ 8 days 60 ND 8 (13%) 12 (20%) A high proportion of
PC >2 days and risk Placebo 8 days† 59 ND 11 (19%)† 11 (19%)† candidiasis cases
factors|| were respiratory-tract
infections
111 2002 P, R, DB, Patients with intra- Fluconazole 1 day 53 ND ND 4 ( 8%) No data other than
PC abdominal 400 mg IV death rate could be
perforation Placebo 1 day† 56 ND ND 8 (14%)† extracted from the
paper

P=prospective; R=randomised; DB=double blind; PC=placebo-controlled; ICU=intensive-care unit; ND=not described in the original paper; IV=intravenous; SDD=non-absorbable
syrup containing polymyxin B (150 mg), neomycin (1000 mg), and vancomycin (1000 mg) in 60 mL, administered in 15 mL doses six times daily. *p<0·05 for study drug vs
placebo. † Difference not statistically significant. ‡Fluconazole 3 mg/kg once every 3 days during the first 2 weeks, then 3 mg/kg on alternate days for 2 weeks, then 3 mg/kg daily
for 2 weeks. §Relative risk for candidaemia 0·10 (95% CI 0·02–0·74; p<0·05); candidiasis 6·6 vs 19 per 1000 patient-days, relative risk 0·35 (0·11–0·94, p 0·02). ||At least one of
the following within 48 h of inclusion: placement of a central venous line; total parenteral nutrition; artificial ventilation >24 h; broad-spectrum antibiotics. ¶Fluconazole 800 mg IV or
orally initially, then 400 mg daily IV or orally.

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 Review Management of candidiasis

is expected to be higher than 10%.16,152

Patient at risk of severe candidiasis
This selective approach may help to
limit the amount of antifungal drugs
used for prophylaxis and delay the
Colonisation by Candida spp
emergence of infections due to non-
albicans candida strains observed in
No Yes immunocompromised patients. It
should not, however, be generalised to
Assess the presence of groups of critically ill patients in whom
risk factors (see legend) it has not be proven to be beneficial.

Strategies for the critically ill

Yes Many critically ill patients have several
risk factors for candidal infection. Many
Identification of become colonised with Candida spp
specific groups of Unstable or during their hospital stays, but in
patients septic patient contrast to immunocompromised
(see text)
individuals, only a minority will
develop candidiasis. As discussed in
Yes the first part of this review,11 the
Yes No obtain 2 sets of predictive value of the non-quantitative
blood cultures assessment of candida colonisation is
low. Accordingly, antifungal treatment
or prophylaxis recommended for
Antifungal Pre-emptive immunocompromised patients cannot
prophylaxis therapy be systematically applied to all critically
ill, non-neutropenic patients.
Taking into account both the
Search for colonisation (twice per week)
relative importance of risk factors and
wound/skin breakdown perineal swab
the dynamics of colonisation by
catheter insertion site urine
sputum/oropharynx post-surgical drainage Candida spp, we propose a strategy for
the clinical diagnosis and practical
management of critically ill patients
suspected to have or at risk of severe
Assess the degree of colonisation by
candidiasis (figure 4).133 Although not
<0·5 calculating the colonisation index ⭓0·5
(number of positive sites/number of sites cultured) validated by prospective clinical studies,
this strategy clearly distinguishes
Figure 4. Risk factors significantly associated with the development of candidaemia include: prophylactic from pre-emptive therapy.
candida colonisation, exposure to antibiotics, intravascular access, bladder catheter, neutropenia, In any case, attempts at reducing the
diarrhoea, parenteral nutrition, antacids, surgery, steroids, chemotherapy, renal failure, mechanical importance of the documented risk
ventilation, length of stay, severity of disease, and age.
11
factors should be made.
shift toward non-albicans candida strains reported in Pre-emptive antifungal therapy should be given to patients
immunocompromised patients.6,11,119,161,162 with well-established risk factors, including a known degree
No recommendations for antifungal prophylaxis in non- of colonisation with Candida spp. In these patients, the risk
immunocompromised patients were included in the recently of severe candidiasis is so high that the benefit of immediate
published guidelines for treatment of candidiasis17 because no antifungal treatment outweighs its potential side-effects,
single prophylactic study had sufficient statistical power to including the possible emergence of resistant strains.
establish the regimen for larger groups of critically ill Alternatively, in cases of suspected candidiasis, the
patients.152 However, several studies, including seven that were worsening general condition of a critically ill patient with
placebo controlled, showed the possible benefit of triazole- multiple organ failure may also justify empirical antifungal
based antifungal prophylaxis in well-targeted subgroups of treatment before blood-culture results are available. For
non-neutropenic, critically ill patients.92,110,151,163–168 In contrast to patients with some risk factors, but in whom the immediate
these studies, which were designed to include carefully selected institution of antifungal treatment is not justified,
groups of patients at very high risk of candidiasis, three assessment of the degree of candidal colonisation will allow
studies, in which antifungal prophylaxis was administered early identification of those who might benefit from pre-
to low-risk patients, had negative results111,169,170 (table 4). emptive antifungal therapy.
These findings strongly suggest that antifungal prophylaxis in Prophylaxis should be considered only for selected groups
non-immunocompromised patients should be considered of patients in whom the frequency of candidaemia is
only for selected groups in which the frequency of candidiasis sufficiently high for the intervention to be beneficial.92,110,165–167

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 Management of candidiasis
Review

The proposed strategies need to be tested in prospective
controlled clinical trials. Careful screening for acquisition of
resistance should be done periodically in wards where such
strategies are implemented.
Perspectives for the future
Therapeutic modalities: other approaches
Recent findings in patients with chronic mucocutaneous
candidiasis have documented altered patterns of cytokine
production in response to Candida spp with decreased
production of some proinflammatory cytokines and increased
amounts of interleukin 18.171 These novel insights into
immune mechanisms of protection against candida create new
possibilities of immunomodulation and vaccination that
could prove beneficial in the future.172
Recovery from candidiasis produces an intense antibody
response to heat-shock protein 90.173 Patients who die produce
little or no such antibody. In preclinical trials, both a murine
monoclonal antibody and human recombinant antibody to
heat-shock protein have shown protective potential in animal
models.174 In addition, a human recombinant antibody against
C albicans heat-shock protein antigen has shown antifungal
activity and synergy with amphotericin B against several
fungal species.175
Search strategy and selection criteria
Data for this review were identified by searches of Medline,
Current Contents, and references from relevant original
articles published in English, French, or German between
1975 and 2003; many articles were identified through
searches of the extensive files of the authors. Key word terms
included “candidaemia”, “candidiasis”, “invasive candida
infections”, “mycosis”, and “fungal infections” combined with
“critically ill”, “management”, “guidelines”, “strategy”,
“antifungals”, and “prophylaxis”.
A potential approach is to block or compete with these
receptors. This concept has been tested in cell cultures
and in animal models; some natural strains of lactobacillus
compete for the receptor, thus blocking the adhesion of
most candida strains.177 Clinical studies should test this
approach.
Multicentre studies
New antifungal agents, non-culture detection systems, and
better defined clinical concepts are urgently needed.
Importantly, the low frequency of candidiasis in most
institutions means that only large, multicentre clinical trials
can provide appropriate evidence.

Probiotics Acknowledgments
We thank Rosemary Sudan for continous editorial assistance.
The virulence of Candida spp is partly linked to their ability
to adhere to mucosal surfaces through complex sugar Conflicts of interest
molecules, which should be considered as true receptors.176 None declared.

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