Candiduria: Should we treat, when and how?

Candiduria: Should we treat, when and how? Hail M. Al-Abdely, MD Consultant Infectious Diseases King Faisal Specialist Hospital & Research Center

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?

Funguria or Candiduria Candiduria = 99% of Funguria

How common is Candiduria?

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, 56:420-426



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, 30:292–305



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, 6:123–128

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 >7 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 Dis;7:342-7 Lundstrom T, Sobel J. Clin Infect Dis. 2001 ;32:1602-7

Microbial pathogens causing nosocomial catheterassociated urinary tract infections in U.S. acute-care hospitals, 1990-92 Hospital wide

Intensive care units

(% of total)

(% of total)

Escherichia coli

26

18

Enterococci

16

13

Pseudomonas aeruginosa

12

11

Klebsiella and Enterobacter

12

13

Candida spp.

9

25

Pathogens

Jarvis WR, Martone WJ. J Antimicrob Chemother 1992;29:19-24.

Who gets Candiduria?

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, 120:444-448 Platt R, et al. Am J Epidemiol 1986, 124:977-985 Storfer SP, et al. Infect Dis Clin Pract 1994, 3:23-29 Phillips JR. Pediatr Infec Dis 1997, 16:190-194

Clin Infect Dis 2000, 30:14–18

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.

Underlying diseases or conditions in 861 patients with funguria. Underlying disease or condition

No. (%) of patients

Surgical procedure

450 (52.3)

Diabetes mellitus

336 (39)

Urinary tract disease

325 (37.7)

Neurogenic bladder Prostatism, stones, or other obstructing lesions Renal failure Recurrent infection Intrinsic renal disease

105 (12.2) 100 (11.6) 65 (7.5) 32 (3.7) 23 (2.7)

Malignancy

191 (22.2)

Malnutrition

146 (17)

Trauma

59 (6.9)

Neutropenia

37 (4.3)

Transplant

30 (3.5)

None

94 (10.9) Kauffman CA, et al. Clin Infect Dis 2000, 30:14–18.

Urinary drainage devices in and procedures undergone by 861 patients with funguria Device or procedure

No. (%) of patients

Indwelling urethral catheter

668 (77.6)

Intermittent urethral catheterization

40 (4.6)

Suprapubic catheter

19 (2.2)

Nephrostomy drainage

19 (2.2)

Ileal conduit

9 (1)

Ureteral stent

10 (1.2)

None

145 (16.8)

Kauffman CA, et al. Clin Infect Dis 2000, 30:14–18.

Initial yeast isolates from urine 861 patients with funguria Yeast isolates

No. (%) of patients

Candida albicans

446 (51.8)

Candida glabrata

134 (15.6)

Candida tropicalis

68 (7.9)

Candida parapsilosis

35 (4.1)

Candida krusei

9 (1)

Other

20 (2.3)

Undetermined

184 (21.4)

Kauffman CA, et al. Clin Infect Dis 2000, 30:14–18.

Why do we get candiduria?

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?

Routes of entry of uro-pathogens to catheterized urinary tract

Maki DG, Tambyah PA. 2001 Emerg Infect Dis;7(2):342-7

Scanning electron micrograph of an infected catheter showing dense and complex biofilm on the extraluminal surface

Maki DG, Tambyah PA. 2001 Emerg Infect Dis;7(2):342-7

Stark RP, Maki DG. N Engl J Med 1984;311:560-4.

Why should we treat Candiduria?

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

mycoses 42, 285–289 (1999)

Antifungal therapy for 861 patients with funguria Antifungal therapy

No. (%) of patients

Fluconazole only

161 (18.7)

Amphotericin B only Bladder irrigation Intravenously Intravenously and by bladder irrigation

100 (11.6) 30 (3.5) 11 (1.3)

Fluconazole and amphotericin B Bladder irrigation Intravenously

36 (4.2) 21 (2.4)

Other

11 (1.3)

None

491 (57.0) Kauffman CA, et al. Clin Infect Dis 2000, 30:14–18.

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

Why should we not treat it?

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

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, 69:56–64



1984: Stamm showed that cases of pyelonephritis and symptomatic cystitis had bacterial counts 1000 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

Sobel JD, et al.: Clin Infect Dis 2000, 30:19-24

Sobel JD, et al.: Clin Infect Dis 2000, 30:19-24

Sobel JD, et al.: Clin Infect Dis 2000, 30:19-24

Mortality 





12 in fluconazole group and 14 in placebo group (P=0.69) No mortality was attributed to fungal infection or treatment No cases of candidemia Sobel JD, et al.: Clin Infect Dis 2000, 30:19-24

How to treat candiduria?

How to treat candiduria? 

Modify risk factors



Medical therapy

Candiduria

Repeat microscopy and culture

No candida

Asymptomatic (previously healthy)

Asymptomatic (predisposed)

Stop

Look for predisposing condition

Manage predisposing condition

None found

Predisposing Condition found

Candiduria resolves

Symptomatic

Systemic antifungal

Candiduria persists

Condition not serious

Observation

Unstable patients

Condition serious

Systemic antifungal

Adopted from: Fisher JF. Curr Infect Dis Reports 2000, 2:523-530

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

Evolution of Treatment of Candiduria candiduria uncommon and benign,

NO Rx

1960s

Slightly more common but benign, treatment toxic (Am B, 5-FC).

More common but benign in most patients, imidazoles are not effective. Am B toxic,

No Rx

Rx: Bladder irrigation with Am B

1970s

1980s

Common, Candiduria benign. revisited. Fluc safe and Era of EBM effective. Infrequent iv Am B Rx: is safe. Selective Rx: FLUC, therapy bladder irrigation Iv Am B

1990s

2000

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

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

Medical Therapy of Candiduria (3) 

Others • 5-Flucytosine  

Advantage: High concentration in urine, covers nonalbicans Candida Disadvantage: Resistance and toxicity

• Caspofungin:  

Advantage: broad-spectrum Disadvantage: No data

• Terbinafine: 

No data

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

Oral fluconazole compared with bladder irrigation with amphotericin B for treatment of fungal urinary tract infections in elderly patients Jacobs et al. Clin Infect Dis 1996, 22:30–35

  



 

Prospective randomized trial Elderly >65 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

Jacobs et al. Clin Infect Dis 1996, 22:30–35

Clearance of funguria with short-course antifungal regimens: a prospective, randomized, controlled study Leu H-S, et al. Clin Infect Dis 1995, 20:1152–1157

Study arms (each 30 adult patients who has 1000cfu/ml candiduria in 2 consecutive cultures)



1. 2. 3. 4. 5. 6.

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

Clearance of funguria with short-course antifungal regimens: a prospective, randomized, controlled study Leu H-S, et al. Clin Infect Dis 1995, 20:1152–1157 Treatments

Clearance–Day 1 No. (%)

Clearance-Day 7 No. (%)

Untreated controls No.=30

-

12/30 (40.0)

Fluconazole No.=30

17/29 (58.6)

17/22 (77.3)

Iv Am B (single dose) No.=30

16/29 (55.2)

18/25 (72.0)

Am B bladder irrigation (5mcg/ml) No.=30

23/28 (82.1)

9/21 (42.9)

Am B bladder irrigation (100mcg/ml) No.=30

26/30 (86.7)

13/19 (68.4)

Am B bladder irrigation (200mcg/ml) No.=30

25/30 (83.3)

15/22 (68.2)

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

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 7–14 days is more likely to be successful. Removal of urinary tract instruments or placement of new devices may be beneficial.

IDSA Recommendations (2) 









Treatment with fluconazole (200 mg/day for 7–14 days) and with amphotericin B deoxycholate at widely ranging doses (0.3–1.0 mg/kg per day for 1–7 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 (50–200 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

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.