Candida Urinary Tract Infections—Diagnosis (2024)

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Abstract

When yeastlike organisms are discovered in the urine, the major decision that must be made is whether or not this signifies infection of either the upper or lower urinary tracts, colonization of the bladder, or contamination of the urine sample. Most of the time, these yeasts are Candida species, and that genus will be the focus of this review; however, on rare occasions other organisms appear in urine and must be differentiated from Candida. Many yeast infections are superficial in nature, but some represent life-threatening, invasive disease. A logical approach to the evaluation of candiduria must precede therapeutic intervention. When Candida species are discovered in the urinary tract, the prudent physician should neither dismiss the finding out of hand nor begin antifungal agents in an empiric fashion. The goal of this review is to elucidate what we know about diagnostic tests that might help differentiate contamination, colonization, and infection of either the upper or lower urinary tracts with Candida species.

CLINICAL EVALUATION

Because yeasts in a urine sample are often contaminants, verification of their presence is a logical first step. Contamination can be differentiated from colonization or infection by obtaining a new urine sample to verify funguria [1–3]. A carefully performed, clean-voided, midstream sample is usually satisfactory. Occasionally, however, it will be necessary to obtain a catheterized specimen. This is the case most often in older women or in patients who are unable to comply with directions for obtaining a clean-voided specimen. For those patients who have an indwelling bladder catheter, it is suggested that the catheter be replaced with a new device and then the second urine specimen be obtained. If the second specimen yields no yeasts, then further diagnostic workup is unnecessary.

Most patients with candiduria are asymptomatic, and yeasts are noted in the urine as a serendipitous finding on a routine urinalysis or urine culture. Most of these patients do not have a Candida urinary tract infection (UTI). However, in those individuals who do have symptomatic Candida infections, the symptoms are indistinguishable from those caused by bacterial infections. Cystitis is associated with dysuria, urgency, suprapubic discomfort, and rarely fever; pyelonephritis leads to fever, chills, and flank pain, with or without lower tract symptoms. Oliguria, strangiuria (difficult and painful urination), the passage of particulate matter, and/or pneumaturia suggest a complication such as the presence of a fungus ball [4–6].

Some patients with established candiduria have no symptoms because of an inability to mount an inflammatory response or because they are unable to communicate. For example, a neutropenic patient rarely has dysuria, frequency, or flank pain. Patients in the intensive care unit (ICU) who are often sedated and intubated may be unable to vocalize any symptoms they might be experiencing. Patients with indwelling catheters rarely complain of dysuria but sometimes will note suprapubic or flank pain [7].

Candida prostatitis as a cause of candiduria usually presents with lower abdominal discomfort, pressure posterior to the symphysis pubis or in the perineum, anorectal dysesthesia, or sexual dysfunction [8–10]. Rarely acute prostatitis with abscess or emphysematous prostatitis accounts for the presence of yeast in the urine [11–14]. In these unusual cases, fevers, urinary retention, and a tender prostate are ordinarily noted. In other instances, patients present less dramatically with urinary retention clinically thought to be due to benign prostatic hyperplasia until biopsies prove the presence of Candida [15]. In what must be an extremely unusual occurrence, the origin of candidemia in 1 patient was reported to be a clinically quiescent focus of Candida infection in the prostate [16]. However, it was not clear from the description which event had occurred first, candidemia or prostate involvement.

Candiduria resulting from epididymo-orchitis can have either an acute or a chronic presentation based upon the few available reports but has been invariably associated with enlarged, tender testicl*s and/or scrotal masses [17–20]. Bladder catheterization is a common underlying risk factor.

For critically ill patients, candiduria, whether symptomatic or not, should initially be regarded as a potential marker for the presence of invasive candidiasis [21]. Seminal studies by Louria et al showed that the kidney becomes infected in ∼80% of patients when candidemia occurs and that candiduria is a common result of this hematogenous infection [22]. One must always consider invasive candidiasis and candidemia in ill patients with candiduria. Obtaining blood cultures and examining the retina and the skin for the telltale lesions of candidiasis are important diagnostic procedures.

In summary, in patients who are able to give a history, symptoms are useful in differentiating infection from colonization by Candida. However, clinical symptoms and signs are not useful in distinguishing bacterial from fungal UTIs and, unfortunately, in many patients at highest risk for fungal UTIs, may be absent or unable to be assessed. Thus, other diagnostic laboratory and imaging studies need to be pursued in the evaluation of proven candiduria.

URINALYSIS AND MICROSCOPY

Pyuria is a helpful sign of a Candida UTI, but in patients with indwelling catheters, it loses both sensitivity and specificity. Most patients with urinary catheters have white blood cells in the urine as a nonspecific finding [23]. Unfortunately, the question of whether candiduria represents an infection or merely colonization arises most often in patients who have indwelling bladder catheters; thus, the presence of pyuria is not a useful diagnostic test in most instances. Measurement of leukocyte esterase activity provides no further benefit over that gained by assessing the presence of pyuria. Concomitant infection with bacteria also reduces the helpfulness of pyuria in deciding if there is a UTI due to Candida. In the absence of a catheter, if only yeasts and not bacteria are grown from a urine sample, pyuria may be a significant finding pointing toward a Candida infection. Similarly, the presence of protein and blood found on urinalysis can be supporting evidence of a Candida UTI only if yeasts alone, and not bacteria, are grown from the urine sample.

The first clue that a fungal infection is present may be the finding of yeasts visualized by microscopy. A centrifuged specimen should be viewed with the aid of Gram stain. In urine, Candida albicans and other less commonly seen species, such as Candida parapsilosis and Candida tropicalis, will appear as budding yeasts, 4–10 μm in diameter, that often show formation of hyphal elements. Smaller budding yeasts, only 2–4 μm in diameter, without any hyphal structures, are likely to be C. glabrata. It was thought at one time that the presence of hyphae could distinguish infection from colonization [24]. However, given the fact that C. glabrata cannot produce hyphae but clearly cause UTI, this observation is not useful. It has been shown that C. albicans mutants that do not form hyphae cause UTI in an experimental murine model, confirming that the presence of hyphae is not a valid marker for infection [25]. Yeasts found in association with a variety of gram-negative bacilli and gram-positive cocci may suggest the presence of a fistula between the bladder and the colon or the vagin*.

Several other yeastlike organisms that can infect the genitourinary tract must be differentiated from Candida species. Saccharomyces cerevisiae causes a UTI that is indistinguishable from that of Candida [26], and these yeasts have the same microscopic appearance as Candida species. Other yeastlike organisms, such as Rhodotorula, Trichosporon asahii, and Blastoschizomyces capitatus, have been associated with disseminated infections in highly immunocompromised individuals and could appear in urine samples as a result of fungemia. T. asahii (formerly T. beigelii) has been reported as causing symptomatic UTIs in renal transplant recipients [27]; in such cases, blastoconidia, arthroconidia, and hyphae can be seen.

Rarely, Blastomyces dermatitidis or Cryptococcus neoformans may be present in urine as a manifestation of disseminated infection. Both target the prostate and would more commonly be noted in urine collected after prostatic massage [28, 29]. B. dermatitidis are large round yeasts with thick walls and single broad-based buds; C. neoformans vary in size from 4 to 10 μm in diameter and have large polysaccharide capsules surrounding the yeasts and narrow-based buds.

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. Although this species grows well on blood agar, the organism grows slowly, and colonies may not appear for 48 h or more, which is after the time when many laboratories discard culture plates that have been set up to assess urine bacterial growth. Thus, C. glabrata may be seen on microscopy but not grown in culture, unless the laboratory is notified to incubate the primary plates longer than usual in order to look for slowly growing colonies or unless specific urine cultures for fungi are requested [30]. In the latter case, urine is inoculated onto a Sabouraud agar slant and kept for several weeks.

Quantitation of the number of organisms in the urine routinely is used to define bacterial UTIs. However, quantitation has not proved useful in the diagnosis of Candida UTIs [31]. Initial experimental attempts to assess the role of quantitative urine cultures were undertaken by investigators in the 1970s [32–34]. In several of these studies, renal biopsies were performed to establish upper tract involvement. In patients without indwelling catheters, proven renal infection was found with colony counts as low as 10⁴ colony-forming units (CFUs)/mL [34]. For those patients who had indwelling catheters, colony counts ranged between 2 × 10⁴ and ≥10⁵ CFUs/mL; in catheterized patients, there was no correlation with biopsy-proved renal infection. These data confront clinicians with the conundrum that for patients who have an indwelling catheter, as few as 2 × 10⁴ CFUs/mL may indicate infection, whereas ≥10⁵ CFUs/mL may indicate colonization. These studies have not been repeated, and it is highly unlikely that any subsequent studies will be performed that use biopsy-proved renal infection as the gold standard. A more recent experimental animal model of hematogenous renal candidiasis lends credence to these early human studies, in that it was noted that Candida in the urine, in any concentration, reflected renal involvement [35].

A marked incremental increase in Candida CFUs from urine collected prior to and after prostate massage is suggestive of Candida prostatitis. Candida epididymo-orchitis is generally diagnosed when an ultrasound-guided diagnostic aspirate yields Candida on culture.

OTHER DIAGNOSTIC STUDIES ON URINE

In the 1970s, an assay for antibody-coated yeasts in urine was devised as a marker for infection. However, this was subsequently shown to be a nonspecific finding that was present in most yeast-containing urines that were tested, including urine samples from several patients who did not have Candida in their kidneys at necropsy [36–38].

Identification of casts containing yeasts in the urine was evaluated to distinguish upper from lower tract infection and colonization. The description of this finding in urine from patients with upper tract infections [39] led to subsequent experimental studies in animals [40]. In rabbits with disseminated candidiasis, casts containing hyphae and blastoconidia could be visualized within the first 3 d of infection and persisted for up to 10 d in rabbits given a higher inoculum. Although they could be seen on direct examination of a wet mount of urine, they were more easily seen when the urine was filtered and the filter was stained for fungi. It does appear that finding casts containing yeasts is a specific indicator of upper tract infection, but the technique is time consuming, requires expert evaluation, and is insensitive if wet mounts only are examined.

IMAGING STUDIES

In symptomatic or critically ill patients with candiduria, diagnostic imaging may be an important component of an evaluation. Because of its portability and safety, ultrasonography is the preferred initial study in patients in ICUs or in those with impaired renal function. The ultrasound may show focal, segmental, hypoechoic renal lesions in Candida pyelonephritis, and when hydronephrosis is present, separation of the central renal echoes or dilated calyces and renal pelvis may be apparent. Fungus balls are rare findings in adults but common in infants in ICUs who have candiduria. Indeed, in a study of 20 such infants with Candida UTI who had ultrasound studies, 7 (35%) had renal fungus balls [41], usually appearing as nonshadowing, echogenic foci. With respect to Candida infections of the male reproductive organs, transrectal ultrasound has been useful to delineate a prostatic abscess as the cause of candiduria [42]. Likewise ultrasonography has been the initial imaging procedure of choice to demonstrate hypoechoic Candida abscesses in the epididymis or testicl* [17].

An excretory urogram (intravenous pyelogram), imaged using conventional radiography, can reveal hydronephrosis, a focal mass in the collecting system, or a nonfunctioning kidney. However, most excretory urograms are now performed with the benefit of CT. A CT urogram is superior to both an x-ray urogram and ultrasonography 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 [43].

Experience with magnetic resonance (MR) imaging in Candida UTI is limited. Investigators from one institution reported that an MR image was superior to a CT image in the demonstration of fungus balls [44]. An MR image with gadolinium enhancement is particularly useful in demonstrating pyelonephritis in children with fever-producing UTI [45]. Whether or not the technique could be employed diagnostically to localize the source of candiduria in adults has not been systematically studied.

Renal cortical scintigraphy using technetium-99m-labeled glucoheptonate or dimercaptosuccinic acid (DMSA) is reportedly more sensitive than excretory urography or ultrasonography in the diagnosis of acute pyelonephritis and has been found to be equivalent to spiral CT and MR imaging in an experimental pig model of acute renal infection [46, 47]. However, as indicated above, MR imaging was shown to be superior to scintigraphy in a study of children with fever-producing UTIs [45]. Tc-99m DMSA imaging provides visualization of the renal parenchyma without interference from the retention of a tracer in the collecting system. Pyelonephritis can produce decreased uptake of this radiopharmaceutical. In renal infection it is postulated that the transport mechanism for Tc-99m DMSA across the cell membranes into tubular cells is inactivated, resulting in decreased localization of the tracer (ie, cortical defect) at the site of infection. Thus, renal scintigraphy generally demonstrates that the involved kidney exhibits poor function [48], the cause of which could be renal candidiasis in patients who have Candida species isolated from their urine in pure culture.

Data are sparse with regard to the utility of other nuclear medicine studies for patients with candiduria. Published only in abstract form, a prospective study employing ¹¹¹indium-labeled leukocytes was performed in 8 asymptomatic patients with confirmed candiduria [49]. In 4 of the patients, bilateral renal uptake of the radionuclide occurred, suggesting to the authors that subclinical pyelonephritis could be frequent in patients with candiduria. Obviously, additional studies specifically targeting candiduric patients are needed before radionuclide scans can be routinely recommended for diagnostic evaluation.

The prudent physician should consult with colleagues in the departments of radiology and urology as to which imaging procedure would be most useful for an individual patient who has candiduria and who requires in-depth evaluation.

Supplement sponsorship. The supplement was sponsored through research funds of Georgia Health Sciences University, Medical College of Georgia, Augusta, Georgia.

Potential conflicts of interest. J. F. F. serves on the speaker's bureaus for Continuing Education Company and Southern Medical Association. C. A. K. has received grant support from Merck, royalties from Springer Publishing and UpToDate, and payment from Pfizer for chairing the Data Adjudication Committee for an Aniduafungin study. J. D. S. serves on the speaker's bureaus for Astellas and Pfizer; his institution has received grant support from Merck. C. A. N. no conflicts.

References

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