Fungal Infections of the Urinary Tract

Introduction
Epidemiology
Risk Factors
Candiduria
Approach to candiduria
Management of candiduria
Candiduria in renal transplant recipients
Renal Aspergillosis
Renal Mucormycosis
Endemic Fungi

1. Fungal Infections of the Urinary Tract Dr Abdullah Ansari SR Nephrology SGPGIMS Lucknow

2. History

3. Introduction Fungal pathogens are the cause of increasing nosocomial infections in hospital communities

4. Epidemiology

5. Epidemiology

6. Urinary tract involvement by invasive mycoses

7. Candida species

8. Candida Candida species are the most common source of funguria , Candida albicans being the most common species Studies have reported that 10 to 40% of all UTI are caused by Candida species Platt et al. showed that 25 % of all catheter-associated UTIs linked to Candida The highest associations are found in ICU where one quarter of all documented UTIs can be attributed to Candida Sobel and Lundstrom reported that Candida species are the most common isolated pathogen from urine

9. Candida Candida spp. are common inhabitants of the perineum but are not found in urine in appreciable numbers in healthy hosts However, a variety of predisposing factors allow these commensals to grow in the urine and in some cases to invade the bladder or the upper urinary tract Candida UTIs are associated with the use of indwelling urinary devices such as Foley catheters, stents and nephrostomy tubes

10. Risk factors for Candiduria Type Risk factors Renal (hematogenous) Neutropenia, recent surgery, central venous catheter, parenteral nutrition, antibiotics, dialysis Lower urinary tract Indwelling bladder catheter, older age, female, diabetes, obstruction, antibiotics, urinary tract instrumentation Upper urinary tract Older age, diabetes, antibiotics, obstruction, urinary tract instrumentation (e.g., nephrostomy tube, ureteral stent)

11. In this multicenter Spanish study of ICU patients, independent risk factors associated with candiduria were Age >65 years Female gender Diabetes mellitus Prior antibiotic use Mechanical ventilation Parenteral nutrition Length of hospital stay before ICU admission

12. Pathogenesis

13. Renal candidiasis Hematogenous spreading Animal models: Multiple micro-abscesses develop throughout the cortex Penetrate glomeruli into proximal tubules and shed into urine Healthy animals clear infection, but immunocompromised animals do not Autopsy studies: Multiple abscess in renal interstitium , glomeruli and peritubular vessels Papilary necrosis, rarely emphysematous pyelonephritis

14. Lower urinary tract candidiasis Catheterization may introduce organism or allow migration of organisms into the bladder along the surface of catheter from the external peri-urethral surfaces Ascending infection that originates in the bladder can lead to upper urinary tract infection, especially if vesicoureteric reflux or obstruction of urinary flow occurs Virulence factors , such as those that control adherence and biofilm formation, are also likely relevant, but have not been studied in the context of Candida UTI

15. Microbiology Species identification is important for therapeutic reasons Resistance to fluconazole is common in C. glabrata and C. krusei C. albicans, C. tropicalis and C. parapsilosis are almost susceptible to fluconazole World J Urol 1999;17:410-414

16. Clinical manifestation – site of infection Candida cystitis Signs and symptoms of bladder irritation (frequency, dysuria, urgency, hematuria, pyuria) Cystoscopy: pearly white, soft, slightly elevated patches, hyperemia of the bladder mucosa Candida pyelonephritis Fever, leukocytosis, rigor CVA tenderness US or CT scan: useful in diagnosing intrarenal or perinephric abscess Fungus ball is a major complication

17. Fungal bezoar (fungal ball) Anywhere but most commonly pelvis and upper ureter > bladder Consists of yeast, hyphal elements, epithelial and inflammatory cells and sometimes, renal medullary tissue secondary to papillary necrosis Signs of obstruction Excretory urography or retrograde pyelography: filling defect in the collecting system Emphysematous pyelonephritis C. albicans and C. tropicalis in diabetic patients without urinary obstruction Leads to nephrectomy Perinephric abscesses Diabetic, postoperative, renal transplant and patients on chronic antibiotic therapy

18. Urinalysis and microscopy Pyuria is often not a helpful diagnostic criterion for infection in candiduria In patients with indwelling bladder catheter, pyuria is routinely noted regardless of infection Concomitant bacteriuria is frequently noted in patients with candiduria and may be responsible for pyuria In patients who do not have an indwelling bladder catheter or bacteriuria, the presence of pyuria is helpful

19. Urine culture The techniques routinely used in most clinical laboratories for the detection of bacteria will also detect yeasts in urine The exception is C. glabrata , which grows slowly on blood agar, and colonies may not appear for 48 hours, which is often after urine cultures have been discarded Urine may be inoculated onto a Sabouraud agar slant and kept for several weeks

20. Urine culture: quantification No studies have established the importance of quantitative urine cultures for the diagnosis of Candida UTI In patients who did not have indwelling catheters, renal infection was found with colony counts as low as 10 4 cfu /ml In patients who had indwelling catheters, colony counts between 2 × 10 4 and 10 5 cfu /ml were noted, and there was no correlation with biopsy-proven infection A murine model of hematogenous renal candidiasis noted that renal involvement could be seen with any concentration of Candida in the urine

21. Imaging studies: Ultrasonography The ultrasound may show focal, segmental, hypoechoic renal lesions in Candida pyelonephritis Fungus balls may appear as hydronephrosis, are rare findings in adults but common in infants in ICUs In males, transrectal ultrasound has been useful to delineate a prostatic abscess as the cause of candiduria

22. Imaging studies: Ultrasonography Heteroechoic lesions filling the dilated pelvicalyceal system A possible diagnosis is of fungal balls obstructing the pelvicalyceal systems

23. Imaging studies: Urography An intravenous pyelogram can reveal hydronephrosis, a focal mass in collecting system or a nonfunctioning kidney A CT urogram is superior to both IVP and USG in defining pyelonephritis and perinephric abscess The enhanced sensitivity of CT results in better visualization of perinephric fluid, gas in tissues, and the presence of fungus balls causing obstruction

24. Imaging studies: Urography Fungal hydronephrosis: Several fungus balls (dark round “holes” in contrast dye) in the ureter and pelvis of the right kidney causing hydronephrosis

25. Case 1 A 75-year-old female presented with fever and dyspnea for 3 days Underlying disease : T2DM, HTN, left MCA infarction Status bed ridden She was on Foley catheter due to neuropathic bladder Last admission due to pneumonia 1 month ago O/E: T 100.4°F, BP 110/70 mmHg, P 110/min, RR 24/min CVS: normal S1, S2, no murmur RS: crepitation at right lower lung field Abdomen: soft, not tender

26. Case 1 Labs: CBC: Hb 12 g/dL, WBC 14,000 (N 90%, L18, M 2%), Plt 110,000 BUN 25, Cr 1.2, Na 135, K 4, Cl 100, HCO3 15 UA: pH 6, sp.gr. 1.020, WBC 5-10, RBC 0-1, leukocyte neg, nitrite neg, yeast 2+ Urine culture: Candida albicans < 10 5 CFU/mL CXR

27. Case 1 Piperacillin/tazobactam was initiated for treatment of pneumonia What should you do next Start amphotericin B Start fluconazole Start an echinocandin Change Foley catheter and repeat UA Repeat UA and observe only

28. Candiduria

29. Asymptomatic Candiduria

30. Natural History of Asymptomatic Candiduria Majority of patients with candiduria : asymptomatic Colonization > infection Most observational studies: candiduria does NOT commonly lead to candidemia (1.3-8%) Candiduria as a source of candidemia  urinary tract obstruction and have undergone urinary tract procedure Marker for greater mortality BUT death not related to Candida infection Likely a marker for severity of illness Treatment did not improve outcome

31. Multicenter prospective surveillance study 861 patients: yeast in urine culture 530 (61.6%) patients  evaluate outcome 117/155 (75%) resolved without treatment Only 7 patients (1.3%) developed candidemia

32. 316 asymptomatic candiduric hospitalized patient Randomized: fluconazole 200 mg vs placebo 14 days

33. Management of asymptomatic candiduria Fisher JF, Sobel JD, Kauffman CA, et al. Candida urinary tract infections–treatment. Clin Infect Dis 2011;52 (Suppl 6):S458

34. Management of asymptomatic candiduria Recommendations Elimination of predisposing factors eg. Foley catheter Treatment with antifungal agents is NOT recommended unless the patient high risk for dissemination Neutropenic patients Very low-birth-weight infants (<1,500 g) Undergo urologic manipulation Drugs Oral fluconazole, 400 mg daily, OR AmB deoxycholate, 0.3–0.6 mg/kg daily Several days before and after the procedure IDSA guideline management of Candida 2016

35. Management of asymptomatic candiduria in renal transplant recipients

36. Case 2 A 75-year-old male was admitted in the ICU with severe community acquired pneumonia He was complicated with Acinetobacter baumannii pneumonia and treated with intravenous colistin for 10 days and vancomycin was added for phlebitis 5 days later, he developed new onset fever with septic shock O/E: V/S: T 100.8° F , BP 80/40 mmHg, P 120/min, RR 26/min (on ventilator) CVS: unremarkable RS: crepitation right lung (same as previous) Abdomen: soft, not tender

37. Case 2 Labs: CBC: Hb 10 g/dL, WBC 15,000 (N 80%, L10, band 10%), Plt 120,000 BUN 30, cr 1.3, Na 135, K 4,Cl 100, HCO3 13 UA: pH 6, sp.gr. 1.020, WBC 5-10, RBC 0-1, leukocyte neg, nitrite neg, yeast 2+ Urine culture : Candida albicans CXR: same as 2 days ago

38. Case 2 What should you do next Start amphotericin B Start fluconazole Start an echinocandin Change Foley catheter and repeat UA Repeat UA and observe only

39. Candiduria in ICU Setting Evaluate possibility of disseminated candidiasis 46-80% of persons with candidemia  accompanying with candiduria However!!! Candiduria commonly found in hospitalized patients esp. in ICU Removing catheter  resolve 20-40% and reinserted of catheter can resolve in 20% of candiduria Correct risk factors eg. Discontinue antibiotics if no indication

40. Candiduria and Candidemia In a large prospective study, only 7 (1.3%) of 530 patients who had candiduria and were followed for 12 weeks developed candidemia 1 A retrospective study, 11 (10.5%) of 105 patients with candiduria developed candidemia 2 A treatment trial, specifically enrolled asymptomatic or minimally symptomatic patients with candiduria , none of 316 patients developed candidemia 3 In the presence of obstruction, candidemia can follow candiduria 4,5 Saudi Med J 2006;27(11):1706-10 Clin Infect Dis 2001; 32(11):1602-7 Clin Microbiol Infec 2006;12(6): 538-43 Expert Rev Anti Infect Ther 2007;5(2):277-84 Drug Aging 1996;8(2):89-96

41. A 1-year prospective observational study in 24 adult ICUs 262 patients with nosocomial candidemia and/or candiduria The mean incidences of candidemia and candiduria were 6.7 and 27.4/1000 admissions, respectively 8% of candiduric patients developed candidemia with the same species

42. Predisposing Factors for Candidemia Neutropenia Non-neutropenic host Prolonged broad spectrum antibiotics Intravascular catheterization ICU admission Abdominal & thoracic surgery Parenteral nutrition Severe burn NON-specific !!

43. Candida scores Leon score 1 Non-neutropenic ICU patients Criteria Multifocal Candida colonization Surgery TPN Severe sepsis (X 2) Positive: Total score ≥ 3 Sensitivity 81% Specificity 74% Ostrosky-Zeichner score 2 Major criteria ICU stay ≥ 4 days and Systemic ATB therapy or Central venous catheter Minor criteria TPN Any dialysis Any major surgery Pancreatitis Steroid use Immunosuppressive drug use Positive: 2 major + 2 minor criteria Sensitivity 34% Specificity 90% Cristo´bal Leo´n , Sergio Ruiz-Santana, Pedro Saavedra, et.al; Crit Care Med 2009 Vol. 37, No. 5 L. Ostrosky-Zeichner , C. Sable, J. Sobel, et.al; Eur J Clin Microbiol Infect Dis (2007) 26:271–276

44. Siriraj Candidemia Assessment Score ( SiCAS ) SiCAS (Non-neutropenia) Positive score ≥ 0 Punjasamarnwong S., et al. 2014 Parameter Points Parenteral nutrition 2 Candiduria 2 Solid tumor 3 Severe sepsis 5 Constant -5

45. Empirical antifungal therapy in non-neutropenic patients Recommendations Empiric antifungal therapy should be considered in critically ill patients with risk factors for invasive candidiasis and no other known cause of fever and should be based on clinical assessment of risk factors, surrogate markers for invasive candidiasis, and/or culture data from nonsterile sites (strong recommendation; moderate-quality evidence) Empiric antifungal therapy should be started as soon as possible in patients who have the above risk factors and who have clinical signs of septic shock (strong recommendation; moderate-quality evidence) Pappas PG., et al. Clinical Practice Guideline for the Management of Candidiasis 2016

46. Case 3 A 39-year-old woman with type 2 diabetes mellitus developed urinary dysuria, frequency, urgency and pelvic discomfort without systemic features shortly after renal transplantation Her medications: mycophenolate mofetil, tacrolimus and prednisone O/E: V/S: T 98.8 ° F , BP 130/80 mmHg, P 80/min, RR 18/min Abdomen: mild tender at suprapubic area Other: unremarkable

47. Case 3 Labs: CBC: Hb 12 g/dL, WBC 8,000 (N 60%, L135, M 5) Plt 120,000 BUN 18, cr 1.3, Na 135, K 4,Cl 100, HCO3 24 UA: pH 6, sp.gr. 1.020, WBC 20-30, RBC 0-1, leukocyte neg, nitrite neg, yeast 2+ Urine culture: C. albicans

48. Case 3 What should you do next Start amphotericin B Start fluconazole Start an echinocandin Change Foley catheter and repeat UA Repeat UA and observe only

49. Treatment of symptomatic candiduria

50. Antifungal treatment Cell membrane Polyene antibiotics: Amphotericin B Azole antifungals Allylamine antifungals: terbinafine DNA/RNA Synthesis Flucytosine Cell Division Griseofulvin Cell Wall Echinocandins

51. Azole antifungals Fluconazole 80% excrete in the urine High concentration in urine (10 time to plasma) Active against most of C. albicans (most common cause of fungal UTI) Drug of choice for Candida UTI Other azoles: Minimal excretion of active compound in urine Not useful for Candida UTI

52. Flucytosine 97% excrete in the urine High concentration in urine Good activity against many Candida species except C. krusei Side effects: Bone marrow suppression GI disturbance Rash hepatotoxicity

53. Amphotericin B AmB deoxycholate: Active against most of Candida species High concentration in urine Renal toxicity Lipid formulation: Designed to decrease renal toxicity Do not achieve levels in urine and kidney Should not be used

54. Echinocandins Low concentrations (<2% of the dose) of active drug in urine Generally are ineffective in treating Candida UTI Case reports of successful treatment I nvasive infections of bladder or kidney Hematogenous spreading

55. Local Antifungal Administration Continuous bladder infusion of amphotericin B 50 mg in 1 liter of sterile water through a triple-lumen catheter Bladder irrigation clears candiduria more quickly than systemic antifungal agents However, the effect is brief, and recolonization occurs within 1 to 2 weeks Irrigation through a percutaneous nephrostomy tube with amphotericin B is recommended for obstruction caused by a fungus ball, in addition to systemic antifungal therapy with fluconazole Absorption does not occur, and direct infusion is not nephrotoxic

56. Symptomatic Candida cystitis Recommendations For fluconazole-susceptible organisms Oral fluconazole, 200 mg (3 mg/kg) daily for 2 weeks For fluconazole-resistant C. glabrata AmB deoxycholate, 0.3–0.6 mg/kg daily for 1–7days OR Oral flucytosine, 25 mg/kg 4 times daily for 7–10 days For C. krusei AmB deoxycholate, 0.3–0.6 mg/kg daily, for 1–7days Removal of an indwelling bladder catheter, if feasible, is strongly recommended IDSA guideline management of Candida 2016

57. Symptomatic Ascending Candida Pyelonephritis Recommendations For fluconazole-susceptible organisms Oral fluconazole, 200–400 mg (3–6 mg/kg) daily for 2 weeks For fluconazole-resistant C. glabrata AmB deoxycholate, 0.3–0.6 mg/kg daily for 1–7 days, with or without oral flucytosine, 25 mg/kg 4 times daily Monotherapy with oral flucytosine, 25 mg/kg 4 times daily for 2 weeks For C. krusei AmB deoxycholate, 0.3–0.6 mg/kg daily, for 1–7day Elimination of urinary tract obstruction is strongly recommended For patients with nephrostomy tubes or stents insitu , consider removal or replacement, if feasible IDSA guideline management of Candida 2016

58. Candida Urinary Tract Infection Associated With Fungus Balls Recommendations Surgical intervention is strongly recommended in adults Antifungal treatment Irrigation through nephrostomy tubes, if present, with AmB deoxycholate, 25–50 mg in 200–500 mL sterile water, is recommended IDSA guideline management of Candida 2016

59. Candiduria in Renal Transplant Recipients The epidemiology not been well characterized in renal transplant recipients Although infections are normally asymptomatic , but they can lead to pyelonephritis and disseminated infection The indications for antifungal treatment are not well established Moreover, antifungal use may select more resistant Candida species Some of these drugs may interact with immunosuppressive therapy or require intravenous administration

60. A nested case-control study, 192 case patients had 276 episodes of candiduria 11% of all renal transplant recipients developed at least 1 episode of candiduria Most case patients were asymptomatic Candida glabrata was the most common pathogen, 98 (51%) of 192 case patients Independent predictors of candiduria were female sex, intensive care unit admission, antibiotic use during the month before candiduria , presence of an indwelling bladder catheter, diabetes, neurogenic bladder, and malnutrition

61. A variety of regimens were used for treatment 119 case patients (62%) underwent removal of the indwelling bladder catheter within 1 week after diagnosis of candiduria Candiduria cleared in 148 case patients (77%) Candiduria is associated with reduced survival rates, this is likely a marker for severity of illness

62. A retrospective observational study of a cohort of 996 subjects over 2 years 34 patients had 83 episodes of candiduria , with an incidence of 3.4% Of 45 outpatient episodes (54.2%), 17 were treated and 1 required hospitalization (5.9%), and of 28 nontreated outpatients, two were hospitalized (7.1%) All cases of hospital admission had simultaneous bacterial UTI, none developed candidemia, and two patients did not receive any antifungal therapy

63. 5/11 treated ( 45.5% ) and 4/23 untreated ( 17.4% ) patients developed recurrences 50 cases (60%) were associated with antibiotic therapy and 34 (41%) with the presence of a urinary catheter The frequency was higher among women (6.3 vs 1.7%) Antifungal therapy was not associated with either a reduction in recurrence or the appearance of more resistant species

64. Graft site candidiasis A unique syndrome seen early after kidney transplantation It results from contamination of donor kidney with intestinal flora including fungi, during the harvest procedure Transmission of fungal species to the graft vessel can cause mycotic arteritis , with aneurysm formation and rupture Most patients lose the graft, and mortality is high

65. Management of asymptomatic candiduria in renal transplant recipients

66. Other fungi

67. Other yeasts Cryptococcus neoformans Systemic multiorgan i nfection in immunosuppressed, including GU tract In autopsy series, kidney involvement in 25 to 50%, but GU symptoms are rare The prostate is frequently infected and may be a reservoir for persistent infection Diagnosed by biopsy of mass or nodule, granulomatous inflammation is typically seen Treatment of localized GU infection is fluconazole 400 mg/day for 6 to 12 months

68. Other yeasts Saccharomyces cerevisiae A very rare cause of UTI The manifestation is the same as for Candida spp S. cerevisiae is often resistant to fluconazole, and may require amphotericin B

69. Molds The urinary tract is an uncommon site, infections u sually in immunocompromised Hematogenous spread to the kidney with invasive disease results in numerous renal microabscesses and infarcts This may be an incidental finding at autopsy Isolated pyelonephritis can present with fever and flank pain, similar to bacterial pyelonephritis Treatment is surgical removal of the obstructing mass, often nephrectomy, and systemic antifungal therapy and l ocal irrigation with conventional Amp-B Mortality is extremely high

70. Renal Aspergillosis Aspergillosis is the most common mold infection of the urinary tract Three different patterns described ( Flechner , 1981): Disseminated aspergillosis with hematogenous renal involvement Aspergillosis of renal pelvis with bezoars formation Ascending panurothelial aspergillosis Extrarenal aspergillosis of the urinary tract is sparse Patients who have symptomatic UTI usually present with urinary tract obstruction from fungal balls, visualized on CT scan or ultrasound However, mortality is high up to 80%

71. Renal Mucormycosis It is rare and often a manifestation of disseminated disease, renal involvement in up to 20% of cases Isolated renal mucormycosis is rare, and mainly described in developing countries like India and China Renal parenchymal necrosis results from angioinvasion of fungal hyphae, leading to vascular thrombosis and infarction IRM present with fever, flank pain, tenderness, hematuria, pyuria and renal failure, usually the result of near total occlusion of renal arteries The survival for IRM is around 65%. However , in bilateral renal involvement with AKI, mortality is nearly 100%

72. Endemic Fungi All of the major endemic mycoses have been reported to infect the GU tract For all of these organisms, infection is by hematogenous spread to the GU tract For upper tract infection, treatment is the same as that for disseminated infection The treatment of focal infection, which is likely to involve the lower GU tract, often requires surgical removal of infected tissue, as well as antifungal therapy

73. Endemic Fungi Blastomyces dermatitidis It h as the greatest propensity to cause symptomatic infection In patients with disseminated blastomycosis, involvement of the GU tract occurs in a third of cases and usually manifests as prostate or epididymal infection In most patients, discovered incidentally when urine cultures yield the organism or a biopsy is performed for a prostatic or epididymal mass

74. Endemic Fungi Histoplasmosis Symptomatic GU tract involvement with histoplasmosis is uncommon At autopsy, kidney lesions are often found in disseminated histoplasmosis Individual cases of testicular abscesses, epididymitis, and prostate nodules have been reported

75. Endemic Fungi Coccidioidomycosis It rarely causes symptomatic UTI At autopsy, kidney lesions are found in more than 50% of disseminated cases Localized infection, manifesting as abscesses or mass lesions of the epididymis or prostate also occurs

76. Key Messages