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

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

3. Funguria or Candiduria Candiduria = 99% of Funguria

4. How common is Candiduria?

5. How common is this problem? 1910: Raffin was the first to report candiduria 1910: Raffin was the first to report candiduria 1946: first well-documented case of candiduria. 1946: first well-documented case of candiduria. Moulder MK. J Urol 1946, 56:420-426 1957: Cross-sectional study 1957: Cross-sectional study Candiduria in only 15 of 1500 patients.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, 30:292–305More 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 1972: In a prospective study of healthy adults Urine cultures were positive in 10 of 440Urine cultures were positive in 10 of 440 Culture results reverted to negative when clean catch techniques were usedCulture results reverted to negative when clean catch techniques were used Schonebeck J, Ansehn S: Scand J Urol Nephrol 1972, 6:123–128

6. 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. How common is Candiduria? Maki DG, Tambyah PA. 2001 Emerg Infect Dis;7:342-7 Lundstrom T, Sobel J. Clin Infect Dis. 2001 ;32:1602-7

7. Hospital wide Intensive care units Pathogens (% of total) Escherichia coli2618 Enterococci1613 Pseudomonas aeruginosa1211 Klebsiella and Enterobacter1213 Candida spp.925 Microbial pathogens causing nosocomial catheter- associated urinary tract infections in U.S. acute-care hospitals, 1990-92 Jarvis WR, Martone WJ. J Antimicrob Chemother 1992;29:19-24.

8. Who gets Candiduria?

9. Who gets it? Diabetes mellitus Diabetes mellitus Antibiotics Antibiotics Indwelling urinary catheters Indwelling urinary catheters Other risk factors. Other risk factors. Extremes of ageExtremes of age Female sexFemale sex Immunosuppressive agentsImmunosuppressive agents Use of iv cathetersUse of iv catheters Interruption of the flow of urineInterruption of the flow of urine Radiation therapyRadiation 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

10. Clin Infect Dis 2000, 30:14–18

11. Prospective Multicenter Surveillance Study of Funguria in Hospitalized Patients Study design: 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.

12. Underlying disease or condition No. (%) of patients Surgical procedure 450 (52.3) Diabetes mellitus 336 (39) Urinary tract disease 325 (37.7) Neurogenic bladder Neurogenic bladder Prostatism, stones, or other obstructing lesions Prostatism, stones, or other obstructing lesions Renal failure Renal failure Recurrent infection Recurrent infection Intrinsic renal disease 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) Underlying diseases or conditions in 861 patients with funguria. Kauffman CA, et al. Clin Infect Dis 2000, 30:14–18.

13. 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) Urinary drainage devices in and procedures undergone by 861 patients with funguria Kauffman CA, et al. Clin Infect Dis 2000, 30:14–18.

14. Yeast isolates No. (%) of patients Candida albicans446 (51.8) Candida glabrata134 (15.6) Candida tropicalis68 (7.9) Candida parapsilosis35 (4.1) Candida krusei9 (1) Other20 (2.3) Undetermined184 (21.4) Initial yeast isolates from urine 861 patients with funguria Kauffman CA, et al. Clin Infect Dis 2000, 30:14–18.

15. Why do we get candiduria?

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

17. Routes of entry of uro-pathogens to catheterized urinary tract Maki DG, Tambyah PA. 2001 Emerg Infect Dis;7(2):342-7

18. 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

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

20. Why should we treat Candiduria?

21. Why should we treat it? Symptomatic UTI Symptomatic UTI Ascending infection. Ascending infection. Invasive cystitisInvasive cystitis PyelonephritisPyelonephritis Fungus ballFungus ball Hematogenous spread. Hematogenous spread. Invasive candidiasis/candidemiaInvasive candidiasis/candidemia Candiduria as the only sign of invasive candidiasis/candidemia Candiduria as the only sign of invasive candidiasis/candidemia

25. mycoses 42, 285–289 (1999)

28. Antifungal therapy No. (%) of patients Fluconazole only 161 (18.7) Amphotericin B only Bladder irrigation Bladder irrigation Intravenously Intravenously Intravenously and by bladder Intravenously and by bladder irrigation irrigation 100 (11.6) 30 (3.5) 11 (1.3) Fluconazole and amphotericin B Bladder irrigation Bladder irrigation Intravenously Intravenously 36 (4.2) 21 (2.4) Other 11 (1.3) None 491 (57.0) Antifungal therapy for 861 patients with funguria Kauffman CA, et al. Clin Infect Dis 2000, 30:14–18.

29. Who is at risk of invasive candidiasis from candiduria Patients with neutropeniaPatients with neutropenia Infants with low birth weightInfants with low birth weight Patients with renal allograftPatients with renal allograft ICU patients with multiple site colonizationICU patients with multiple site colonization Patients who will undergo urologic manipulationsPatients who will undergo urologic manipulations Patients with significant urinary tract obstructionPatients with significant urinary tract obstruction

30. Why should we not treat it?

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

32. Significance of High Colony Counts and Pyuria 1956: Edward Kass defined significant bacteruria as 100,000 cfu/ml. Kass EH: Trans Assoc Am Physicians 1956, 69:56–64 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 <100,000. Stamm WE: Eur J Clin Microbiol 1984, 3:279–281. 1984: Stamm showed that cases of pyelonephritis and symptomatic cystitis had bacterial counts <100,000. Stamm WE: Eur J Clin Microbiol 1984, 3:279–281. Problems: Problems: These definitions were conducted with E. coli These definitions were conducted with E. coli Never obtained for patients with urinary catheters Never obtained for patients with urinary catheters Never done with candida Never done with candida Ability candida grow fast in urine can give high counts even from contaminated specimen Ability candida grow fast in urine can give high counts even from contaminated specimen Colony counts

33. Significance of High Colony Counts and Pyuria Indicates “inflammation” along the urinary tract Indicates “inflammation” along the urinary tract Coupled with significant colony count indicates “infection”. Coupled with significant colony count indicates “infection”. Problems: Problems: Catheter irritation can cause pyuria and hematuria Catheter irritation can cause pyuria and hematuria Co-existing bacterial pathogen is common Co-existing bacterial pathogen is common Pyuria

34. Treatment No. (%) of patients whose funguria Resolved (n = 288) Persisted or recurred (n = 242) None 117 (75.5) 38 (24.5) Catheter removal only 41 (35.3) 75 (64.7) Antifungal drugs, with or without catheter removal 130 (50.2) 129 (49.8) Outcome of funguria in 530 patients for whom outcome was documented Kauffman CA, et al. Clin Infect Dis 2000, 30:14–18

35. Candidemia found in 7 (1.3%) patients Candidemia found in 7 (1.3%) patients All had intravascular catheters and multiple underlying diseasesAll had intravascular catheters and multiple underlying diseases Five of 7 patients with candidemia died Five of 7 patients with candidemia died Two patients (0.4%) died because of candidiasis Two patients (0.4%) died because of candidiasis Candidemia in 861 patients with Funguria Kauffman CA, et al. Clin Infect Dis 2000, 30:14–18.

36. Sobel JD, et al.: Clin Infect Dis 2000, 31:209–210

37. Patients have 2 consecutive positive urine cultures for yeast that were performed at least 24 h apart 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 >1000 cfu/Ml. Candiduria was defined as the presence in both cultures of >1000 cfu/Ml. Catheterized patients were eligible only if a follow-up culture was positive after removal or replacement of the catheter. 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 Asymptomatic candiduria was defined as absence of both urinary symptoms and fever Patients were stratified by catheterization status Patients were stratified by catheterization status Treatment 400mg loading followed by 200mg QD for 13 days 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 Urine cultures done at days 3, 7 & 14 and 2 wks after the end of Rx

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

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

42. How to treat candiduria?

43. Modify risk factors Modify risk factors Medical therapy Medical therapy

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

45. 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 Medical Therapy

46. candiduria uncommon and benign, NO Rx 1960s Evolution of Treatment of Candiduria 1970s Slightly more common but benign, but benign, treatment toxic (Am B, 5-FC). No Rx 1980s More common but benign in most patients, imidazoles imidazoles are not effective. Am B toxic, Rx: Bladder irrigation with Am B 1990s Common, benign. Fluc safe and effective. Infrequent iv Am B is safe. Rx: FLUC, bladder irrigation Iv Am B2000 Candiduria revisited. Era of EBM Rx: Selective therapy

47. Medical Therapy of Candiduria (1) Azoles Azoles FluconazoleFluconazole Advantage: Safe, high concentration in urine and effective when compared with other therapies Advantage: Safe, high concentration in urine and effective when compared with other therapies Disadvantage: Limited spectrum because of resistance. Effect is short-term Disadvantage: Limited spectrum because of resistance. Effect is short-term Itraconazole:Itraconazole: Advantage: broad-spectrum Advantage: broad-spectrum Disadvantage: Unfavorable pharmacokinetics, no concentration in urine, limited data showed failures Disadvantage: Unfavorable pharmacokinetics, no concentration in urine, limited data showed failures Ketoconazole:Ketoconazole: More or less like itraconazole More or less like itraconazole Voriconazole:Voriconazole: Advantage: broad-spectrum Advantage: broad-spectrum Disadvantage: No data on efficacy Disadvantage: No data on efficacy

48. Medical Therapy of Candiduria (2) Amphotericin B-based Amphotericin B-based Intravenous AmB deoxycholateIntravenous AmB deoxycholate Advantage: Broad-spectrum, prolonged concentration in urine Advantage: Broad-spectrum, prolonged concentration in urine Disadvantage: toxicity Disadvantage: toxicity Topical AmB deoxycholate (bladder irrigation):Topical AmB deoxycholate (bladder irrigation): Advantage: broad-spectrum, low toxicity Advantage: broad-spectrum, low toxicity Disadvantage: Local therapy of the bladder Disadvantage: Local therapy of the bladder Lipid formulations of AmB:Lipid formulations of AmB: Advantage: broad-spectrum, low toxicity Advantage: broad-spectrum, low toxicity Disadvantage: No concentration in urine. Reports of many failures Disadvantage: No concentration in urine. Reports of many failures

49. Medical Therapy of Candiduria (3) Others Others 5-Flucytosine5-Flucytosine Advantage: High concentration in urine, covers non- albicans Candida Advantage: High concentration in urine, covers non- albicans Candida Disadvantage: Resistance and toxicity Disadvantage: Resistance and toxicity Caspofungin:Caspofungin: Advantage: broad-spectrum Advantage: broad-spectrum Disadvantage: No data Disadvantage: No data Terbinafine:Terbinafine: No data No data

50. The main therapeutic modalities The main therapeutic modalities Systemic FluconazoleSystemic Fluconazole Variable duration Variable duration Systemic Amphotericin BSystemic Amphotericin B Short duration Short duration Topical Amphotericin B (Bladder irrigation)Topical Amphotericin B (Bladder irrigation) Short duration Short duration Continuous Continuous Intermittent with catheter clamping Intermittent with catheter clamping Medical Therapy of Candiduria (4)

51. 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 Prospective randomized trial Elderly >65 years Elderly >65 years Stratified by presence of indwelling urinary catheter 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 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) 109 (50 fluc versus 59 AmB irrigation) Outcome: Outcome: Eradication at 2 days after therapyEradication at 2 days after therapy Findings Findings Same baseline characteristicsSame baseline characteristics

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

53. Study arms (each 30 adult patients who has 1000cfu/ml candiduria in 2 consecutive cultures) Study arms (each 30 adult patients who has 1000cfu/ml candiduria in 2 consecutive cultures) 1.Untreated controls 2.Fluconazole: 200mg oral single dose followed by 100mg QD for 3 days 3.Iv Am B (15mg single dose) 4.Am B bladder irrigation for 3 days (5 mcg/ml intermittent Q8hrs) 5.Am B bladder irrigation for 3 days (100 mcg/ml intermittent Q8hrs) 6.Am B bladder irrigation for 3 days (200 mcg/ml intermittent Q8hrs) Outcome measure: Outcome measure: Clearance of candiduria at day 1 and day 7Clearance 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

54. Treatments Clearance–Day 1 No. (%) Clearance-Day 7 No. (%) Untreated controls No.=30- 12/30 (40.0) FluconazoleNo.=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)

55. Treatment of urinary Fungus Ball Occurs mainly with obstructive uropathy Occurs mainly with obstructive uropathy Evidence comes only from anecdotal reports. Evidence comes only from anecdotal reports. Surgical evacuationSurgical evacuation Irrigation of antifungal agents through nephrostomy tubesIrrigation of antifungal agents through nephrostomy tubes Amphotericin B Amphotericin B Fluconazole Fluconazole 5-flucytosine 5-flucytosine

56. 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.

57. 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 IDSA Recommendations (2)

58. Conclusion Generally candiduria is a benign condition that almost always associated with urinary instrumentation and may not warrant therapy 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. Treatment of asymptomatic candiduria in non-neutropenic catheterized patients has never been shown to be of value. No diagnostic criteria for urinary candidiasis 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. 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. 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. 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. Until better diagnostic techniques become available, the decision to initiate antifungal therapy remains mostly one of clinical judgment.