Short-term Fluconazole Therapy for the Treatment

of Candiduria in ICU and ICU Step-down Patients

g. Christopher Wood1, Katarzyna adamczyk2, Bradley a. Boucher1, Martin a. Croce3, david a.
Kuhl4, Carey l. rhea5, Matthew Chambers6, Joseph M. swanson1, amado X. Freire7 and
timothy C. Fabian3
1
Department of Clinical Pharmacy, University of Tennessee College of Pharmacy, Memphis, TN, USA. 2Department of Pharmacy, Morristown
Medical Center, Morristown, NJ, USA. 3Department of Surgery, University of Tennessee College of Medicine, Memphis, TN, USA.
4
Department of Pharmacy Practice, Union University School of Pharmacy, Jackson, TN, USA. 5Department of Pharmacy, Methodist North
Hospital, Memphis, TN, USA. 6Department of Pharmacy, Mississippi Baptist Medical Center, Jackson, MS, USA. 7Department of Medicine,
University of Tennessee College of Medicine, Memphis, TN, USA.

OBJECTIVE: Candiduria is very common in critically ill patients. It is often benign; however, it can develop into a serious systemic infection and treatment
is suggested in symptomatic critically ill patients. The optimal duration of therapy is unclear. Long-term therapy (14 days) is recommended by the current
guidelines, but previous data suggest that shorter-duration therapy may be effective. Minimizing the use of antifungal agents is desirable to avoid fungal
resistance and adverse events. The purpose of this study was to determine the efficacy of short-term treatment of candiduria.
METHODS: This was an observational study in medical, surgical, and trauma intensive care unit (ICU) and ICU step-down patients. A pathway utilizing a 3-
day course of fluconazole for candiduria was implemented. The candiduria recurrence rate was compared in patients treated before (control groups with short-
# $ #
term, ie, 3 days, or longterm, ie, 7 days, therapy) and after the implementation of the pathway (study group: 3 days).
RESULTS: Thirty-seven study patients were compared to 59 control patients. There were statistically no differences in the recurrence rate for candiduria
.
among study patients, control patients with long-term therapy, and control patients with short-term therapy (32% vs 55% vs 38%, respectively; P 0.05).
CONCLUSION: Three days of fluconazole treatment for candiduria appeared to be as effective as long-term therapy in this population. KEYWORDS:
urinary tract infections, antifungals, fungal infections, critical care, health care-associated infections
CITATION: Wood et al. short-term Fluconazole therapy for the treatment of Candiduria in COPYRIGHT: the authors, publisher and licensee libertas academica limited. this is
iCu and iCu step-down Patients. Clinical Medicine Insights: Trauma and Intensive Medicine an open-access article distributed under the terms of the Creative Commons CC-BY-nC
2015:6 1923 doi:10.4137/CMtiM.s20140. 3.0 license.
RECEIVED: september 17, 2014. RESUBMITTED: January 15, 2015. ACCEPTED FOR CORRESPONDENCE: cwood@uthsc.edu
PUBLICATION: January 17, 2015.
Paper subject to independent expert blind peer review by minimum of two reviewers. all
ACADEMIC EDITOR: Chuanju liu, editor in Chief editorial decisions made by independent academic editor. upon submission manuscript
was subject to anti-plagiarism scanning. Prior to publication all authors have given
TYPE: Original research signed confirmation of agreement to article publication and compliance with all
FUNDING: this study was funded by a Pharmacy resident health services research grant applicable ethical and legal requirements, including the accuracy of author and
from the american society of health-system Pharmacists and was carried out at the contributor information, disclosure of competing interests and funding sources,
Regional Medical Center, Memphis, TN, USA The authors confirm that the funder had no compliance with ethical requirements relating to human and animal study participants,
influence over the study design, content of the article, or selection of this journal. and compliance with any copyright requirements of third parties. this journal is a member
of the Committee on Publication ethics (COPe).
COMPETING INTERESTS: Ka and Clr were PgY2 critical care residents and MC was a
PgY1 resident at the regional Medical Center, Memphis, tn. none of the other authors have Published by libertas academica. learn more about this journal.
a conflict of interest to report.

Introduction purpose of this study was to compare the efficacy of short-term

Candiduria continues to be a major complication of
hospitalization. Urinary tract infections (UTIs) are the second
most common hospital-acquired infection, and Candida sp. are
the second most common nosocomial UTI pathogens.1 The
severity of candiduria varies. Some patients are asymptomatic
and conditions resolve spontaneously, but in up to 36% of
patients, candiduria may progress to a life-threatening systemic
infection.24 According to the current guidelines of the
Infectious Diseases Society of America (IDSA), treatment of
candiduria is reasonable in symptomatic critically ill patients
when candiduria may be related to disseminated candidiasis. 5
The guidelines recommend fluconazole 200 mg (or 3
mg/kg/day) for 14 days as first-line therapy.5 However, there
are relatively few data on the optimal duration of treatment for
candiduria.
Retrospective data from the study center suggested that the
# units were collected in a retrospective,
candiduria recurrence rates after short-term ( 3 days) and long-
$
term ( 7 days) therapy were equivalent.6 As such, a clinical
pathway for candiduria management that featured short-term
treatment with fluconazole for 3 days was developed. The
fluconazole therapy after the implementation of the pathway
with the efficacy of short- and long-term therapy used before
the implementation of the pathway.
Materials and Methods
Study design. This study was conducted at the Regional
Medical Center in Memphis, TN, USA. The study was
approved by the University of Tennessee Institutional Review
Board and waiver of informed consent was granted. This study
complied with the principles of the Declaration of Helsinki. All
patients in the medical/surgical and trauma intensive care units
(ICUs) and ICU step-down wards with an episode of candiduria
were considered for the study. Patients were identified using a
hospital database and comprised those admitted between 2002
and 2006. The study had a prepathway phase, wherein data
from consecutively treated patients with candiduria in the study
Wood et al
observational manner (control group). These patients met the
inclusion and exclusion criteria for the study group (described

CliniCal MediCine insights: trauMa and intensive MediCine 2015:6 19

below). There was no candiduria clinical pathway in place in
the prepathway phase of the study. In this phase, urine cultures
were generally ordered as part of a fever/sepsis evaluation in
patients with signs and symptoms of infection. Candiduria was
$ $
considered clinically relevant at 10,000 or 100,000 colony-
forming units (cfu)/mL depending on the admission service.
#
Control group patients may have received either short-term ( 3
$
days) or long-term ( 7 days) therapy depending on physician
preference. An important observation was that long-term
$
antifungal therapy ( 7 days) was found to be a risk factor for
subsequent fungal colonization or infection.6 Based on these
results, a clinical pathway for candiduria was implemented
(Fig. 1). The vital component was limiting the duration of
therapy for candiduria to 3 days. After the implementation of
the pathway, all patients treated with the pathway were
evaluated prospectively (study group).
The primary outcome for this study was the recurrence rate
of candiduria during hospitalization in the study group
compared to the long-term and short-term control groups.
Recurrence was defined as a second episode of candiduria
(defined below) after the end of therapy for the first episode.
Follow-up urine cultures were not routinely performed; rather,
they were performed at the discretion of the medical team as
clinically

indicated. It was hypothesized that candiduria recurrence in the

study group would be similar in both control groups; suggesting
that short-term therapy of candiduria may be adequate in this
patient population. Patients in the study group were enrolled if
they were 18 years or older and diagnosed with candiduria
$
defined as 10,000 cfu/mL of Candida species in urine. Patients
#
were excluded if they had malignancy, candiduria 48 hours
from admission, hypersensitivity to fluconazole, septic shock,
,
white blood cell count 4,000/mm3, use of immunosuppressive
medications, previous antifungal treatment, presence of
documented candidiasis, if they were not treated according to
the clinical pathway, or if they had Candida krusei identified
on urine culture. The first episode of candiduria in each patient
was considered the study episode. Per the clinical pathway, the
first episode of candiduria in the study group was treated with
fluconazole 200 mg daily either orally or intravenously (IV) for
a total of 3 days. Because the treatment course was short, all
patients received the same fluconazole dose regardless of their
renal function. Patients were monitored daily for resolution of
signs and symptoms, and were followed for primary and
secondary outcomes until hospital discharge.
 Statistical analysis. Continuous data are expressed as
mean standard deviation (SD) and were analyzed using
StatView software (SAS Institute Inc, Cary, NC, USA).
Statistical significance was determined by chi-square test,

&OLQLFDOVXVSLFLRQRIFDQGLGXULD

2 EWDLQXULQHFXOW
XUH

3 UHVHQFHRI
FIXP/ 12
1 RWUHDWPH
RI &DQGLGD
VS" QW

<(6

) LUVWHSLVRG 12 8 VHQRQIOXFRQD]ROH
RIFDQGLGXULD"
H HPSLULFWKHUDS\

<(6

5 HPRYHFKDQJHXULQDU\
EODGGHUFDWKHWHULISUHV
HQW

%HJLQ)OXFRQD]ROH
PJ,932GDLO\ GD\V

Figure 1. Candiduria clinical pathway.

Notes: temp .101F or ,96F; WBC .10,000. *systemic amphotericin B, amphotericin B bladder irrigation, or voriconazole.

20 CliniCal MediCine insights: trauMa and intensive MediCine 2015:6

CliniCal MediCine insights: trauMa and intensive MediCine 2015:6 21

 Table 1. demographics of the patients.
Short-term fluconazole for Candiduria

Regarding the primary outcome, there was no statisti-

SDWLHQWVHYDOXDWHG
IRUHQUROOPHQ cal difference in the recurrence rate of candiduria among the
W study group, the long-term control group, and the short-term
.
SDWLHQWVQRWHOLJLEO control group (32% vs 55% vs 38%, respectively; P 0.05).
H Secondary outcomes were also similar among the three groups
3DWKZD\YLRODWLRQ
$JH\HDUV (Table 2). Candida species isolated in the study group were C.
6HSWLFVKRFN albicans (43%), C. glabrata (32%), C. tropicalis (16%), and C.
&RQFXUUHQWFDQGLGLDVLV
3UHYLRXVDQWLIXQJDOWKHUDS\
parapsilosis (8%). Identification of Candida species was not a
0DOLJQDQF\ laboratory standard during the enrollment period for the control
3UHJQDQF\ group; therefore, 82% of patients in the control group had an
unspeciated isolate.
SDWLHQWVLQFOXGHGLQGDWDDQDO\VLV
PHGLFDOVXUJLFDO Discussion
WUDXPD In this study, a clinical pathway featuring 3 days of fluconazole
therapy resulted in a similar candiduria recurrence rate as was
Figure 2. Flow of study participants. seen with longer-term therapy. In addition, the rates of
subsequent candidemia were similar. As such, these results
question the need to use long-duration therapy to treat
Fishers exact test, or Students t-test for parametric data where symptomatic candiduria in this population.5 Advantages of
appropriate. Nonparametric data were compared using Mann short-term fluconazole therapy include limiting the shift toward
, fluconazole-resistant Candida species, minimizing cytochrome
Whitney U-test. Statistical significance was defined as P 0.05.
P450 interactions, and cost savings. Other studies also suggest
that short-term therapy of candiduria is acceptable.713
Results
Seventy-four patients in the study group were evaluated for Leu et al7 randomized 180 hospitalized patients to one of
enrollment; 37 met the inclusion criteria (16 medical/surgical six different regimens. Five days of fluconazole, single-dose IV
and 21 trauma) (Fig. 2). In the control group, there were 37 amphotericin B, and amphotericin B bladder irrigation (ABBI)
patients who received short-duration fluconazole therapy (20 (200 mg/L) for 3 days were all equally effective at day 7 (range:
medical/surgical and 17 trauma) and 22 patients with a long ,
68%77%) and were significantly better than no treatment (P
duration of fluconazole therapy (19 medical/surgical and 3
0.05).7 Jacobs et al8 randomized 109 elderly hospitalized
trauma). The baseline characteristics are presented in Table 1.
patients with candiduria to either ABBI (50 mg/L) or
The only statistically significant difference between the study
fluconazole for 5 days. Both treatments were equally effective
and control groups was a higher rate of diabetes in the control
.
group. after 1 month (84% vs 80%, respectively; P 0.05).8 Similarly,
Fan-Havard et al9 randomized 53 patients with candiduria to
ABBI 50 mg/L for 1 day, ABBI for 7 days,

VARIABLE CONTROL GROUP STUDY GROUP

(n = 37)
SHORT TERM (n = 37) LONG TERM (n = 22)
Sex, no. (%)

Male 11 (30) 10 (45) 16 (43)

Mean age (y sd) 51 18 50 17 55 17

Race, no. (%)

Caucasian 21 (57) 8 (36) 18 (49)

african american 15 (41) 14 (64) 19 (51)

hispanic 1 (3) 0 (0) 0 (0)

Risk factors for candiduria

 diabetes mellitus, no. (%) 17 (46)a 13 (59)b 7 (19)

Prior antibiotics 37 (100) 22 (100) 35 (95)

antibiotic days, median 9 10.5 9

Candida .100,000 cfu/ml in urine culture, no. (%) 32 (86) 15 (68) 30 (81)
Notes: Compared to study group, P = 0.013; compared to study group, P = 0.0016. All other comparisons not statistically significant.
a b

Wood et al

Table 2. Clinical outcomes.

VARIABLE CONTROL GROUP STUDY GROUP

(n = 37)
SHORT TERM (n = 37) LONG TERM (n = 22)
Recurrence of candiduria, no. (%) 14/37 (38) 12/22 (55) 12/37 (32)

Med/surg iCu 7/20 (35) 10/19 (53) 5/16 (31)

trauma iCu 7/17 (41) 2/3 (67) 7/21 (33)

Development of candidemia, no (%) 1/37 (3) 3/22 (14) 2/37 (5)

Med/surg iCu 0/20 (0) 3/19 (16) 0/16 (0)

trauma iCu 1/17 (6) 0/3 (0) 2/21 (10)

Hospital LOS, (mean SD, d) 52 39 61 44 51 39

Med/surg iCu 43 32 52 38 49 49

trauma iCu 62 48 118 82 53 31

Mortality, no. (%) 11/37 (30) 4/22 (18) 10/37 (27)

Med/surg iCu 6/20 (30) 4/19 (21) 7/16 (44)

trauma iCu 5/17 (29) 0/3 (0) 3/21 (14)

Note: P = ns for all overall between-group comparisons. Abbreviation:
NS, nonsignificant.

or fluconazole 200 mg/day for 7 days. The eradication candiduria go on to develop candidiasis. 24 This view seems to rates were
similar among the groups (77%, 75%, and 79%, be corroborated by the IDSA guidelines. 10
.
respectively; P 0.05).9 In addition, two nonrandomized This study has three primary strengths. First, this study is observational
studies showed that short-term treatment with unique because it compared short- and long-term fluconazole
ABBI for 35 days was 80%100% effective (total n = 126).12 for treating candiduria. Second, the candiduria recurrence
Two other trials studied longer durations of flucon- rates in the study group were in the range of those reported azole. 10,11 Sobel
et al10 randomized 316 patients to fluconazole in other studies. Third, this study included both trauma and 200 mg/day for 14 days
or catheter replacement alone. Fluco- medical ICU patients. Thus, the data should be applicable to a nazole resulted in superior
,
eradication at 14 days (50% vs 29%, wide variety of patient groups. respectively; P 0.001), but not at 1 month (61% vs 56%, This
.
study also has several limitations. First, the sample respectively; P 0.05). Similarly, Potasman et al11 random- size was relatively
small and thus there is a potential for a Type II ized 60 patients to receive fluconazole for 14 days or catheter statistical error in the
primary outcome. Second, this was not replacement alone. Again, fluconazole resulted in a more rapid a randomized trial, but it
rather used a before/after design. clearance of candiduria, but the eradiation rates were similar Obviously, larger randomized studies
are needed to validate between the groups after 8 weeks (87% vs 93%, respectively; or refute these findings. However, the control
and study
.
P 0.05).11 time periods were consecutive and we do not feel that there

CliniCal MediCine insights: trauMa and intensive MediCine 2015:6 23

 Overall, there does not appear to be a clear advantage in were significant changes in the standards of care over these
efficacy rates for long-term (14 days) therapy over short-term time periods that would have affected the efficacy of canditherapy
#
( 7 days). The candiduria recurrence rate of 32% in duria therapy. Third, there were more patients with diabetes the current study
seems acceptable in comparison to the recur- in the control group than in the study group. It is possible rence/failure rate in other
studies. Importantly, few patients in that diabetic patients were more susceptible to recurrence of the previous studies were critically
ill, whereas all of the patients candiduria, which could bias the results in favor of short-term in the current study were in an ICU or
an ICU step-down unit. therapy. It is unclear to us why there was this disparity in Some may argue that even a short course of
antifungal patients. therapy may be unwarranted. Two randomized trials sug-
gested that catheter removal or replacement alone was equiva- Conclusion
10,11
lent to 14 days of antifungal therapy. However, two other In conclusion, this study compared short- and long-term flustudies
provide a warning that not treating with antifungal conazole therapy for the treatment of candiduria in ICU and agents can result in
worse outcomes.2,7 It is likely that the need ICU step-down patients using a before/after study design. for antifungal therapy comes
down to patient-specific factors Three days of fluconazole treatment resulted in similar canand symptoms of active infection.
$
Ultimately, we feel that diduria recurrence rates as with therapy for 7 days. These it is important to treat candiduria in symptomatic
critically results suggest that 3 days of fluconazole administration could ill patients because up to 36% of critically ill patients with
be used to treat candiduria in this patient population.

22CliniCal MediCine insights: trauMa and intensive MediCine 2015:6

Acknowledgments
A portion of the data from the control group (early period) was
presented as an abstract (Chambers MP, Kuhl DA, Wood GC,
Boucher BA, Freire AX. Increased systemic candidiasis with
prolonged antifungal treatment in patients with candiduria in
the ICU. Chest. 2005;128(suppl):134S135S) and as a platform
presentation at the American Thoracic Society International
Conference, 2005.
Author Contributions
Conceived and designed the experiments: GCW, KA, BAB,
MAC, DAK, MC, AXF, TCF. Analyzed the data: GCW, KA,
DAK, CLR, JMS. Wrote the first draft of the manuscript:
GCW, KA. Contributed to the writing of the manuscript: BAB,
MAC, DAK, CLR, MC, JMS, AXF, TCF. Agree with
manuscript results and conclusions: GCW, KA, BAB, MAC,
DAK, CLR, MC, JMS, AXF, TCF. Jointly developed the
structure and arguments for the paper: GCW, KA, BAB, MAC,
DAK, CLR, MC, JMS, AXF, TCF. Made critical revisions and
approved final version: GCW, KA, BAB, MAC, DAK, CLR,
MC, JMS, AXF, TCF. All authors reviewed and approved of
the final manuscript.
France: incidence, molecular diversity, management and outcome. Intensive Care
Med. 2008;34:292299.
5. Pappas PG, Kauffman CA, Andes D, et al; Infectious Diseases Society of America.
Clinical practice guidelines for the management of candidiasis: 2009 update by the
Infectious Diseases Society of America. Clin Infect Dis. 2009;48:503535.
6. Chambers MP, Kuhl DA, Wood GC, et al. Increased systemic candidiasis with
prolonged antifungal treatment in patients with candiduria in the ICU. Chest.
2005;128(suppl):134S135S. [Abstract].
7. Leu HS, Huang CT. Clearance of funguria with short course antifungal regimens:
a prospective randomized controlled study. Clin Infect Dis. 1995;20:11521157.
8. Jacobs LG, Skidmore E, Freeman K. Oral fluconazole compared with amphotericin
B bladder irrigation for fungal urinary tract infections in the elderly. Clin Infect Dis.
1996;22:3035.
9. Fan-Havard P, ODonovan C, Smith SM, Oh J, Bamberger M, Eng RH. Oral
fluconazole versus amphotericin B bladder irrigation for treatment of candidal
funguria. Clin Infect Dis. 1995;21:960965.
10. Sobel JD, Kauffman CA, McKinsey D, et al. Candiduria: a randomized, doubleblind
study of treatment with fluconazole and placebo. Clin Infect Dis. 2000;30: 1924.
11. Potasman I, Castin A, Moskovitz B, Srugo I, Nativ O. Oral fluconazole for candida
urinary tract infection. Urol Int. 1997;59:252256.
12. Lundstrom T, Sobel J. Nosocomial candiduria: a review. Clin Infect Dis. 2001;
32:16021607.
13. Boedeker KS, Kilzer WJ. Fluconazole dose recommendation in urinary tract
infection. Ann Pharmacother. 2001;35:369372.

REFERENCES
1. Hidron AI, Edwards JR, Patel J, et al; National Healthcare Safety Network Team,
Participating National Healthcare Safety Network Facilities. Antimicrobial- resistant
pathogens associated with healthcare-associated infections: annual summary of data
reported to the National Healthcare Safety Network at the Centers for Disease Control
and Prevention, 20062007. Infect Control Hosp Epidemiol. 2008;29:9961011.
Short-term fluconazole for Candiduria

2. Kauffman CA, Vazquez JA, Sobel JD, et al. Prospective multicenter surveillance
study of funguria in hospitalized patients. The National Institute for Allergy and
Infectious Diseases (NIAID) Mycoses Study Group. Clin Infect Dis. 2000;30: 1418.
3. Nassoura Z, Ivatury RR, Simon RJ, Jabbour N, Stahl WM. Candiduria as an early
marker of disseminated infection in critically ill patients: the role of fluconazole
therapy. J Trauma. 1993;39:390394.
4. Bougnoux ME, Kac G, Aegerter P, dEnfert C, Fagon JY; CandiRea Study Group.
Candidemia and candiduria in critically ill patients admitted to intensive care units in