Journal de Mycologie Médicale (2017) 27, 293—302

Available online at

ScienceDirect
www.sciencedirect.com

GENERAL REVIEW/REVUE GÉNÉRALE

Candiduria: Evidence-based approach to

management, are we there yet?
W.A. Alfouzan a,b,*, R. Dhar b

a
Department of Microbiology, Faculty of Medicine, Kuwait University, PO Box 760, 51007 Fintas, Kuwait
b
Microbiology Unit, Department of Laboratories, Farwania Hospital, Kuwait

Received 3 January 2017; received in revised form 15 March 2017; accepted 7 April 2017
Available online 10 May 2017

KEYWORDS Summary Candiduria is considered one of the most controversial issues in patient manage-
Candiduria; ment. Neither the diagnosis nor the optimal treatment options are standardized. This is further
Candida albicans; complicated by lack of defined laboratory criteria for diagnosis as most of the studies were set
Non-albicans species; for bacterial rather than fungal urinary tract infection (UTI). Furthermore, since Candida species
Pathogenesis; is a known commensal of the genitourinary tract its presence in the urine sample adds ambiguity
Risk factors; to making a definitive diagnosis of candidal UTI. Guidelines for diagnosis and management of
Management candiduria have changed considerably over the past decades. In 1960s, the condition was
believed to be benign with no intervention required. However, over the years new dimensions
were added to address the issues associated with candiduria until the latest Infectious Diseases
Association of America (IDSA) guidelines were published in 2009, which indicated that there was
an increase in the incidence of candiduria caused by more resistant non-Candida albicans
species. Further complicating the issue is the observation that candiduria may be the only
indicator of a more serious invasive candidiasis, especially in immunocompromised patients.
Long-term urinary catheterization is considered to be the most significant risk factor for
candiduria followed by antibiotic use and diabetes. Strategies for management are based on
the evaluation of candiduria in the context of the clinical setting to determine its relevance and
make an appropriate decision about the need for antifungal therapy. Fluconazole is the main
drug used for its efficacy and least complications. Other options include bladder irrigation with
amphotericin B, flucytosine or parenteral amphotericin B. Since azoles other than fluconazole
and all echinocandins are poorly excreted in urine they have been found to be less effective in
candiduric patients.
# 2017 Published by Elsevier Masson SAS.

* Corresponding author. Department of Microbiology, Faculty of Medicine, Kuwait University, PO Box 760, 51007 Fintas, Kuwait.
E-mail address: [email protected] (W.A. Alfouzan).

http://dx.doi.org/10.1016/j.mycmed.2017.04.005
1156-5233/# 2017 Published by Elsevier Masson SAS.
294 W.A. Alfouzan, R. Dhar

Introduction In a recent study, it has been shown that biofilm produc-

tion may help maintain the role of these organisms as
Unlike bacteriuria (presence of bacteria in the urine), can- commensals and pathogens, by evading host defense mecha-
diduria (presence of Candida in the urine sample) presents a nisms and reduced in vivo susceptibility to antifungal agents,
conundrum for the physician because of lack of evidence- especially in patients with urinary catheters [22].
based information on pathogenicity of Candida species (spp.)
in the urinary tract [1—6]. Although most of the community- Definitions and laboratory diagnosis of
acquired and hospital-acquired urinary tract infections candiduria
(UTIs) are caused by bacteria, Candida spp. is being increa-
singly isolated from nosocomial UTIs, which constitute the Urinalysis
most common nosocomial infections [7—11]. Candiduria has
especially been found to be an important problem in patients Since microbiological methods for detection of Candida spp.
admitted to intensive care unit (ICU), particularly those who in the urine sample has not been standardized, definition of
are immunocompromised, have serious underlying disease, candiduria remains enigmatic. It is imperative to include
indwelling urinary catheters, and disturbed microbiome as a microscopic visualization of yeast cells with the culture of
result of the use of broad-spectrum antibiotics [7,9,12—16]. the urine sample. Microscopically identifying yeast cells with
Among fungal infections in humans Candida spp. are the or without hyphal elements can be a clue to the presence of
most common cause of a range of non-life-threatening candiduria. Although it was earlier believed that the pre-
mucocutaneous diseases to invasive and life-threatening sence of hyphae could distinguish infection from colonization
conditions. This dimorphic yeast is a commensal that colo- [3] it has now been shown that C. glabrata and C. albicans
nizes gastrointestinal and reproductive tracts, especially mutants, which do not produce hyphae can cause UTI,
female genital tract, and the skin [1,7—10]. Candida albicans thereby proving that presence of hyphae is not a valid marker
is the most common infective agent of all Candida spp. that for infection [23,24].
are known to cause disease in humans. More recently non-
albicans spp. are emerging as pathogens, which can also be
found as colonizer of mucocutaneous surfaces [1,2,9,16,17]. Urine culture
The pathogenesis and prognosis of candidal infections are
affected by the host immune status and also differ greatly Most Candida spp. can be isolated on routine culture media,
according to disease presentations. Therefore, diagnosis, which are used for detection of bacteria in the urine with the
management and treatment choices vary and need to be exception of C. glabrata. Although this species appears to
considered in the overall setting of the affected human host grow well on blood agar, the colonies do not appear before
[1]. However, management of candiduria remains contro- 48 h of incubation, which is longer than most urine culture
versial as the detection of Candida spp. in urine samples may plates set up for bacterial growth are discarded [24]. Unlike
signify contamination, colonization, asymptomatic infec- in bacterial UTI neither the quantification of growth used as
tion, lower UTI, upper UTI with a potential for ascending diagnostic criteria (CFU/ml) cut-off nor the collection tech-
pyelonephritis, renal candidiasis leading to invasive and nique (suprapubic versus bag collection) for neonatal candi-
disseminated candidiasis, which not only causes significant duria is standardized [1,25]. Using it as a gold standard,
morbidity and mortality but also prolonged hospital stay and several earlier studies compared renal biopsy findings with
increasing cost [2,18]. Certain diagnostic tests are being used the urine cultures to establish upper UTI due to Candida spp.
to differentiate the various clinical possibilities associated The results from the studies showed that in patients without
with candiduria but ambiguity remains. It is, therefore, impe- indwelling catheters the colony counts as low as 104 CFU/mL
rative to evaluate candiduria in an individual case before of Candida in urine correlated well with proven renal infec-
initiating therapy with an antifungal agent [3,11,19,20]. tion. However, in catheterized patients no such correlation
was determined as patients with lower colony counts had
renal involvement whereas those with colony counts of  105
Pathogenesis CFU/ml did not show any evidence of UTI [26]. Recent
reports on adult candiduria have considered a range of
It has been documented that Candida spp. have equal pro- 103—105 CFU/ml to diagnose candiduria with National Ins-
pensity to cause infection in the urinary tract by the hema- titutes of Health using the lower cut-off value (103 CFU/ml)
togenous (descending) or the ascending route from the as their definition [19,20,27—29]. From experimental studies
perineum, unlike UTIs due to Gram-negative bacilli, espe- in rabbit models, it was established that urinary concentra-
cially E. coli, which almost always cause infection via the tion of C. albicans were not predictive of the fungal burden in
ascending route [1]. The hematogenous seeding of the renal the kidney and that negative cultures in rabbits did not rule
tissue by Candida spp. may lead to the development of out renal candidiasis, making it difficult to distinguish bet-
multiple microabscesses of the cortex resulting in the shedd- ween colonization/asymptomatic candiduria and infection,
ing of the organism in the urine. However, the pathogenesis thereby concluding that Candida in the urine in any concen-
of ascending infection due to Candida spp. is not well tration reflected renal involvement [30]. Furthermore, in
understood. Although, it has been established that obstruc- most retrospective studies, urine samples were cultured on
tion and or presence of stones in the urinary tract is an blood and MacConkey agars only, which may not be optimal
important prerequisite for renal involvement, the exact substitute for fungal culture resulting in some of the Candida
mechanism of adherence and growth in the calyx have not spp. not being isolated. Even when some of the laboratories
been well elucidated [3,21]. have used chromogenic agar, it allows the identification of
Candiduria 295

predominantly bacterial uropathogens. In contrast, studies Risk factors for candiduria

where a specific fungal medium was included to detect
candiduria higher numbers of non-albicans spp. were isola- Most of the studies done in adult patients have reported the
ted [31,32]. Apparently, variable cut-off definitions and risk factors for candiduria to be anatomic abnormalities of
unreliable culture techniques may have compromised the the urinary tract, comorbidities including uncontrolled dia-
analysis of the incidence and outcome of candiduria. betes, prior use of broad-spectrum antibiotics, indwelling
urinary catheter, major abdominal surgery, ICU admission,
Incidence of candiduria advanced age and female sex [7,11,13,48]. The risk factors
for community-acquired candiduria differ from nosocomial
For aforementioned reasons, most data on incidence of infection in that the patients in the former group are younger
candiduria are likely to be underestimated. Furthermore, in age, female gender and pregnant and are more likely to
the incidence of candiduria is dependent on the setting and experience dysuria [1]. The other patient population at risk
the population studied keeping in mind the discrepancies for candiduria, are the prematurely born neonates, espe-
associated with definitions of candiduria. This has resulted in cially those who receive antibiotics and have indwelling lines
wide variation in the numbers of incidence as is evident from [49—53]. Lower incidence of candiduria is observed in pedia-
various studies. Whereas a point prevalence survey done in tric ICUs because of less utilization of urinary catheters as
228 hospitals from 29 European countries showed the inci- compared to adult ICUs [54]. Some studies, which compared
dence of nosocomial candidal UTI to be 9.4%, other studies the risk factors for catheter-related nosocomial candiduria
reported  40% of urine samples yielding growth of Candida caused by C. albicans versus C. glabrata have found an
spp. [29,33,34]. In two other retrospective studies done in association of C. gabrata infection with use of fluconazole
Italy and Israel, much lower rates of 0—1.4% and 0.14—0.77%, and quinolone [55]. In contrast, other studies did not docu-
respectively were reported because data analyzed was from ment any association of quinolone and fluconazole use to
hospitalized and out-patients [35,36]. Our data, published higher rates of C. glabrata-mediated candiduria [13,41].
earlier, showed the incidence to be 3.3% [16]. Since candi-
duria is rarely seen as a community acquired infection in Clinical presentation
healthy people with structurally normal urinary tract, the
incidence among outpatients is usually very low, ranging Majority of the patients with candiduria are asymptomatic
from 0—0.3% [11]. Also, the incidence of candiduria varies and do not present with classical symptoms such as fre-
in the hospital setting, being most common in patients quency, dysuria, urgency or fever. Nosocomial Candida-
admitted to ICUs [20,27,37] and burn units [38]. The rates related UTIs are usually catheter associated and the mean
of nosocomial UTIs caused by Candida spp. have been repor- interval between ICU admission and candiduria has been
ted to vary from 11% to 30% in some of the studies reported to be 17.2  1.1 days and 11.1  6 days in a couple
[11,20,31,39,40]. In a large study done in renal transplant of studies from Europe and India, respectively [13,38,48].
patients it was observed that at least one episode of candi- Analogous to bacteriuria, candiduria can be the result of
duria occurred within 54 days of transplant in 11% of patients uncomplicated cystitis and or pyelonephritis and may yet
[41] whereas in another study 39.9% of urine samples from remain asymptomatic. The occurrence of concomitant can-
catheterized patients with chronic liver disease grew Can- didemia is low and has been seen in 1—8% of candiduric
dida spp. in pure cultures at  104 CFU/ml [29]. Of all fungal patients, with ICU patients running the highest risk
UTIs, which occurred more frequently in catheterized patients [7,16,32,37,40]. A large multi-centric study suggests that
than those not catheterized (40% vs. 22%, P = .001) C. albicans only 4% of patients with candiduria are symptomatic [7].
was most commonly isolated pathogen (21% vs. 13%, P = 0.009) Ascending infection may lead to lower UTI, which is sugges-
[1,40] although other studies claim that non-albicans spp. are tive of cystitis and often associated with dysuria, hematuria,
being isolated more often from these patients [27,29]. In the urgency and suprapubic tenderness [2]. Although emphyse-
preterm neonates with low birth weight the percentage of matous cystitis is an extremely rare complication in lower
candiduria has been shown to be lower because of the routine UTI, prostatic abscesses are not uncommon in diabetic
use of fluconazole prophylaxis [42—45]. patients [56,57]. Indistinguishable from bacterial pyelone-
phritis patients with candidal upper UTI may also present
Distribution of Candida spp. in candiduria with fever, leukocytosis and tenderness in the costovertebral
angle. Pyelonephritis due to Candida spp. is often compli-
The data from most studies have revealed that more than cated by pyonephrosis or abscess and fungal ball formation.
half of the Candida spp. isolated from urine samples are Patients with candidemia (from a source other than urinary
C. albicans (54—68%) followed by C. glabrata (8—36%), and tract) and hematogenous seeding of kidneys may present
C. tropicalis (4—10%) [1,13,22]. However, over the years the with high fever and hemodynamic instability due to sepsis
incidence of non-albicans strains has been rising steadily and renal insufficiency [2].
with C. glabrata being increasingly isolated from urine
throughout the world and C. parapsilosis becoming a domi- Clinical diagnosis
nant species causing candidiasis including candiduria among
neonates [7—10,13,46,47]. Recurrent infections occur due For candiduria, therapeutic decisions are based on the final
the same strain as shown by molecular studies and 5—8% of impression of the clinical diagnosis. However, due to the lack
candiduria patients may harbor two or more species simul- of availability of definitive diagnostic tools it is often difficult
taneously [7]. to differentiate between colonization, contamination or
296 W.A. Alfouzan, R. Dhar

true UTI due to Candida spp. [30,58,24]. Only very few D-arabinitol/creatinine ratio could be used to differentiate
criteria are currently known to help in separating these between candidal pyelonephritis and colonization [60].
different conditions associated with candiduria and more Complicated UTIs such as emphysematous tissue invasion,
sensitive and specific parameters are required for detection papillary necrosis and perinephric abscess formation are
of candidal UTI [2,7]. observed more predominantly in diabetic patients as compa-
red to obstructive fungus balls and also occur in the setting of
prostatitis and epididymitis [56,57].
Clinical evaluation

Although Candida spp. are part of the normal human gas- Imaging studies
trointestinal flora, they infrequently colonize other muco-
cutaneous surfaces of the body by adhering to the superficial Diagnostic imaging techniques have been used to confirm
mucosal cells. This often occurs in patients with underlying renal lesions in Candida pyelonephritis. Although rarely
risk factors, especially those with an indwelling urinary found in adults, fungal balls are more commonly seen by
catheter, resulting in candiduria without any symptoms or ultrasonography in infants with candiduria. In a study of 20
signs of UTI. Also, culture of urine in women with heavy infants with Candida UTI, ultrasonography revealed that 35%
colonization of vulvovaginal area may yield heavy growth of infants had renal fungus balls [61]. Ultrasound technique can
Candida spp. In order to confirm contamination of the urine also help in diagnosing Candida abscesses in prostate, epi-
sample with Candida spp. a repeat culture of mid-stream didymis or testicles [62,63]. Utilization of CT urogram can
urine sample or preferably another specimen by sterile result in better visualization of perinephric fluid, gas in
bladder catheterization must be done [2,4,24]. For those tissues and the presence of fungas balls [64].
patients who have an indwelling bladder catheter, urine
culture should be repeated either after removal or replace- Candiduria: to treat or not to treat?
ment with a new one. A negative culture for Candida spp.
would indicate that the previous sample was in all likelihood
Since it is difficult to differentiate if candiduria in a patient is
to be contaminated or represent colonization and prevents
because of the fungal colonization of urinary tract or true UTI
the necessity for any further diagnostic work up
it poses a dilemma for the physician to decide whether to
[3,11,58,24], whereas implication of regrowth of Candida
initiate antifungal therapy or not. In a recent study, it has
spp. could be asymptomatic candiduria, or true UTI. No
been suggested that a classification scheme might be follo-
reference standard is available for the definitive diagnosis
wed for systematic management of candiduria (Figs. 1 and
of UTI due to Candida spp. and to differentiate it from
2). In order to do so it is proposed that the patients be
asymptomatic candiduria or the differentiation of upper
grouped as those with:
from lower UTIs. Previous studies have observed that most
patients with candiduria are asymptomatic with only 4% of
 asymptomatic candiduria (previously healthy patients);
patients in one large multicenter study and 14% in another
 asymptomatic candiduria (predisposed outpatients);
smaller series showing symptoms suggestive of UTI. Howe-
ver, information on symptoms is often missing from patients  asymptomatic candiduria (predisposed inpatients);
in the ICU, who are invariably sedated and or ventilated and  symptomatic candiduria (cystitis, pyelonephritis,
catheterized with a Foley catheter [24]. Furthermore, even prostatitis, epididymo-orchitis, or urinary tract fungus
the aberrant septic markers are non-specific as these may be balls);
raised because of infection at any other site in these criti-  clinically unstable condition with candiduria [65] (Fig. 2).
cally ill patients [2].

Asymptomatic candiduria (previously healthy

Analysis of laboratory data
patients)
The presence of pyuria may be helpful but only for patients
Once candiduria is confirmed after urine culture is repeated
who are without an indwelling catheter. Both long-term and
to exclude the possibility of contamination, patient’s his-
intermittent catheterization can cause some degree of local
tory, physical examination and laboratory data should be
inflammation leading to appearance of leukocytes in the
analyzed for symptoms and signs of predisposing factors as
urine [2]. To complicate the matter further, 25—30% of
these could help in identifying occult diabetes mellitus,
patients with candiduria have concomitant bacteriuria,
structural abnormalities of urinary tract, compromised renal
which could cause pyuria [3,7,24,59]. An earlier study from
function and metabolic abnormalities [3,65]. In the event of
Kuwait showed mixed growth of Candida spp. with bacteria
not finding any underlying risk factor no therapeutic inter-
in 8.1% cases [16].
vention is required as in most cases candiduria resolves
As stated earlier quantification of number of organisms in
within weeks to months [65].
the urine does not help in making the diagnosis of candidal
UTI (unlike bacterial UTI) as there are no standard guidelines
to follow. Also, other data from experiments in rabbits Asymptomatic candiduria (predisposed
suggest that detection of renal candida casts may be a useful outpatients)
diagnostic marker in differentiating upper versus lower uri-
nary tract candidiasis but the frequency of this finding is Since even in predisposed patients long-term consequences
unknown in humans [21]. Another study suggests that of candiduria are benign restraint must be exercised in
[(Figure_1)TD$IG]
Candiduria 297

Candiduria

Repeat urine microscopy & culture

Candida Negative Candida Positive

No antifungal treatment Asymptomatic Candiduria

Previous healthy Predisposed Predisposed

patient outpatient inpatient

Look for predisposing conditions •Evidence for disseminated candidiasis

•Unstable / neutropenic patient

None found Predisposing

conditions found No Yes

Manage predisposing
Observation conditions
Treatment options :
• Fluconazole 400-800 mg IV/d
• Caspofungin 70 mg IV loading 50 mg/d
• Anidulafungin 200 mg IV loading 100 mg/d
• Voriconazole 6 mg IV q 12h 4mg Iv q 12h
• Amphotericin B 0.6-0.7 mg/kg/d +/- Flucytosine
Figure 1 Algorithm for the management of asymptomatic candiduria.

initiating therapy with antifungal agents in these patients Asymptomatic candiduria (predisposed
[66]. Most often proper management of the risk factors alone inpatients)
can aid in the clearance of yeast in the urine. However,
appropriate assessment of the clinical condition of patients Interestingly, more than 50% of the patients in ICUs are
is mandatory to exclude the possibility of invasive candidiasis colonized with Candida spp. at some point during their
to which they are vulnerable. admission and become predisposed to candiduria for multi-
[(Figure_2)TD$IG]
298 W.A. Alfouzan, R. Dhar

Symptomatic Candiduria

Cystitis, pyelonephritis Prostatitis , epididymo-orchitis

Treatment options Treatment options

• Fluconazole 400 mg po x 2-4 wks • Fluconazole 400mg po x 4 wks
• Flucytosine 25 mg/kg po qid x 2-4 • Surgical drainage
wks
• Amphotericin B 0.3-1 mg /kg IV, 1 or
more doses Fungus ball

Treatment options
• Fluconazole 400 mg po x 4 wks
• Flucytosine 25 mg/kg po qid x 2-4 wks
• Amphotericin B 0.3-1mg/kg,1 or more doses
• Surgical drainage
Figure 2 Algorithm for the management of symptomatic candiduria.

ple reasons, most common of them being indwelling bladder culture-positive surveillance sites for Candida spp. over
catheter [13,34,67]. Many studies have shown that removing number of sites cultured, has been introduced [71]. If the
or replacing the catheters in these cases helps in clearing CCI is  0.5 a pre-emptive antifungal therapy is suggested
candiduria. In an earlier study, conducted among hospitali- [72]. However, using a low CCI threshold of 0.5 raises the
zed patients, in an intent-to-treat analysis, it was found that concern of overuse of antifungal therapy in the ICUs leading
candiduria cleared by day 14 in 79 (50%) of 159 patients to emergence of resistance species [73—75]. Recently, a new
treated with fluconazole and 45 (29%) of 157 patients receiv- promising ‘Candida score’ (CS) has been proposed, which
ing placebo (P < 0.001). The clearance of yeast was observed entails using four independent risk factors to support deci-
in 33 (52%) of 64 catheterized and 42 (78%) of 54 non- sion-making as to which non-neutropenic, critically ill
catheterized patients who completed 14-day treatment. patients need pre-emptive treatment with antifungal agents
However, long-term eradication rates were found to be [76]. The four weighted risk factors identified are: multifocal
disappointing and not associated with clinical benefit [19]. Candida spp. colonization (1 point), surgery upon ICU admis-
Also, treatment of asymptomatic candiduria in renal trans- sion (1 point), total parenteral nutrition, TPN (1 point), and
plant recipients [41] or immunocompetent patients [67] did severe sepsis (2 points). It has been shown that a CS of > 2.5
not appear to result in improved outcome. In a recent study, is associated with a 7.75-fold increase in proven invasive
the data indicated that systemic fluconazole was associated candidiasis (95% CI, 4.74—12.66) when compared to those
with a significant higher short-term clearance of funguria with a lower score. The sensitivity and specificity of cut-off
after 14 days of treatment (OR = 0.43, CI 95% 0.26—0.65) value of CS = 2.5 was determined to be 81% and 74%, res-
[68]. Data from another recent study done in ICU patients has pectively [76]. Yet, another study used a different criteria a
revealed that no difference in cure rates was found between to assess the risk of invasive candidiasis in the ICU patients
amphotericin B (50 mg/L for 5 days) bladder irrigation and and it included: ICU stay for at least 4 days plus either any
fluconazole (200 mg/day) treatment groups (59.6% vs. antibiotic use or central venous catheter, plus at least two of
52.8%, P = 0.55) although there was higher clearance rate the following criteria: TPN, any dialysis, any major surgery,
in the former (92.3% vs. 67.9%, P < 0.001) [69]. However, the pancreatitis, any use of steroids or other immunosuppressive
risk of invasive candidiasis may be related to the density and agents [77].
length of colonization over time and some correlation was Regarding risk of developing candidemia in critically ill
found between ICU mortality rates and multiple-site coloni- patients with candiduria, data from different studies have
zation with Candida spp. [67,70,71]. Therefore, a Candida revealed that only 0—1.3% of asymptomatic patients (espe-
colonization index (CCI), which is defined as the ratio of cially those who acquired the infection by the ascending
Candiduria 299

route) with candiduria developed candidemia whereas 10% of echinocandins may not be useful because of minimum
patients who have candiduria in the presence of obstruction excretion of active drug in the urine.
develop candidemia [78,79]. On the other hand, it has been
documented that candidemia is common in the hospital
setting and 46—80% of patients with candidemia have conco- Pyelonephritis
mitant candiduria [13,80]. Antifungal therapy is suggested Failure to treat candiduria by bladder irrigation using ampho-
for patients who have to go for urinary tract procedure to tericin B may indicate presence of upper candidal UTI.
relieve obstruction [73]. However, in a case-control study Haematogenous spread or descending infection is the most
univariate analysis indicated a significant association of common route for the development of renal parenchymal
candidemia with candiduria and the isolation of fungus at infection. It has been shown that 90% of the autopsied
other sites, as well as multivariate analysis showed an asso- patients with candidemia had renal candidiasis. However,
ciation between candidemia and candiduria (OR = 9.79, 95% ascending infection of the kidneys can occur in the presence
CI 2.14—44.76) [81—83]. Most studies have shown identical of urinary tract obstruction or profound immunosuppression.
genetic strains of Candida spp. being isolated from urine and As for cystitis, fluconazole remains the drug of choice for
blood whereas other studies have proved that 52% of Candida pyelonephritis since in animal experiments it was found to
isolates from these specimens are genetically different signi- attain adequate concentration in the renal tissue [89]. Fur-
fying that urinary tract is not necessarily the source for thermore, fluconazole is effective against commonly isola-
candidemia, especially in a non-ICU population [84]. Fur- ted Candida spp., such as, C. albicans (40—60%), C. tropicalis
thermore, strain microevolution with significant genetic (25%) and C. parapsilosis (25%) from majority of cases of
changes has been attributed to the causation of recurrent Candida UTI [7,19,86,90]. However C. glabrata exhibits
or persistent candidemia [85]. highly variable susceptibility to fluconazole with MICs rang-
ing from 0.25—256 mg/L and some other non-albicans spp.
appear resistant in in-vitro studies [91]. In animal models of
Symptomatic candiduria (cystitis, haematogenous renal parenchymal candidiasis itraconazole,
pyelonephritis, prostatitis, epididymo-orchitis, posaconazole and voriconazole have shown excellent acti-
or urinary tract fungus balls) vity [92—94]. Whereas posaconazole has potent activity
against C. glabrata, C. krusei and variety of other non-
Cystitis albicans species, voriconazole has been found to have excel-
Controlled trials have revealed that whereas catheter remo- lent activity in renal parenchyma making it superior to
val alone cleared candiduria in 35% of cases and treatment fluconazole and amphotericin B for the treatment of pyelo-
with fluconazole eradicated it in 50% of catheterized patient nephritis [94]. Since < 5% of the drug is excreted in the urine
as compared to 29% patients who received a placebo. Flu- it cannot be used for the treatment of lower UTI [95]. Also,
conazole is considered the drug of choice for the treatment echinocandins (caspofungin, anidulafungin, and micafungin)
of cystitis as most Candida spp with the exception of are found to clear Candida renal parenchymal infections
C. glabrata, C. krusei and some not so well-known resistant effectively [96]. However, all the echinocandins are mostly
species, are highly susceptible to this drug. Furthermore, metabolized in the tissues with inadequate amounts of active
fluconazole is primarily excreted in the urine as active drug drug being excreted in the urine making them of little use in
where the concentration of the drug can exceed the MIC of the lower UTI. With the proven efficacy of flucytosine in
Candida isolate by manifold. At a dose of 200—400 mg different forms of candidal UTI, it may be considered as a
orally per day fluconazole can reach the concentration useful option for patients who are intolerant to fluconazole
of > 100 mg/L in the urine which is adequate not only for [65]. The other advantage is that it can be administered
susceptible (MIC  8 mg/L) strains but also for dose-depen- orally at a dose of 25 mg/kg 6 hourly with adjustment for
dent (MIC, 16—32 mg/L) and at times even for resistant renal insufficiency. In view of its potentially serious side
(MIC,  64 mg/L) organisms. Studies comparing bladder irri- effects patients receiving long-term therapy with flucytosine
gation with amphotericin B and treatment with oral fluco- need to be closely monitored and in these cases, this agent
nazole observed similar results of 83% eradication with both may be combined with amphotericin B in order to avoid
the regimens. However, recurrence is reported more often emergence of resistant strains. Although amphotericin B
with amphotericin B bladder irrigation compared to fluco- deoxycholate has generally been found to be efficacious in
nazole [86,87]. Although amphotericin bladder washouts virtually all forms of invasive candidiasis, including UTI, less
are found to be highly effective in eradication of invasive nephrotoxic lipid formulation of this agent are not recom-
fungal cystitis, only previously catheterized patients are mended for treating renal candidiasis because of poor pene-
eligible for the procedure. Invasive fungal cystitis appears tration in the renal parenchyma [97]. Treatment with
to be a rare condition or infrequently recognized in criti- fluconazole is recommended for high risk, especially those
cally ill patients and hence no clear cut guidelines exist for who are hospitalized with diabetes, obstructive uropathies,
antifungal therapy for this condition. However, treatment urinary stents, nephrostomy tubes or patients undergoing
with fluconazole (200 mg/day for 14 days) may be conside- genitourinary procedure. It is also important to determine
red in symptomatic patients with concomitant renal in- the anatomic site obstruction or complication to evaluate
sufficiency. Even though intravenously administered source of candiduria by radiological investigations, such as,
amphotericin B (0.3 mg/kg) seems to be equally effective ultrasonography or CT scan. In a small imaging study using
in eradicating candiduria, fluconazole is preferred as most white blood cells labeled with indium-111 concluded that
Candida spp. are susceptible to this drug, ease of adminis- 50% of the studied patients (n = 8) with candiduria showed
tration and fewer toxic effects [11,86,88]. Other azoles or renal uptake in 111In-labeled leukocyte scintigraphy with
300 W.A. Alfouzan, R. Dhar

persistence of uptake after antifungal treatment [98]. This upper from lower urinary tract involvement in a case with
finding raises the concern that subclinical pyelonephritis may candiduria.
be more frequent in patients with candiduria than previously
thought.
Disclosure of interest
Prostatitis and epididymo-orchitis
These are unusual forms of candidiasis with dearth of treat- The authors declare that they have no competing interest.
ment modalities as found in the literature. Based on case
reports surgical approach (incision and drainage if an abscess
is present, debridement or resection of the tissue) is empha- References
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