Review article

To treat or not to treat – critically ill patients with candiduria

Eike Hollenbach
Interdisciplinary Intensive Care Unit, Department of Medicine, University of Leipzig, Leipzig, Germany

Summary The prevalence of candiduria has increased in patients admitted to intensive care units
(ICUs) and it has emerged as a common nosocomial infection among critically ill
patients. Generally, urinary candidiasis should be regarded as a risk factor for invasive
candidiasis, but not as a disease that needs to be treated on its own. However, decision-
making in critically ill patients with candiduria may become a balancing act, because
candiduria may be the only indication for invasive candidaemia with significant
morbidity and mortality. Of further concern, there is a worldwide increase in the
incidence of non-albicans spp. isolated from urine with highly variable susceptibility to
fluconazole, which has been the first-line therapy for Candida infections during the last
decades. This article discusses everyday problems with urinary candidiasis in
interdisciplinary ICUs.

Key words: Candiduria, intensive care unit, ICU, antifungal therapy.

which is commonly seen in interdisciplinary

Introduction
Although most urinary tract infections (UTIs) are of
bacterial origin, as many as 12% of positive urine
cultures yield a fungal pathogen.1–8 Candiduria is
defined as a superficial infection with Candida spp., and
as such does not belong to the group of invasive
candidiasis (IC) (like e.g. candidaemia, disseminated
candidiasis, deep organ involvement, endocarditis)
according to the Infectious Diseases Society of America
(IDSA) and the European Organization for Research and
Treatment of Cancer ⁄ Mycoses Study Group
(EORTC ⁄ MSG).9–11 Some modifications of this definition
apply for patients with neutropenia.12
Candiduria is an increasingly important problem in
patients admitted to intensive care units (ICUs), partic-
ularly those with a compromised immune system,
impaired natural defence barriers, underlying serious
disease, permanent urinary catheters, multiple manip-
ulations by health care personnel and altered bacterial
flora as a result of the use of broad-spectrum antibiotics
Correspondence: Eike Hollenbach, MD, Interdisciplinary Intensive Care Unit,
Department of Medicine, University of Leipzig, Liebigstrasse 20, D-04103
Leipzig, Germany.
Tel: +49 341 9712700. Fax: +49 341 9712707.
E-mail: eike.hollenbach@medizin.uni-leipzig.de
Accepted for publication 26 May 2008
ICUs.1,4,8,13–15
Management of candiduria remains controversial,
mainly due to cliniciansÕ uncertainties when to initiate
antifungal therapy for candiduria.6,16–18 This decision is
particularly critical, because candiduria is a well-estab-
lished risk factor for IC which in turn is associated with
significant morbidity, mortality and cost in ICU
patients.19,20 In addition, candiduria may be the only
indication for candidaemia, because blood cultures have
been shown to detect less than 30–50% of autopsy-
proven candidiasis, and serological tests are likewise
hampered by limited sensitivity.21 On the other hand,
detection of Candida spp. in urine samples may signify
either harmless colonisation, or lower tract infection, or
upper UTI with a potential for ascending pyelonephritis
and renal candidiasis.4,6,22–24
Epidemiology of candiduria in ICUs
Fungal UTIs encompass a broad variety of fungi. The
overwhelming majority of UTI are caused by Candida
spp., but Cryptococcus and Aspergillus spp. are also
prevalent.25,26
In healthy people, the prevalence of candiduria is as
low as 0–0.3%,6 whereas nosocomial fungal UTI
represent the second most frequent causative microor-
ganism of UTI in patients with urinary catheters,

 2008 The Author

12 Journal compilation  2008 Blackwell Publishing Ltd • Mycoses, 51 (Suppl. 2), 12–24

Table 1 Incidence of Candida isolates from urine of 861 patients
with funguria (data adapted from Ref. 1)
No. (%) of
Candida spp. patients
C. albicans 446 (51.8)
C. glabrata 134 (15.6)
C. tropicalis 68 (7.9)
C. parapsilosis 35 (4.1)
C. krusei 9 (1)
Other1 20 (2.3)
Undetermined 184 (21.4)
1
Includes Candida lusitaniae (5), Candida pseudotropicalis (4), Candida
lipolytica (3), Cryptococcus neoformans (2), Trichosporon beigelii (2),
Saccharomyces cerevisiae (1), Candida kefyr (1), Candida rugosa (1),
and Candida zeylanoides (1).
Thirty-five patients (4.1%) had more than one species isolated at
baseline.
ranging between 12 and 27% of total pathogens
verified.1–8 The National Nosocomial Infection Surveil-
lance System (NNIS) identified Candida spp. as one of the
major causative agents of UTI in patients admitted to
medical and interdisciplinary ICUs in the USA,28 with
Candida albicans being the most frequent cause of
candiduria followed by Candida glabrata and other less
common Candida spp.1,3–5,13,27–29 as summarised in
Table 1. Generally, the incidence of C. glabrata isolated
from urine is increasing throughout the world.4,28,30
This trend is dramatic, given that C. glabrata is not
reliably susceptible to fluconazole, which has been the
mainstay of therapy for Candida infections since the
early 1990s.31 Epidemiologic studies suggest that non-
albicans spp. are more prevalent in urine compared to
other sites of Candida infection (i.e. oropharynx and
vagina), possibly due to urine composition and ⁄ or pH.6
More than one Candida spp. is found in the urine of
about 10% of patients, mainly in co-existence with
bacteriuria.24
The prevalence of candiduria in critically ill patients is
generally increasing and currently ranges from 19 to
44% of urine specimens, depending on patient popula-
tion and definition of candiduria.13,29,32
Routes of infection and risk factors for
candidal UTI
Fungal UTIs are either via an ascending route or by
hematogenous spread. Ascending infection is considered
by far the most common route for infection. Women are
more often affected due to their shorter urethra, and
vulvovestibular colonisation with Candida in the range
of 10–65%.6
 2008 The Author
Journal compilation  2008 Blackwell Publishing Ltd • Mycoses, 51 (Suppl. 2), 12–24
Critically ill patients with candiduria
Urinary catheterisation is the most important risk
factor for candidal UTIs. Urinary catheterisation allows
for direct introduction or migration of organisms into
the bladder along the surface of the catheter. All
catheters become colonised if left in situ for a long
time.8,38 Vesicourethral reflux or obstruction of urinary
flow predispose to infection of the upper urinary tract
and may result in acute pyelonephritis and candida-
emia. In rare cases, renal medullary tissue may be
affected secondary to papillary necrosis.
In contrast, haematogenous spread is the most
common route for renal candidiasis. This might be of
outstanding importance, because 90% of patients with
candidaemia who died had autopsy-proven renal
involvement.34 Candida may gain access to the blood-
stream by intestinal translocation which occurs even in
a healthy person with an intact intestinal mucosa
barrier. In a self-experiment, candidaemia occurred at 3
and 6 h, and candiduria at 2.75 and 3.5 h after
ingestion of 1012 C. albicans,35 a relatively low number
when compared to the physiological fungal burden of
the gut. Of note, transient candidaemia may lead to
isolated renal infection, and blood cultures are often no
longer positive when renal candidiasis becomes mani-
fest.6 Other routes of Candida infection are via central
venous catheters or devices and other localised sources
of fungal infection like an intraabdominal focus or a
septic thrombophlebitis.31
Patients with diabetes are at increased risk for
candiduria, because they are predisposed to enhanced
fungal growth and thus Candida colonisation of the
lower genital tract in the presence of glycosuria.
Further, host resistance to fungal invasion is reduced
in diabetics due to impaired activity of phagocytic cells.
An additional, underestimated condition is neurogenic
bladder in diabetics which promotes stasis of urine and
subsequent fungal translocation ⁄ invasion.6
Additional risk factors in ICU patients include prior
use of broad-spectrum antibiotics, vancomycin or
agents targeting anaerobes, advanced age, female sex,
extended hospital stay before ICU admission, total
parenteral nutrition (TPN), urinary tract abnormalities
(most commonly those leading to obstruction or incom-
plete emptying of the bladder), central venous lines, use
of immunosuppressive agents, radiation therapy, geni-
tourinary tuberculosis, neutropenia, urinary tract
instrumentation, haemodialysis, prior surgery, renal
transplantation and mechanical ventila-
tion.1,6,13,14,29,38–45 Independent risk factors demon-
strated for candiduria were the use of antimicrobial
agents in the preceding 30 days [odds ratio (OR) 8.1;
95% confidence interval (CI) 2.1–31.9] and plasma
13
E. Hollenbach
glucose >180 mg dl)1 (OR 3.1; 95% CI 1.1–9.1).43
Furthermore, emergency surgery, extrarenal depuration
procedures and TPN were identified as independent risk
factors for candiduria in association with IC in previ-
ously healthy and asymptomatic patients.23 Risk factors
for nosocomial candiduria also predispose a patient to
bacteriuria and – not surprisingly – candiduria is almost
invariably preceded by bacteriuria.6,43
Clinical manifestations
Candiduria may reflect various conditions, from asymp-
tomatic candiduria and superficial lower UTI, to candi-
dal colonisation associated with urinary catheterisation
and renal candidiasis. Thus, a wide spectrum of clinical
findings may occur. A large multicentre study suggests
that the vast majority of patients with candiduria are
asymptomatic and only 4% complain of symptoms.1
Symptomatic lower UTI is equivalent to cystitis and may
be associated with dysuria, haematuria, urgency and
suprapubic tenderness. Cystoscopy findings include soft,
pearly white, elevated patches with friable and hype-
raemic mucosa underneath. It has to be emphasised
that cystoscopy is only indicated in patients with
suspected fungus ball and – in very rare cases – in
ascending infections.6 Generally, symptomatic Candida
cystitis is extremely rare compared to the frequency of
candiduria. Prostatic candidal abscesses are not uncom-
mon in patients with diabetes, whereas an emphyse-
matous cystitis is an extremely rare complication in
lower UTI.36,37 In contrast to lower UTI, patients with
upper UTI present with fever, leucocytosis and tender-
ness in the costovertebral angle. Basically, ascending
pyelonephritis and urosepsis by Candida spp. cannot be
clinically distinguished from bacterial upper UTI and
urosepsis. As a rule, upper UTI occurs almost exclu-
sively in the presence of urinary obstruction and stasis.
Candida pyelonephritis is often complicated by local
suppurative disease, resulting in pyonephrosis or
abscess. Obstruction of the upper urinary tract caused
by fungal balls presents clinically as renal colic due to
the passage of fungal ÔstonesÕ and must be excluded by
ultrasonography. Patients with candidaemia and hae-
matogenous seeding into the kidneys (Ôrenal candidia-
sisÕ) may present with high fever and haemodynamic
instability due to sepsis and renal insufficiency.
Diagnosis
For candiduria, therapeutic decisions are primarily
based on personal anecdotal experience of the clini-
cians.16 This is probably due to the fact that no
14 Journal compilation  2008 Blackwell Publishing Ltd • Mycoses, 51 (Suppl. 2), 12–24
diagnostic tools are available to readily differentiate
between candidal UTI, colonisation or contamination in
the ICU setting. It has been shown that 96% of patients
with candiduria are asymptomatic.1 However, informa-
tion on symptoms is often missing from patients at ICUs
due to the frequent use of indwelling urinary catheters
and, thus, failure to perceive frequency or dysuria as
well as the inability to vocalise symptoms while sedated
and ⁄ or ventilated. Furthermore, laboratory findings of
inflammation are of limited value regarding candiduria,
because inflammation at other sites is frequently present
in critically ill patients.
The finding of Candida organisms in the urine may
represent contamination, colonisation of the drainage
device, UTI, or even candidaemia.23 In fact, data
obtained from experimental animal systems of haemat-
ogenous renal candidiasis proved that any concentra-
tion of Candida spp. in the urine could reflect renal
involvement.46 Furthermore, blood cultures have
approximately 40–75% false-negative results and may
take 3–4 days for definitive results, and autopsy studies
have taught us that negative blood cultures and tissue
biopsies have been obtained in more than 50% of
disseminated fungal infection.38,55 Therefore, sensitive
and specific parameters are needed for detection of
fungal UTI, aside from the necessity to diagnose IC.
Unfortunately, there are only very few criteria to help
separate these different conditions associated with
candiduria.
Contamination can usually be differentiated from
colonisation or UTI by obtaining new urine samples and
checking if Candida persists. If patients do not have an
indwelling urinary catheter, then it seems preferable to
obtain another specimen by sterile bladder catheterisa-
tion to avoid contamination by perineal flora. Further
diagnostic studies are dispensable if the second specimen
yields no fungi.
Bladder irrigation with amphotericin B deoxycholate
(50–200 mg ml)1) is rarely indicated to transiently
eliminate colonisation of the bladder;47,48 however, it
might serve as a diagnostic tool because urine samples
remaining positive for Candida presumably reflect upper
UTI.48 Granular cast containing Candida hyphal ele-
ments are rarely found in urine when renal paren-
chyma is infected.
Quantitative Candida urine cultures are frequently
discussed as a tool for fungal UTI diagnosis.16,49 There
are a few interesting studies undertaken in the 1970s
that used renal biopsies to prove renal involve-
ment.42,50,51 However, renal candidiasis was docu-
mented with candidal colony counts in the urine
ranging from 10 000 to 40 000 CFU ml)1 in patients
 2008 The Author

without indwelling urine catheters, and colony counts
ranging from 20 000 to 100 000 CFU ml)1 in the
presence of indwelling urethral catheters. No correla-
tion was documented between colony counts in the
urine and biopsy-proven renal infection.42 Thus, quan-
titative Candida cultures of urine – independent of the
extraordinary capacity of Candida to grow in urine – are
not helpful. Furthermore, there were some attempts to
distinguish infection from colonisation of the bladder by
the presence of pseudohyphae or by antibody-coated
yeasts in the urine, but some species, such as C. glabrata,
cannot make pseudohyphae, and C. albicans can be
induced to form pseudohyphae by varying the pH and
nutrients in the urine, while antibody-coated yeast has
been shown to be non-specific.52–54
Generally, there is as yet no reliable method with
satisfactory sensitivity and specificity to differentiate
colonisation from candidal UTI. This holds especially
true for a typical ICU patient with an indwelling
catheter when Candida spp. are detected in the urine.
Therefore, simply culturing the organism does not imply
clinical significance, regardless of the concentration of
organisms in the urine.
Colonisation vs. infection by Candida and
usefulness of ‘Candida scores’
Candida spp. are part of the normal human gut flora and
occur less frequently on mucocutaneous surfaces. This
condition is usually described as fungal colonisation,
and it is characterised by the adherence and settlement
of yeast, usually on drainage catheters or other foreign
bodies in the urinary tract without any signs or
symptoms of clinical infection.6 More than 50% of ICU
patients are known to be colonised with Candida.13,29,33
Fungal UTI is defined as significant candiduria in the
presence of symptoms.9,12
Colonisation – particularly of multiple sites – should
clearly be regarded as a risk factor and not as a disease
requiring antifungal treatment. A large body of evidence
proves lack of benefit from treatment of the different
forms of colonisation, such as asymptomatic candiduria
in immunocompetent patients.157 However, the risk of
IC may be related to the density and extension of
colonisation over time, and some correlation was found
between ICU mortality and multiple-site fungal coloni-
sation with Candida spp.56–58 Therefore, a Candida
colonisation index (CCI) – defined as the ratio of the
number of culture-positive surveillance sites for Candida
spp. over number of sites cultured – was introduced.56 It
was suggested that a pre-emptive antifungal therapy
should be considered as soon as the CCI is 0.5 or
 2008 The Author
Journal compilation  2008 Blackwell Publishing Ltd • Mycoses, 51 (Suppl. 2), 12–24
Critically ill patients with candiduria
above.59 However, using the CCI with a threshold of 0.5
may increase the use of antifungal drugs and, concom-
itantly, the incidence of resistant species as shown in
surgical ICUs.9,60,61 This correlation was prospectively
re-assessed in one study with 92 non-neutropenic
patients in a medical ICU.58 This latter study did not
clearly recommend the use of the CCI but could
demonstrate an association between use of broad-
spectrum antibiotics and a prolonged stay in the ICU
associated with a higher CCI, whereas other outcomes
could not be clearly associated with this index.
On the other hand, a promising new ÔCandida scoreÕ
(CS) was recently proposed based on a large prospective,
cohort, observational and multicentre study in Spain
with a weekly assessment of fungal colonisation and
other potential risk factors.62 The aim of this study was
to develop a score to support decision-making as to
which non-neutropenic, critically ill patients need an
early antifungal treatment. Using a logistic regression
model, four independent risk factors were identified:
multifocal Candida spp. colonisation, surgery upon ICU
admission, severe sepsis and TPN. The CS is based on
weighting the respective risk factor: surgery upon ICU
admission (1 point), TPN (1 point), severe sepsis (2
points), and multifocal colonisation (1 point). A score of
>2.5 is associated with a 7.75-fold increased likelihood
of proven IC (95% CI, 4.74–12.66) when compared to
individuals with a CS of less than 2.5.62 Furthermore, a
cut-off of 2.5 provides a sensitivity of 81% and a
specificity of 74% for identifying patients with current or
future IC. Identified patients seem to strongly benefit
from early pre-emptive antifungal treatment, supporting
the validity of the CS.62
Another retrospective, multi-centre study was carried
out with 2890 patients who were identified as being at
high risk for IC in the intensive care setting by the
following criteria: ICU stay for at least 4 days, plus either
any antibiotic use or a central venous catheter, plus at
least two of the following criteria: TPN, any dialysis, any
major surgery, pancreatitis, any use of steroids or other
immunosuppressive agents.63 Applying these criteria,
34% of cases in ICUs were captured with an overall rate
of IC of 9.9% (relative risk 4.36, sensitivity 0.34,
specificity 0.90, negative predictive value 0.9). Both
scores seem to be appropriate for routine use.
Significance of candiduria in critically ill
patients
An important issue to determine the significance of
candiduria in critically ill patients is the risk of
candiduria for candidaemia. In one trial, none of 316
15
E. Hollenbach
asymptomatic or minimally symptomatic patients with
candiduria developed candidaemia,24 and in another
study1 only seven (1.3%) of 530 patients with candid-
uria and a follow-up for 12 weeks developed candida-
emia. However, candidaemia can follow candiduria in
the presence of obstruction.72 As a result, prophylactic
antifungal agents should be administered to patients
undergoing urinary tract procedures to relieve obstruc-
tion.9 As a rule, for patients with sepsis who have
candiduria, it is mandatory to obtain blood cultures and
to exclude urinary obstruction.
Contamination of a urine specimen is common,
especially from a catheterised patient or a woman with
heavy colonisation of the vulvovaginal area. Candida
has an extraordinary capacity to grow in urine, thus,
small contaminations may easily result in high colony
counts. Confirmation is usually required, especially for
the asymptomatic patient. Furthermore, there is general
agreement that asymptomatic candiduria is benign
and – if the predisposing factors are corrected – usually
self-limiting.9,24 However, recognition of candiduria is
crucial for the diagnosis of fungal sepsis, as it may be the
only, and is often the first, indication of IC.22
Currently, conclusive data about the importance of
pyuria or quantitative Candida urine cultures for UTI are
lacking.16 Pyuria usually reflects and supports the
diagnosis of infection. However, pyuria can be explained
by mechanical injury of the bladder mucosa by a
urinary catheter. Furthermore, pyuria is frequently the
result of coexistent bacteriuria16,21 as about 25–30% of
patients with candiduria also have bacteriuria, making
it indistinguishable whether pyuria is primarily caused
by bacteria or Candida.1 Additionally, indwelling cath-
eters and even intermittent catheterisation are associ-
ated with inflammation and increased white blood cell
counts.64 Therefore, candiduria should be significant for
the clinician in patients who are likely to develop
complications due to an untreated fungal infection.
Pyelonephritis and the risk of acute worsening of renal
failure secondary to pyelonephritis are not well estab-
lished.16,65 Furthermore, no data suggest that upper
candidal UTI leads to chronic renal failure, perinephric
abscess or papillary necrosis in the absence of obstruction,
in fact, diabetes prerequisites to those complications
more than obstructive fungus balls.16,66–71
Association of candiduria and candidaemia
In patient cohorts consisting exclusively of critically ill
patients, candiduria is significantly associated with
candidaemia with an incidence from 46 to 68%.13,73
Of note, candiduria is mainly detected prior to
16 Journal compilation  2008 Blackwell Publishing Ltd • Mycoses, 51 (Suppl. 2), 12–24
candidaemia indicating an ascending route of infection
in these studies. Therefore, relevant studies emphasise
that candiduria should never be ignored in sepsis, as it
may be the first sign of an IC.17,22,74 Furthermore,
absence of candiduria cannot completely exclude sys-
temic infection, as transient candidaemia may occur,
but candiduria seems to correlate with invasive disease
significantly more than colonisation of other body
sites.75
The largest multicentre study in the ICU setting
proved that rectal and urinary colonisation had a low
positive predictive value for candidaemia, as only 1% of
colonised critically ill patients (n = 4276) presented
with proven candidaemia.76 This association was con-
firmed in another prospective multicentre trial of 861
patients with documented funguria and an incidence of
candidaemia of 1.3%.1 These rates of candidaemia in
critically ill patients with candiduria were surprisingly
low, suggesting that candiduria is not necessarily a
useful predictor for progression to disseminated candi-
diasis. However, blood cultures in patients with candid-
uria – especially in the non-ICU setting – may be
infrequently drawn and thus, documented association
of candiduria and IC (i.e. candidaemia) might largely be
underestimated. Univariate analysis indicated a signif-
icant association of candidaemia with candiduria and
the isolation of fungi at other sites in a case–control
study.77 Multivariate analysis showed an association
between candidaemia and candiduria (OR = 9.79, 95%
CI 2.14–44.76) as well. Identical genetic strains isolated
from blood and urine are found in most studies.78–81
Other studies proved that 52% of Candida isolates from
urine and blood are genetically different, but Candida
rapidly produce genetic variants. 77,82 Thus, the data
indicate that the urinary tract is not necessarily the
source for the candidaemia, at least in a non-ICU
population,77 but strain microevolution with significant
genetic changes has been attributed as a cause of
recurrent or persistent candidaemia.82 However, a
definite urinary source is identified in only 10% of
patients with candidaemia, and urinary tract obstruc-
tion is the commonest risk factor for dissemination of a
candidal UTI83,84 caused by the ascending spread.10
In general, as discussed above, candiduria alone is
ranked very low in the CS, and thus, candiduria should
always be seen in the context of the clinical picture of
the particular patient.
Association of candiduria and mortality
After adjusting for other covariates (i.e. length of ICU
stay, age, treatment with antibiotics), the overall ICU
 2008 The Author

mortality rate among patients with candiduria is
approximately threefold increased and may reach 20–
50% in large prospective multicentre surveillance or
retrospective studies.1,4,13,43,75,85 However, it has been
frequently suggested that candiduria is a marker of a
decreased functional status and of multiple serious
underlying illnesses, as documented by studies in elderly
patients with candiduria and generally higher mortality
rates.1,24,86–88
Generally, the risk of IC may be related to the density
and extension of colonisation over time, and some
correlation was found between ICU mortality and
multiple-site fungal colonisation with Candida spp.56–58
Independent factors associated with mortality include
the use of urinary diversion devices (OR 8.8; 95% CI
1.1–70.5), more than two classes of antimicrobials (OR
4.1; 95% CI 1.2–13.9), ICU setting (OR 3.3; 95% CI
1.1–9.3) and renal failure (OR 2.9; 95% CI 1.1–8.2).43
Treatment
It is completely understandable that ongoing contro-
versies exist regarding the appropriate treatment of
candiduria due to the nebulous and difficult definition
and verification about the site and source of candiduria
as well as whether Candida in the urine reflects infection
or colonisation.6,9,13,16,17,23,86 However, recognition of
candiduria is crucial for the diagnosis of fungal sepsis in
critically ill patients, as it may be the only, and is often
the first, indication of IC.22 Therefore, it has to be
decided in the daily routine at an ICU whether candid-
uria requires any therapeutic intervention and treat-
ment either by antifungals or – even first – by removal
or change of indwelling catheters. The IDSA has defined
indications for therapy of candiduria in late 2003.9
According to this guideline, it is recommended that the
following groups with candiduria have to be treated
with antifungals: infants with very low birth weights,
patients undergoing genitourinary procedures, patients
with neutropenia, renal transplant recipients and
symptomatic patients. The recommendations are usu-
ally graded IIIB, i.e. there is only moderate evidence and
evidence is based on clinical experience, opinions of
respected authorities, descriptive studies, or reports of
expert committees.
Most societies favour a graded therapeutic concept for
IC, consisting of prophylaxis, pre-emptive and empirical
therapy for patients at an ICU as reviewed elsewhere in
this supplement.31 While prophylaxis entails adminis-
tering a drug to prevent disease in a high-risk popula-
tion, the concept of a Ôpre-emptive therapyÕ postulates
an early treatment of an infection with involvement of
 2008 The Author
Journal compilation  2008 Blackwell Publishing Ltd • Mycoses, 51 (Suppl. 2), 12–24
Critically ill patients with candiduria
clinical, laboratory, or radiological surrogate markers of
disease in patients at high-risk before clinical signs and
symptoms of an obvious disease develop.89 Empirical
therapy refers to treatment of high-risk hosts with
symptoms of the disease, even in the absence of positive
cultures or other evidence of disease.55 Studies to
establish these concepts for patients with candiduria
are lacking. Therefore, it is not known whether
subgroups of ICU patients benefit from antifungal
prophylaxis regarding candidal UTI as shown for
IC.9,90 Likewise, conclusive recommendations for
patients to be pre-emptively treated with antifungals
are missing. Some studies have been performed to prove
the applicability of CS in IC as discussed above and
reviewed elsewhere,31 but this has to be investigated
with regard to candiduria. However, some of the scores
include candiduria as a statistically different weighted
factor and therefore, some of those scoring systems can
be used for therapeutic decisions regarding candiduria
as well. In any case, identified patients seem to strongly
benefit from early pre-emptive antifungal treatment,
supporting the validity of the CS.62 However, elimina-
tion, or at least, change, of the urinary catheter should
be attempted first.1 The presence of various risk factors
for candidaemia may indicate a need for prophylactic
treatment. The basis of antifungal prophylaxis is simple
for IC: (i) hand washing, (ii) optimal central venous
catheter placement and care and (iii) strict control of
antimicrobial use. This might hold true for candiduria
as well, and may be extended for the regular change of
urinary catheters.
As ketoconazole and itraconazole are poorly excreted
in the urine,91 fluconazole is excreted unchanged by
the kidneys.92 Usually, fluconazole achieves 10-fold
higher concentrations in the urine than in serum.6
A single 400-mg dose of fluconazole results in urine
concentrations in excess of 100 mg ml)1 in patients
with normal renal function,92 while the MIC50 values
of C. glabrata for fluconazole are in the range of about
8 mg ml)1.31 However, some studies reported reduced
fungal eradication from the urinary tract of patients
with impaired renal function.47 This might be due to
reduced fluconazole concentrations in urine in associ-
ation with reduced glomerular filtration. Interestingly,
fluconazole doses are reduced in patients with renal
insufficiency to avoid too high serum levels and
adverse events. This seems to result in subtherapeutic
urinary concentrations of fluconazole – especially for
non-albicans spp. – and may explain the reduced fungal
eradication. This issue may be critical in adjusting the
fluconazole dosage in patients with renal insufficiency
and especially with renal failure or oliguria ⁄ anuria.
17
E. Hollenbach
Given the favourable ratio of therapeutic effectiveness
of fluconazole to toxicity, maintaining conventional
doses of fluconazole may be reasonable.
Oral fluconazole and amphotericin B bladder irriga-
tion appear to yield similar rates of response.1 However,
mortality is – as discussed above – high in conditions
associated with candiduria, and antifungal therapy has
not made a significant difference to this.24
Several studies have consistently documented the
substantial toxicity of amphotericin B deoxycholate.93–
95
Renal toxic effects like a decreased glomerular
filtration rate and tubular wasting of electrolytes occur
in about 30% of patients receiving amphotericin B
deoxycholate associated with a sixfold increase in
mortality and dramatically increased hospital costs.96,97
Furthermore, infusion-related reactions, i.e. fever, chills,
hypotension or hypoxemia, are frequently observed.
Toxic effects were especially noted when amphotericin B
deoxycholate was administered over less than 6 h.
Thus, continuous 24 h infusions are recommended and
reduce its toxicity at a dose ranging between 0.6 and
1 mg kg)1 day)1 i.v.98,99 The incidence of nephrotox-
icity increases with the number of independent risk
factors for renal toxicity: male gender, body weight
more than 90 kg, co-medication with aminoglycosides
or cyclosporine, chronic renal disease, and administra-
tion of more than 35 mg of amphotericin B deoxych-
olate per day.96,100 Therefore, the use of alternative
therapeutic options seems to be appropriate in patients
with at least two or three renal risk factors. Lipid
formulations of amphotericin B (colloidal dispersion,
lipid-complex and liposomal) are generally less toxic
than, but equally as effective as, amphotericin B
deoxycholate in IC.101,102 Unfortunately, their lipid
formulation may impair their urinary excretion103 and
thus, so far, as no data are available regarding their
efficacy in candiduria, they cannot be recommended in
patients with ascending Candida pyelonephritis or renal
candidiasis. Caspofungin is the first approved agent of
the class of echinocandins with a broad spectrum of
anti-Candida activity.104 However, all echinocandins are
extremely poorly glomerularly filtrated or tubularly
secreted in vivo, as 2–3% of active drug is eliminated in
the urine, resulting in subtherapeutic concentrations in
the urine.105 Nevertheless, there are observations about
several successful outcomes for the treatment of symp-
tomatic candiduria using caspofungin.106 Unfortu-
nately, voriconazole as a new broad-spectrum triazole
achieves minimal urinary excretion as well.107 Like-
wise, posaconazole as another newly introduced agent
of the class of broad-spectrum triazole contained only
trace amounts of unchanged posaconazole in urine.108
18 Journal compilation  2008 Blackwell Publishing Ltd • Mycoses, 51 (Suppl. 2), 12–24
Table 2 Outcome of funguria (data adapted from Ref. 1)
No. (%) of patients whose
funguria
Persisted or
Resolved recurred
Treatment n = 288 n = 242
None 117 (75.5) 38 (24.5)
Catheter removal only 41 (35.3) 75 (64.7)
Antifungal drugs, with 130 (50.2) 129 (49.8)
or without catheter removal
Asymptomatic candiduria
There is general agreement that asymptomatic candid-
uria is benign, antifungal treatment has never been
shown to be of sustained value, and – if the predisposing
factors are corrected – usually self-limiting.9,24,55
Therefore, the most important approach to manage-
ment of asymptomatic candiduria is the modification of
risk factors (Table 2). It has been demonstrated in
hospitalised patients with indwelling catheters that
discontinuation of catheter use alone may result in
eradication of candiduria in almost 40% of patients.24
Admittedly, this is not feasible in most critically ill
patients. However, after a catheter was changed,
untreated candiduria was resolved in 20% of
patients.1,4,24 The further reduction of risk factors
includes, if applicable, better control of diabetes and
termination of antibiotic administration. Eradication of
Candida may be speeded up by fluconazole
(200 mg day)1 for 14 days) as shown in a placebo-
controlled trial, but the rates of negative urine culture
results were equal in both groups with and without
catheters (60% and 73%, respectively).24 However,
fluconazole treatment leads to a prompt candidal
recurrence, and therapy does not appear to alter clinical
outcome.24 There are three randomised trials compar-
ing amphotericin B bladder irrigation with oral fluco-
nazole.1,24,47,87 Generally, both agents eliminated
candiduria efficiently, with a more rapid elimination
with amphotericin B bladder irrigation, but relapses
were equally common. Differences in response rates
between C. albicans and non-albicans spp. were not
encountered, although all studies were underpowered
regarding C. glabrata and C. krusei spp. Currently, no
conclusive data about antifungal therapy in asymptom-
atic patients with diabetes are available.
Taken together, treatment of asymptomatic candidu-
ria is neither indicated nor particularly effective in the
long term. However, treatment of asymptomatic can-
diduria is suggested for patients with renal transplan-
tation or who have or have had neutropenia, and as a
 2008 The Author

prophylaxis for patients who are about to undergo
invasive urologic procedures.9 The optimal antifungal
option for these putative indications is unknown, but
fluconazole administered orally is widely used.
Lower candidal UTI and candidal cystitis
The largest controlled treatment trial with fluconazole
(200 mg daily for 14 days) vs. placebo in patients with
candiduria noted a significant benefit in favour of
fluconazole (response rate 50% vs. 29%).24 This study
clearly shows an association between clearance of
candiduria and indwelling catheters. A clearance of
Candida was found in 78% of patients without an
indwelling urethral catheter. In contrast, 47% of
patients who received placebo and who also had their
catheter removed had a successful eradication as well.24
Clearance rates of 35% with catheter removal alone
were confirmed in a multicentre study (n = 861).1
There are three open, randomised treatment trials
comparing bladder irrigation with amphotericin B and
treatment with oral fluconazole.47,87,109 The first study
observed an 83% rate of eradication of candiduria with
fluconazole in catheterised elderly men, with similar
results using amphotericin B irrigation.109 Another
small prospective study achieved clearance of fungiuria
in 77% of patients after administration of fluconazole
(100 mg per day for 7 days),24 while amphotericin B
irrigation achieved a more rapid clearance.47 However,
eradication rates 1 week to 1 month after completion of
therapy were similar to those obtained with fluconazole.
This was confirmed by another study with an almost
identical design.87 However, the numbers of patients
were relatively small, treatment period too short and the
dosage likely too low in each of those studies.47,87,109
Furthermore, all treatment trials excluded high-risk or
critically ill patients.
Apart from case reports, there have been no retro-
spective or prospective studies comparing different
therapeutic strategies in fungal cystitis. Fluconazole
seems to be the most effective systemic azole agent –
investigated so far – for patients with symptomatic
cystitis. Amphotericin B bladder irrigation or washouts
(50 mg l)1 for 5 days) are highly effective in the
eradication of invasive fungal cystitis,48,110 but only
previously catheterised patients seem to be eligible.
However, intravenously administered amphotericin B
(0.3 mg kg)1) seem to be equally effective in the
eradication of candiduria with the known adverse
effects.48 However, fluconazole has widely replaced
amphotericin B, given that Candida is susceptible to
azoles. Flucytosine, although excellently active against
 2008 The Author
Journal compilation  2008 Blackwell Publishing Ltd • Mycoses, 51 (Suppl. 2), 12–24
Critically ill patients with candiduria
non-albicans spp., should be omitted due to a de novo
resistance against C. albicans in the range of 25%, the
rapid tendency to acquired resistance when used as
monotherapy and its limitations regarding bone mar-
row, hepatic, and gastrointestinal toxicity.111 Invasive
fungal cystitis may be either a rare condition or
infrequently recognised in critically ill patients. Thus,
indications for treatment are not clarified but seem to be
necessary for symptomatic patients with concomitant
renal insufficiency.
Upper candidal UTI
Bladder irrigation using amphotericin B fails to treat
disease above the level of the bladder. Thus, urine
samples obtained following this procedure that remain
positive for yeast presumably reflect upper UTI. There
are very few studies available which addressed treat-
ment strategies for those patients. Treatment of high-
risk patients (hospitalised patients with diabetes,
obstructive uropathies, urinary stents, nephrostomy
tubes, renal insufficiency or patients undergoing geni-
tourinary procedures) using fluconazole is recom-
mended, even in the presence of a bezoar.6,9,84
However, local obstruction and other complications
have to be excluded immediately by ultrasonography or
CT scan and, if necessary, adequate drainage of the
upper urinary tract is essential. In individuals with
candidaemia, Foley catheter change alone results in
clearance of candiduria in less than 20% of patients.9
candidaemia should be treated as reviewed in another
article published in this supplement.31
Patients at potential risk for invasive candidiasis
Patients with bone marrow or liver transplant and
surgical patients with anastomotic leaks or recurrent
gastrointestinal perforations benefit according to small
case series from fluconazole treatment to prevent
IC.112–115 However, recent data question the validity
of the prior data that candiduria in a renal transplant
recipient implies a high probability of upper UTI.112
Amphotericin bladder washes are potentially useful in
temporarily decreasing Candida urine burden, although
their therapeutic value is being questioned.116 However,
candiduria may rarely be the source of subsequent
dissemination84 or a marker of acute haematogenous
dissemination10 in patients with obstructive uropathy
and neutropenia as well as patients without current or
recent placement of medical instruments in the urinary
tract.9 However, there is always much concern for those
patients at potential risk for IC, but data on the outcome
19
E. Hollenbach
Table 3 Infectious diseases associated with funguria (data adapted
from Ref. 1)
No. (%) of
Infection patients
Urinary tract infection 374
Pneumonia 344
Bacteremia 203
Soft tissue, bone and joint infection 110
Gastrointestinal infection 90
Abscess, surgical wound infection 72
Viral infections 26
Head and ⁄ or neck infections 14
Central nervous system infection 12
Cardiovascular infection 11
None 126
Concomitant or preceding infectious diseases associated with
funguria in 861 patients within 1 month of documented funguria.
Some patients had more than one infection.
of therapy are limited by the heterogeneity of the
underlying diseases. The concern about those patients is
in part supported by animal studies highlighting the
great importance of the kidney as an end organ in
immunosuppressed candidemic mice as well as from
clinical experience with patients with neutropenia who
have leukaemia.9,16 Therefore, candiduria should not be
treated by itself, but prophylaxis seems to be justified
based on the whole clinical picture of which candiduria
is one part and in patients with additional risk factors
for invasive candidasis (Tables 2 and 3). Therapy for 7–
14 days is more likely to be successful than shorter
courses of treatment.22 Removal or placement of new
devices of urinary tract instruments, including stents
and Foley catheters, are helpful. Treatment with fluco-
nazole (200 mg day)1 for 7–14 days) and with ampho-
tericin B deoxycholate (0.3–1.0 mg kg)1 per day) has
been shown to be successful.87 Bladder irrigation with
amphotericin B deoxycholate (50–200 mg ml)1) is only
indicated as a diagnostic tool but may transiently clear
funguria.47,48 Relapse of candiduria is frequent, partic-
ularly by continued use of a urinary catheter.
A noteworthy specific population that would be
worthwhile to study is patients with diabetes. From
case reports and retrospective reviews, it appears that
this group is at higher risk for the complications that
can arise from UTIs due to Candida species,65,67,70,71 but
no cohort has been followed long-term to define the
actual risk of these unusual complications.
Conclusions
Candiduria is becoming an increasingly important
problem in patients admitted to ICUs, mainly due to
20
the frequent use of indwelling catheters – which become
colonised if left in place long enough – and patients with
altered immunological mechanisms, impaired natural
defence barriers and altered bacterial flora as a result of
the use of antibiotics.
(43.4)
(40)
The development of reliable methods to distinguish
(23.6) between infection and colonisation and to distinguish
(12.8) upper from lower urinary tract involvement are the
(10.5) most important issues regarding candiduria. Ultrasound
(8.4)
examination to exclude obstruction of the urinary tract
(3)
(1.6)
is – besides clinical examination – the most promising
(1.4) tool to verify a possible fungal UTI in the presence of
(1.3) candiduria. Other methods, like quantitative Candida
(14.6) urine cultures, CT scan, MRI and assays for fungal cell
wall component like b-glucan, seem unlikely to achieve
a breakthrough in diagnostics to differentiate colonisa-
tion from infection or even upper from lower fungal UTI.
Urinary candidiasis usually should only be regarded
as a risk factor for IC with significant morbidity and
mortality, but not as a disease that needs to be treated
on its own. However, candiduria may be the only
finding in IC associated with significant morbidity,
mortality and cost implications in ICU patients. There-
fore, management of candiduria remains controversial,
mainly due to uncertainties in the indication for
antifungal therapy.
A large body of evidence proves lack of benefit from
treatment of the different forms of candidal colonisa-
tion of the urinary system in the absence of urinary
obstruction and sepsis. Treatment of asymptomatic
candiduria is neither indicated nor particularly effec-
tive in the long term. Patients undergoing genitouri-
nary procedures, patients with neutropenia, renal
transplant recipients and symptomatic patients are
recommended to be treated by the IDSA by little
strength of evidence. Furthermore, CS are applicable in
the daily routine to further minimise the risk of
complications like candidaemia in the range of 1–2%
in patients with candiduria without urinary obstruc-
tion. However, candiduria is ranked low in the CS, and
thus, decision for antifungal treatment should be made
in the clinical context of the particular patient. If an
antifungal agent is necessary, drug selection depends
primarily on anatomical site of UTI and renal function.
Irrigation of the bladder with amphotericin B, intra-
venous amphotericin B, oral or intravenous fluconaz-
ole are reasonable options. These options appear
comparable in early clearance of candiduria, although
long-term eradication in the presence of catheters and
other risk factors appears unlikely regardless of ther-
apy. Pyelonephritis and renal candidiasis secondary to
candidaemia depend on therapeutic urine
 2008 The Author
Journal compilation  2008 Blackwell Publishing Ltd • Mycoses, 51 (Suppl. 2), 12–24

concentrations. Currently, fluconazole and amphoter-
icin B achieves high tissue and urine concentrations,
while fluconazole is the treatment of choice due to
infrequent adverse effects. However, fluconazole use is
limited in the context of advanced renal failure and
infections with non-albicans spp., most notably
C. glabrata. Amphotericin B has been shown to be
an alternative, while echinocandins and the newer
broad-spectrum triazoles are precluded due to the low
urine concentrations achieved. It is a further issue to
define better treatment regimens, especially for those
patients with fluconazole-resistant yeasts.
As a rule, for patients with sepsis and candiduria, it is
mandatory to obtain blood cultures and to exclude
urinary obstruction, regardless of any guidelines under-
lining that treatment decisions – in the last instance –
should be based on individual patient data and the
clinical picture.
Conflict of interest
The author has been a consultant, received grant
support or honoraria, and ⁄ or has lectured for Pfizer,
MSD and Schering-Plough.
References
1 Kauffman CA, Vazquez JA, Sobel JD et al. Prospective
multicenter surveillance study of funguria in hospitalized
patients. Clin Infec Dis 2000; 30: 14–8.
2 Chakrabarti A, Reddy TCS, Singhi S. Does candiduria
predict candidemia? Indian J Med Res 1997; 106: 513–6.
3 Weber DJ, Rutala WA, Samsa GP et al. Relative fre-
quency of nosocomial pathogens at a university hospital
during the decade 1980 to 1989. Am J Infect Control
1992; 20: 192–7.
4 Storfer SP, Medoff G, Fraser VJ et al. Candiduria: retro-
spective review in hospitalized patients. Infect Dis Clin
Pract 1994; 3: 23–9.
5 Rivett AG, Perry JA, Cohen J. Urinary candidiasis: a
prospective study in hospitalized patients. Urol Res 1986;
14: 183–6.
6 Lundstrom T, Sobel J. Nosocomial candiduria: a review.
Clin Infect Dis 2001; 32: 1602–7.
7 Schaberg DR, Culver AH, Gaynes RP. Major trends in the
microbial etiology of nosocomial infection. Am J Med
1991; 91(Suppl. 3B): 72–4S.
8 Stamm WE. Catheter-associated urinary tract infections:
epidemiology, pathogenesis, and prevention. Am J Med
1991; 91 [Suppl. 3B]: 65–71.
9 Pappas PG, Rex JH, Sobel JD et al. Guidelines for treat-
ment of candidiasis. Clin Infect Dis 2004; 38: 161–89.
10 Wise GJ, Silver DA. Fungal infections of genitourinary
system. J Urol 1993; 149: 1377–88.
 2008 The Author
Journal compilation  2008 Blackwell Publishing Ltd • Mycoses, 51 (Suppl. 2), 12–24
Critically ill patients with candiduria
11 Piarroux R, Grenouillet F, Balvay P et al. Assessment of
preemptive treatment to prevent severe candidiasis in
critically ill surgical patients. Crit Care Med 2004; 32:
2552–3.
12 Ascioglu S, Rex JH, de Pauw B et al. Defining opportu-
nistic invasive fungal infections in immunocompromised
patients with cancer and hematopoietic stem cell trans-
plants: An international consensus. Clin Infect Dis 2002;
34: 7–14.
13 Alvarez-Lerma F, Nolla-Salas J, Leon C et al. Candiduria
in critically ill patients admitted to intensive care medical
units. Intensive Care Med 2003; 29: 1069–76.
14 Fisher JF, Chew WH, Shadomy S et al. Urinary tract
infections due to Candida albicans. Rev Infect Dis 1982;
4: 1107–18.
15 Gubbins PO, Piscitelli SC, Danziger LH. Candidal urinay
tract infections: a comprehensive review of their diag-
nosis and management. Pharmacotherapy 1993; 13:
110–27.
16 Kauffman CA. Candiduria. Clin Infect Dis 2005;
41(Suppl. 6): S371–6.
17 Fisher JF. Candiduria: when and how to treat it. Curr
Infect Dis Rep 2000; 2: 523–30.
18 Ayeni O, Riederer KM, Wilson FM et al. CliniciansÕ reac-
tion to positive urine culture for Candida organisms.
Mycoses 1999; 42: 285–9.
19 Abi-Said D, Anaissie E, Uzun O et al. The epidemiology of
hematogenous candidiasis by different Candida species.
Clin Infect Dis 1997; 24: 1122–8.
20 Olaechea PM, Palomar M, Leon-Gil C et al. Economic
impact of candida colonization and candida infection in
the critically ill patient. Eur J Clin Microbiol Infect Dis
2004; 23: 323–30.
21 Armstrong D. Treatment of opportunistic fungal infec-
tions. Clin Infect Dis 1993; 16: 1–9.
22 Nassoura Z, Ivatury RR, Simon RJ et al. Candiduria as
early maker of disseminated infection in critically ill
surgical patients: the role of fluconazol therapy. J Trauma
1993; 35: 290–5.
23 Fisher JF, Newman CL, Sobel JD. Yeast in the urine:
solutions for a budding problem. Clin Infect Dis 1995; 20:
183–9.
24 Sobel JD, Kauffman CA, McKinsey D et al. Candiduria:
a randomized, double-blind study of treatment with
fluconazole and placebo. Clin Infect Dis 2000; 30: 19–
24.
25 Flechner SM, McAninch JW. Aspergillosis of the urinary
tract: ascending route of infection and evolving patterns
of disease. J Urol 1981; 125: 598–601.
26 Byrne R, Hamill RJ, Rodriquez-Barradas MC. Crypto-
coccuria: case reports and literature review. Infect Dis
Clin Pract 1997; 6: 513–8.
27 Febre N, Silva V, Medeiros EAS et al. Microbiological
characteristics of yeasts isolated from the urinary tract of
intensive care unit patients undergoing urinary cathe-
terization. J Clin Microbiol 1999; 37: 1584–6.
21
E. Hollenbach
28 Center for Infectious Diseases. National Nosocomial
Infections Surveillance (NNIS) System Report, data
summary from January 1992-April 2000, issued June
2000. Am J Infect Control 2000; 28: 429–48.
29 Passos XS, Sales WS, Maciel PJ et al. Candida coloniza-
tion in intensive care unit patientsÕ urine. Mem Inst Os-
waldo Cruz 2005; 100: 925–8.
30 Knoke M, Schulz K, Bernhardt H. Dynamics of Candida
isolations from humans in 1992–1995 in Greifswald,
Germany. Mycoses 1997; 40: 105–10.
31 Hollenbach E. Invasive candidiasis in the ICU: evidence-
based and on the edge of evidence. Mycosis 2008;
51(Suppl. 2): 1–21.
32 Toya SP, Schraufnagel DE, Tzelepis GE. Candiduria in
intensive care units: association with heavy colonization
and candidaemia. J Hosp Infect 2007; 66: 201–6.
33 Slotman GJ, Shapiro E, Moffa SM. Fungal sepsis: multisite
colonization versus fungemia. Am Surg 1994; 60: 107–
13.
34 Lehner T. Systemic candidiasis and renal involvement.
Lancet 1964; 1: 1414–6.
35 Krause RJ, Matheis H, Wulf K. Fungaemia and funguria
after oral administration of Candida albicans. Lancet 1969;
1: 598–9.
36 Trapnell J, Roberts M. Prostatic abscess. Br J Surg 1970;
57: 565–9.
37 Singh CR, Lyttle WF. Cystitis emphysematosa caused by
Candida tropicalis. J Urol 1983; 130: 1171–3.
38 Mirdha BR, Sethi S, Banerjee U. Prevalence of fungal
species in patients with candiduria. Indian J Med Res
1998; 107: 90–3.
39 Paul N, Mathai E, Abraham OC et al. Emerging micro-
biological trends in candiduria. Clin Infect Dis 2004; 39:
1743–4.
40 Sobel JD, Vazquez JA. Fungal infections of the urinary
tract. World J Urol 1999; 17: 410–4.
41 Hamory BH, Wenzel RP. Hospital-associated candiduria:
predisposing factors and review of the literature. J Urol
1978; 120: 444–8.
42 Goldberg PK, Kozinn PJ, Wise GJ et al. Incidence and
significance of candiduria. JAMA 1979; 241: 582–4.
43 Paul N, Mathai E, Abraham OC et al. Factors associated
with candiduria and related mortality. J Infect 2007; 43:
1–6.
44 Kauffman CA, Tan JS. Torulopsis glabrata renal infec-
tion. Am J Med 1974; 57: 217–24.
45 Frye K, Donovan JM, Drach GW. Torulopsis glabrata
urinary infections: a review. J Urol 1988; 139: 1245–9.
46 Navarro EE, Almario JS, Schaufele RL et al. Quantitative
urine cultures do not reliably detect renal candidiasis in
rabbits. J Clin Microbiol 1997; 35: 3292–7.
47 Leu H-S, Huang C-T. Clearance of funguria with short-
course antifungal regimens: a prospective, randomized,
controlled study. Clin Infect Dis 1995; 20: 1152–7.
48 Fong IW, Cheng PC, Hinton NA. Fungicidal effect of
amphotericin B in urine: in vitro study to assess feasibility
22 Journal compilation  2008 Blackwell Publishing Ltd • Mycoses, 51 (Suppl. 2), 12–24
of bladder washout for localization of site of candiduria.
Antimicrob Agents Chemother 1991; 35: 1856–9.
49 Sobel JD. Controversies in the diagnosis of candiduria:
what is the critical colony count? Curr Treat Options Infect
Dis 2002; 4: 81–3.
50 Wise GJ, Goldberg P, Kozinn PJ. Genitourinary candidiasis:
diagnosis and treatment. J Urol 1976; 116: 778–80.
51 Kozinn P, Taschdjian CL, Goldberg PK et al. Advances in
the diagnosis of renal candidiasis. J Urol 1978; 119:
184–7.
52 Hall WJ. Study of antibody-coated fungi in patients with
funguria and suspected disseminated fungal infections or
primary fungal pyelonephritis. J Soc Med 1980; 73: 567–9.
53 Everett ED, Eickhoff TC, Ehret JM. Immunofluorescence of
yeast in urine. J Clin Microbiol 1975; 2: 142–3.
54 Harding SA, Merz WG. Evaluation of antibody coating of
yeasts in urine as an indicator of the site of urinary tract
infection. J Clin Microbiol 1975; 2: 222–5.
55 Ostrosky-Zeichner L, Pappas PG. Invasive candidiasis in
the intensive care unit. Crit Care Med 2006; 34: 857–63.
56 Pittet D, Monod M, Suter P et al. Candida colonization
and subsequent infections in critically ill surgical pa-
tients. Ann Surg 1994; 220: 751–8.
57 Slotman G, Shapiro E, Moffa S. Fungal sepsis: multisite
colonization versus fungemia. Am J Surg 1994; 60: 107–
13.
58 Charles PE, Dalle F, Aube H et al. Candida spp. coloni-
sation significance in critically ill medical patients: a
prospective study. Intensive Care Med 2005; 31: 393–
400.
59 Munoz P, Almudena B, Bouza E. Criteria used when
initiating antifungal therapy against Candida spp. in the
intensive care unit. Int J Antimicrob Agents 2000; 15: 83–
90.
60 Safran D, Dawson E. The effect of empiric and prophy-
lactic treatment with fluconazole on yeast isolates in a
surgical trauma intensive care unit. Arch Surg 1997;
132: 1184–9.
61 Gleason T, May A, Carapelli D et al. Emerging evidence of
selection of fluconazole-tolerant fungi in surgical inten-
sive care units. Arch Surg 1997; 132: 1197–202.
62 Leon C, Ruiz-Santana S, Saavedra P et al. A bedside
scoring system (‘‘Candida score’’) for early antifungal
treatment in nonneutropenic critically ill patients with
Candida colonization. Crit Care Med 2006; 34: 730–7.
63 Ostrosky-Zeichner L, Sable C, Sobel J et al. Multicenter
retrospective development and validation of a clinical
prediction rule for nosocomial invasive candidiasis in the
intensive care setting. Eur J Clin Microbiol Infect Dis 2007;
26: 271–6.
64 Nicolle LE. A practical guide to antimicrobial manage-
ment of complicated urinary tract infection. Drugs Aging
2001; 18: 243–54.
65 Scerpella EG, Alhalel R. An unusual cause of acute renal
failure: bilateral ureteral obstruction due to Candida
tropicalis fungus balls. Clin Infect Dis 1994; 18: 440–2.
 2008 The Author

66 Siddique MS, Gayed N, McGuire N et al. Salient features
of Candida pyelonephritis in adults. Infect Dis Clin Pract
1992; 1: 239–45.
67 High KP, Quagliarello VJ. Yeast perinephric abscess: report
of a case and review. Clin Infect Dis 1992; 15: 128–33.
68 Beland G, Piette Y. Urinary tract candidiasis: report of a
case with bilateral ureteral obstruction. Can Med Assoc J
1973; 108: 473–5.
69 Visser D, Monnens L, Feitz W et al. Fungal bezoars as a
cause of renal insufficiency in neonates and infants-rec-
ommended treatment strategy. Clin Nephrol 1998; 49:
198–201.
70 Seidenfeld SM, LeMaistre CF, Setiawan H et al. Emphy-
sematous pyelonephritis caused by Candida tropicalis.
J Infect Dis 1982; 146: 569.
71 Tomashefski JF, Abramowsky CR. Candida-associated
renal papillary necrosis. Am J Clin Pathol 1981; 75: 190–
4.
72 Gross M, Winkler H, Pitlik S, Weinberger M. Unexpected
candidemia complicating ureteroscopy and urinary
stenting. Eur J Clin Microbiol Infect Dis 1998; 17: 583–6.
73 Bross J, Talbot GH, Maislin G et al. Risk factors for nos-
ocomial candidemia: a case-control study in adults
without leukemia. Am J Med 1989; 87: 614–20.
74 Talluri G, Mangone C, Freyle J et al. Polymerase chain
reaction used to detect candidaemia in patients with
candiduria. Urology 1998; 51: 501–5.
75 Magill SS, Swobodac SM, Johnson EA et al. The associa-
tion between anatomic site of candida colonization,
invasive candidiasis, and mortality in critically ill surgical
patients. Diagn Microbiol Infect Dis 2006; 55: 293–301.
76 Blumberg HM, Jarvis WR, Soucie JM et al. Risk factors for
candidal blood stream infections in surgical intensive
care unit patients: the NEMIS prospective multicenter
study. Clin Infect Dis 2001; 33: 177–86.
77 Binelli CA, Moretti ML, Assis RS et al. Investigation of the
possible association between nosocomial candiduria and
candidaemia. Clin Microbiol Infect 2006; 12: 538–43.
78 Ahmad S, Khan Z, Mustafa SA, Khan ZU. Epidemiology of
candida colonization in an intensive care unit of a teaching
hospital in Kuwait. Med Mycol 2003; 41: 487–93.
79 Chen YC, Chang SC, Tai HM et al. Molecular epidemiol-
ogy of candida colonizing critically ill patients in inten-
sive care units. J Formos Med Assoc 2001; 100: 791–7.
80 Voss A, Hollis RJ, Pfaller MA et al. Investigation of the
sequence of colonization and candidemia in nonneu-
tropenic patients. J Clin Microbiol 1994; 32: 975–80.
81 Klempp-Selb B, Rimek D, Kappe R. Karyotyping of Can-
dida albicans and Candida glabrata from patients with
candida sepsis. Mycoses 2000; 43: 159–63.
82 Shin JH, Park MR, Song JW et al. Microevolution of
Candida albicans strains during catheter-related candide-
mia. J Clin Microbiol 2004; 42: 4025–31.
83 Dyess DL, Garrison RN, Fry DE. Candida sepsis: implica-
tions of polymicrobial bloodborne infection. Arch Surg
1985; 120: 345–8.
 2008 The Author
Journal compilation  2008 Blackwell Publishing Ltd • Mycoses, 51 (Suppl. 2), 12–24
Critically ill patients with candiduria
84 Ang BS, Telenti A, King B et al. Candidaemia from a
urinary tract source: microbiological aspects and clinical
significance. Clin Infect Dis 1993; 17: 662–6.
85 Neumann PR, Rakower SR. The risk of positive cultures
for candida in the critically ill patient. Crit Care Med
1978; 6: 73–6.
86 Jacobs LG. Fungal urinary tract infections in the elderly:
treatment guidelines. Drugs Aging 1996; 8: 89–96.
87 Jacobs LG, Skidmore EA, Freeman K et al. Oral fluco-
nazole compared with bladder irrigation with ampho-
tericin B for treatment of fungal urinary tract infections
in elderly patients. Clin Infect Dis 1996; 22: 30–5.
88 Jacobs LG, Skidmore EA, Cardoso LA, Ziv F. Bladder
irrigation with amphotericin B for treatment of fungal
urinary tract infections. Clin Infect Dis 1994; 18: 313–
8.
89 Pfaller MA, Diekema DJ. Epidemiology of invasive can-
didiasis: a persistent public health problem. Clin Microbiol
Rev 2007; 20: 133–63.
90 Bow EJ, Laverdiere M, Lussier N et al. Antifungal pro-
phylaxis for severely neutropenic chemotherapy recipi-
ents-a meta-analysis of randomized-controlled clinical
trials. Cancer 2002; 94: 3230–46.
91 Graybill JR, Raad I, Negroni R et al. Posaconazole long-
term safety in subjects with invasive fungal infections.
44th ICAAC, Washington, DC 2004; Abs M-1025.
92 Boucher BA, King SR, Wandschneider HL et al. Fluco-
nazole pharmacokinetics in burn patients. Antimicrob
Agents Chemother 1998; 42: 930–3.
93 Ullmann AJ, Sanz MA, Tramarin A et al. Prospective
study of amphotericin B formulations in immunocom-
promised patients in 4 European countries. Clin Infect Dis
2006; 43: 29–38.
94 Cornely OA, Vehreschild JJ, Ullmann AJ. Is there a role
for polyenes in treating invasive mycoses? Curr Opin In-
fect Dis 2006; 19: 565–70.
95 Patterson TF. Advances and challenges in management
of invasive mycosis. Lancet 2005; 366: 1013–25.
96 Bates DW, Su L, Yu DT et al. Mortality and costs of acute
renal failure associated with amphotericin B therapy. Clin
Infect Dis 2001; 32: 686–93.
97 Wingard JR, Kubilis P, Lee L et al. Clinical significance of
nephrotoxicity in patients treated with amphotericin B
for suspected or proven aspergillosis. Clin Infect Dis 1999;
29: 1402–7.
98 Imhof A, Walter RB, Schaffner A. Continuous infusion of
escalated doses of amphotericin B deoxycholate: an open-
label observational study. Clin Infect Dis 2003; 36: 943–
51.
99 Peleg AY, Woods ML. Continuous and 4 h infusion of
amphotericin B: a comparative study involving high-risk
haematology patients. J Antimicrob Chemother 2004; 54:
803–8.
100 Harbarth S, Pestotnik SL, Lloyd JF et al. The epidemiology
of nephrotoxicity associated with conventional ampho-
tericin B therapy. Am J Med 2001; 111: 528–34.
23
E. Hollenbach
101 Barrett JP, Vardulaki KA, Conlon C et al. A systematic
review of the antifungal effectiveness and tolerability of
amphotericin B formulations. Clin Ther 2003; 25: 1295–
320.
102 Bowden R, Chandrasekar P, White MH et al. A double-
blind, randomized, controlled trial of amphotericin B
colloidal dispersion versus amphotericin B for treatment
of invasive aspergillosis in immunocompromised
patients. Clin Infect Dis 2002; 35: 359–66.
103 Augustin J, Raffalli J, Aguero-Rosenfeld M et al. Failure of
a lipid amphotericin B preparation to eradicate candid-
uria: preliminary findings based on three cases. Clin Infect
Dis 1999; 29: 686–7.
104 Denning DW. Echinocandin antifungal drugs. Lancet
2003; 362: 1142–51.
105 McCormack PL, Perry CM. Caspofungin: a review of its
use in the treatment of fungal infections. Drugs 2005;
65: 2049–68.
106 Sobel JD, Bradshaw SK, Lipka CJ, Kartsonis NA. Caspo-
fungin in the treatment of symptomatic candiduria. Clin
Infect Dis 2007; 44: 46–9.
107 Johnson LB, Kauffman CA. Voriconazole: a new triazole
antifungal agent. Clin Infect Dis 2003; 36: 630–7.
108 Krieter P, Flannery B, Musick T et al. Disposition of po-
saconazole following single-dose oral administration in
healthy subjects. Antimicrob Agents Chemother 2004; 48:
3543–51.
24 Journal compilation  2008 Blackwell Publishing Ltd • Mycoses, 51 (Suppl. 2), 12–24
109 Fan-Havard P, OÕDonovan C, Smith SM et al. Oral fluco-
nazole versus amphotericin B irrigation for treatment of
candidal funguria. Clin Infect Dis 1995; 21: 960–5.
110 Wise GJ, Kozinn PJ, Goldberg P. Amphotericin B as a
urologic irrigant in the management of noninvasive
candiduria. J Urol 1982; 128: 82–4.
111 Schöenbeck J. Studies on Candida infection of the urinary
tract and on the antimycotic drug 5-flurocytosine. Scand
J Urol Nephrol 1972; 11(Suppl. 1): 7–48.
112 Eggimann P, Francioli P, Bille J et al. Fluconazole pro-
phylaxis prevents intra-abdominal candidiasis in high-
risk surgical patients. Crit Care Med 1999; 26: 1066–72.
113 Garbino J, Lew DP, Romand JA et al. Prevention of severe
candida infections in nonneutropenic, high-risk, critically
ill patients: a randomized, double-blind, placebo-controlled
trial in patients treated by selective digestive decontami-
nation. Intensive Care Med 2002; 28: 1708–17.
114 Goodman JL, Winston DJ, Greenfield RA et al. A con-
trolled trial of fluconazole to prevent fungal infections in
patients undergoing bone marrow transplantation. N
Engl J Med 1992; 326: 845–51.
115 Safdar N, Slattery WR, Knasinski V et al. Predictors and
outcomes of candiduria in renal transplant recipients.
Clin Infect Dis 2005; 40: 1413–21.
116 Drew RH, Arthur RR, Perfect JR. Is it time to abandon the
use of amphotericin B bladder irrigation? Clin Infect Dis
2005; 40: 1465–70.
 2008 The Author