Candiduria: Should we treat, when and how

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Candiduria Should we treat, when and how?

• Hail M. Al-Abdely, MD
• Consultant Infectious Diseases
• King Faisal Specialist Hospital Research Center

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Presentation Outline

• How common is this problem?
• Who gets it?
• Why do we get candiduria?
• Why should we treat it?
• Who should be treated? and who should not?
• How to treat candiduria?
• What are the current recommendations in the
  management of candiduria?

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Funguria or Candiduria
Candiduria 99 of Funguria
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How common is Candiduria?
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How common is this problem?

• 1910 Raffin was the first to report candiduria
• 1946 first well-documented case of candiduria.
• Moulder MK. J Urol 1946, 56420-426
• 1957 Cross-sectional study
• Candiduria in only 15 of 1500 patients.
• More than 50 of these 15 patients had diabetes
  mellitus and were receiving antibiotics. Guze LB,
  Harley LD Yale J Biol Med 1957, 30292305
• 1972 In a prospective study of healthy adults
• Urine cultures were positive in 10 of 440
• Culture results reverted to negative when clean
  catch techniques were used
• Schonebeck J, Ansehn S Scand J Urol Nephrol
  1972, 6123128

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How common is Candiduria?

• From 1980-1990 the nosocomial fungal infection
  rate for urinary tract infections had risen from
  9.0 to 20.5 per 10,000 hospitalized patients
• Nosocomial bacteriuria or candiduria develops in
  up to 25 of patients requiring a urinary
  catheter for gt7 days, with a daily risk of 5
• Candida species are now the commonest organisms
  isolated from urine specimens in surgical ICU
  patients.

Maki DG, Tambyah PA. 2001 Emerg Infect
Dis7342-7
Lundstrom T, Sobel J. Clin Infect Dis. 2001
321602-7
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Microbial pathogens causing nosocomial
catheter-associated urinary tract infections in
U.S. acute-care hospitals, 1990-92
Jarvis WR, Martone WJ. J Antimicrob Chemother
19922919-24.
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Who gets Candiduria?
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Who gets it?

• Diabetes mellitus
• Antibiotics
• Indwelling urinary catheters
• Other risk factors.     
• Extremes of age
• Female sex
• Immunosuppressive agents
• Use of iv catheters
• Interruption of the flow of urine
• Radiation therapy

Hamory BH. J Urol 1978, 120444-448 Platt R, et
al. Am J Epidemiol 1986, 124977-985 Storfer SP,
et al. Infect Dis Clin Pract 1994,
323-29 Phillips JR. Pediatr Infec Dis 1997,
16190-194
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Clin Infect Dis 2000, 301418
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Prospective Multicenter Surveillance Study of
Funguria in Hospitalized Patients

• Study design
• Prospective observational multicenter study
• No attempt was made to influence physicians'
  responses to the report of a urine culture
  yielding yeast.
• Patients were followed until their discharge from
  the hospital or for a maximum of 10 weeks.
• Underlying conditions.
• Urinary tract instrumentation.
• Symptoms and signs of infection.
• Urinalysis results.
• Organisms isolated.
• Treatment.
• Outcomes.

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Underlying diseases or conditions in 861 patients
with funguria.
Kauffman CA, et al. Clin Infect Dis 2000,
301418.
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Urinary drainage devices in and procedures
undergone by 861 patients with funguria
Kauffman CA, et al. Clin Infect Dis 2000,
301418.
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Initial yeast isolates from urine 861 patients
with funguria
Kauffman CA, et al. Clin Infect Dis 2000,
301418.
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Why do we get candiduria?
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Why do we get candiduria?

• Defense mechanisms against development of
  candiduria?
• Flushing effect of urine
• Normal urinary tract anatomy
• Normal urinary tract function
• Balanced distribution of perineal flora
• Causes of breach of defense mechanisms?

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Routes of entry of uro-pathogens to catheterized
urinary tract
Maki DG, Tambyah PA. 2001 Emerg Infect
Dis7(2)342-7
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Scanning electron micrograph of an infected
catheter showing dense and complex biofilm on
the extraluminal surface
Maki DG, Tambyah PA. 2001 Emerg Infect
Dis7(2)342-7
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Stark RP, Maki DG. N Engl J Med 1984311560-4.
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Why should we treat Candiduria?
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Why should we treat it?

• Symptomatic UTI
• Ascending infection.
• Invasive cystitis
• Pyelonephritis
• Fungus ball
• Hematogenous spread. 
• Invasive candidiasis/candidemia
• Candiduria as the only sign of invasive
  candidiasis/candidemia

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mycoses 42, 285289 (1999)
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Antifungal therapy for 861 patients with funguria
Kauffman CA, et al. Clin Infect Dis 2000,
301418.
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Who is at risk of invasive candidiasis from
candiduria

• Patients with neutropenia
• Infants with low birth weight
• Patients with renal allograft
• ICU patients with multiple site colonization
• Patients who will undergo urologic manipulations
• Patients with significant urinary tract
  obstruction

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Why should we not treat it?
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Why should we not treat it?

• Candiduria is discovered, rather than detected by
  deliberate research
• Problems with diagnosis
• Contamination
• Urine specimens become contaminated with Candida
  during the process of obtaining a urine
• Vulvo-vestibular colonization with Candida (10
  65)
• Colonization of the drainage device
• No reliable method for differentiating
  colonization from infection.
• Asymptomatic adherence and settlement of yeast
  may result in a high concentration of the
  organisms on urine culture
• Infection
• Tissue invasion can not be determined
• Pyuria and colony counts
• Problems with outcome of Treatment
• Benefits versus risks

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Significance of High Colony Counts and Pyuria
Colony counts

• 1956 Edward Kass defined significant bacteruria
  as 100,000 cfu/ml. Kass EH Trans Assoc Am
  Physicians 1956, 695664
• 1984 Stamm showed that cases of pyelonephritis
  and symptomatic cystitis had bacterial counts
  lt100,000. Stamm WE Eur J Clin Microbiol 1984,
  3279281.
• Problems
• These definitions were conducted with E. coli
• Never obtained for patients with urinary
  catheters
• Never done with candida
• Ability candida grow fast in urine can give high
  counts even from contaminated specimen

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Significance of High Colony Counts and Pyuria
Pyuria

• Indicates inflammation along the urinary tract
• Coupled with significant colony count indicates
  infection.
• Problems
• Catheter irritation can cause pyuria and
  hematuria
• Co-existing bacterial pathogen is common

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Outcome of funguria in 530 patients for whom
outcome was documented
Kauffman CA, et al. Clin Infect Dis 2000, 301418
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Candidemia in 861 patients with Funguria

• Candidemia found in 7 (1.3) patients
• All had intravascular catheters and multiple
  underlying diseases
• Five of 7 patients with candidemia died
• Two patients (0.4) died because of candidiasis

Kauffman CA, et al. Clin Infect Dis 2000,
301418.
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Sobel JD, et al. Clin Infect Dis 2000,
31209210
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• Patients have 2 consecutive positive urine
  cultures for yeast that were performed at least
  24 h apart
• Candiduria was defined as the presence in both
  cultures of gt1000 cfu/Ml.
• Catheterized patients were eligible only if a
  follow-up culture was positive after removal or
  replacement of the catheter.
• Asymptomatic candiduria was defined as absence of
  both urinary symptoms and fever
• Patients were stratified by catheterization
  status
• Treatment 400mg loading followed by 200mg QD for
  13 days
• Urine cultures done at days 3, 7 14 and 2 wks
  after the end of Rx

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Sobel JD, et al. Clin Infect Dis 2000, 3019-24
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Sobel JD, et al. Clin Infect Dis 2000, 3019-24
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Sobel JD, et al. Clin Infect Dis 2000, 3019-24
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Mortality

• 12 in fluconazole group and 14 in placebo group
  (P0.69)
• No mortality was attributed to fungal infection
  or treatment
• No cases of candidemia

Sobel JD, et al. Clin Infect Dis 2000, 3019-24
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How to treat candiduria?
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How to treat candiduria?

• Modify risk factors
• Medical therapy

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Adopted from Fisher JF. Curr Infect Dis Reports
2000, 2523-530
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Medical Therapy
Polyenes Amphotericin B (deoxycholate) -
1958 Liposomal amphotericin B (AmBisome) -
1997 Amphotericin Lipid Complex (ABLC) -
1996 Amphotericin Colloidal Dispersion (ABCD) -
1996 Azoles Miconazole (intravenous) -
1979 Ketoconazole (P.O) - 1981 Fluconazole
(P.O, intravenous) - 1990 Itraconazole (capsule,
solution, intravenous) 1992 Voriconazole (P.O,
intravenous)-2002 Others Griseofulvin -
1959 5-Flucytosine - 1972 Terbinafine
1996 Caspofungin- 2001
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Evolution of Treatment of Candiduria
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Medical Therapy of Candiduria (1)

• Azoles
• Fluconazole
• Advantage Safe, high concentration in urine and
  effective when compared with other therapies
• Disadvantage Limited spectrum because of
  resistance. Effect is short-term
• Itraconazole
• Advantage broad-spectrum
• Disadvantage Unfavorable pharmacokinetics, no
  concentration in urine, limited data showed
  failures
• Ketoconazole
• More or less like itraconazole
• Voriconazole
• Advantage broad-spectrum
• Disadvantage No data on efficacy

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Medical Therapy of Candiduria (2)

• Amphotericin B-based
• Intravenous AmB deoxycholate
• Advantage Broad-spectrum, prolonged
  concentration in urine
• Disadvantage toxicity
• Topical AmB deoxycholate (bladder irrigation)
• Advantage broad-spectrum, low toxicity
• Disadvantage Local therapy of the bladder
• Lipid formulations of AmB
• Advantage broad-spectrum, low toxicity
• Disadvantage No concentration in urine. Reports
  of many failures

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Medical Therapy of Candiduria (3)

• Others
• 5-Flucytosine
• Advantage High concentration in urine, covers
  non-albicans Candida
• Disadvantage Resistance and toxicity
• Caspofungin
• Advantage broad-spectrum
• Disadvantage No data
• Terbinafine
• No data

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Medical Therapy of Candiduria (4)

• The main therapeutic modalities
• Systemic Fluconazole
• Variable duration
• Systemic Amphotericin B
• Short duration
• Topical Amphotericin B (Bladder irrigation)
• Short duration
• Continuous
• Intermittent with catheter clamping

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Oral fluconazole compared with bladder irrigation
with amphotericin B for treatment of fungal
urinary tract infections in elderly
patientsJacobs et al. Clin Infect Dis 1996,
223035

• Prospective randomized trial
• Elderly gt65 years
• Stratified by presence of indwelling urinary
  catheter
• Fluconazole 200mg loading them 100mg QD for 4
  days versus AmB (5mg/ml) continuous bladder
  irrigation for 5 days
• 109 (50 fluc versus 59 AmB irrigation)
• Outcome
• Eradication at 2 days after therapy
• Findings
• Same baseline characteristics

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Clearance of funguria with short-course
antifungalregimens a prospective, randomized,
controlled studyLeu H-S, et al. Clin Infect Dis
1995, 2011521157

• Study arms (each 30 adult patients who has
  1000cfu/ml candiduria in 2 consecutive cultures)
• Untreated controls
• Fluconazole 200mg oral single dose followed by
  100mg QD for 3 days
• Iv Am B (15mg single dose)
• Am B bladder irrigation for 3 days (5 mcg/ml
  intermittent Q8hrs)
• Am B bladder irrigation for 3 days (100 mcg/ml
  intermittent Q8hrs)
• Am B bladder irrigation for 3 days (200 mcg/ml
  intermittent Q8hrs)
• Outcome measure
• Clearance of candiduria at day 1 and day 7

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Clearance of funguria with short-course
antifungalregimens a prospective, randomized,
controlled studyLeu H-S, et al. Clin Infect Dis
1995, 2011521157
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Treatment of urinary Fungus Ball

• Occurs mainly with obstructive uropathy
• Evidence comes only from anecdotal reports.
• Surgical evacuation
• Irrigation of antifungal agents through
  nephrostomy tubes
• Amphotericin B
• Fluconazole
• 5-flucytosine

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IDSA Recommendations (1)

• Asymptomatic candiduria rarely requires therapy.
• Candiduria may, however, be the only
  microbiological documentation of disseminated
  candidiasis.
• Candiduria should be treated in
• symptomatic patients,
• patients with neutropenia,
• infants with low birth weight
• patients with renal allografts
• Patients who will undergo urologic manipulations
• Short courses of therapy are not recommended
  therapy for 714 days is more likely to be
  successful.
• Removal of urinary tract instruments or placement
  of new devices may be beneficial.

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IDSA Recommendations (2)

• Treatment with fluconazole (200 mg/day for 714
  days) and with amphotericin B deoxycholate at
  widely ranging doses (0.31.0 mg/kg per day for
  17 days) has been successful.
• Oral flucytosine (25 mg/kg q.i.d.) may be
  valuable for eradicating candiduria in patients
  with urologic infection due to non-albicans
  species of Candida.
• Bladder irrigation with amphotericin B
  deoxycholate (50200 mcg/mL) may transiently
  clear funguria but is rarely indicated
• Even with apparently successful local or systemic
  antifungal therapy for candiduria, relapse is
  frequent, and this likelihood is increased by
  continued use of a urinary catheter.
• Persistent candiduria in immunocompromised
  patients warrants ultrasonography or CT of the
  kidney

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Conclusion

• Generally candiduria is a benign condition that
  almost always associated with urinary
  instrumentation and may not warrant therapy
• Treatment of asymptomatic candiduria in
  non-neutropenic catheterized patients has never
  been shown to be of value.
• No diagnostic criteria for urinary candidiasis
• Candiduria in neutropenic patients, critically
  ill patients in ICUs, infants with low birth
  weight, and recipients of a transplant may be an
  indicator of disseminated candidiasis.
• Treatment of persistently febrile patients who
  have candiduria but who lack evidence for
  infection at other sites may treat occult
  disseminated candidiasis.
• When treatment is indicated, systemic antifungal
  therapy should be used.
• Until better diagnostic techniques become
  available, the decision to initiate antifungal
  therapy remains mostly one of clinical judgment.

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Thank You