Candida spp. Urinary Tract Infections in 13 Dogs and Seven Cats: Predisposing Factors, Treatment, and Outcome
Records from 20 animals (13 dogs, seven cats) with Candida spp. urinary tract infections were reviewed. Six Candida spp. were isolated; Candida albicans was the most common isolate. Concurrent diseases or nonantifungal drugs administered within 1 month of isolation included antibiotics (n=16), corticosteroids (n=6), diabetes mellitus (n=4), nonurogenital neoplasia (n=3), and noncandidal urogenital disease (n=14). All animals had sources of local or systemic immune compromise that likely predisposed to infection. Of five animals with resolution of infection, three did not receive specific antifungal treatment. The authors conclude that correction of predisposing conditions is likely critical for management of Candida spp. urinary tract infection.
Introduction
The genus Candida is comprised of approximately 200 species of asexual yeast.12 This group is ubiquitous, found on many plants, and is normal flora in the gastrointestinal tract and external genitalia of humans, dogs, and cats.12 Candida spp.secondary to invasion by the host’s own flora.12 The commensal organism becomes pathogenic when conditions favor excessive growth or when a patient’s immune system is compromised.12 Factors thought to promote candidal urinary tract infections in dogs, cats, and humans include an increased intestinal Candida spp. population (e.g., postantibiotic administration), decreased cellular defense mechanisms (e.g., secondary to glucocorticoid administration, radiation exposure, blood dyscrasias), and local alterations in the urinary tract environment (e.g., diabetes mellitus, acidic urine pH, indwelling urinary catheters).13–8
There have been only sporadic case reports of Candida spp. urinary tract infections in the veterinary literature. In large retrospective studies of urinary tract infections diagnosed at referral laboratories, Candida spp. were responsible for <0.5% of approximately 1,000 infections in dogs and cats9 and <0.2% of 8,354 infections in dogs,10 and were isolated from slightly >1% of dogs with recurrent or persistent urinary tract infections.11 Candidal urinary tract infections in dogs have been reported in association with a cystic calculus,12 hypothyroidism and diabetes mellitus,13 and diabetes mellitus alone.14 Candidal urinary tract infections have occurred in cats in association with a perineal urethrostomy,15 diabetes mellitus and urinary tract infection,16 and with poorly controlled diabetes mellitus, bacterial cystitis, and possible hyperadrenocorticism.17 Although several veterinary reviews of funguria have made reference to candidal urinary tract infection as a clinical entity,6718 the authors are unaware of any case series of Candida spp. urinary tract infections in dogs and cats.
The purpose of this study was to characterize the clinical presentations, possible predisposing factors, and outcomes of dogs and cats with Candida spp. urinary tract infections that were identified by a computerized database search from three veterinary teaching hospitals.
Materials and Methods
Computerized medical records were reviewed for all dogs and cats that had urine cultures performed at the North Carolina State University College of Veterinary Medicine (1991–2000), the University of California Veterinary Medical Teaching Hospital (1987–2000), and the University of Tennessee Veterinary Teaching Hospital (1987–2000). Criteria for inclusion were positive Candida spp. urine cultures without evidence of concurrent candidal infection outside the urinary tract at the time of isolation; however, animals with concurrent Candida spp. identified from skin cultures were not excluded. Patients were excluded if they had yeast identified on urine sediment examination but did not have urine cultures performed or if growth of Candida spp. was seen in enrichment media but not on appropriate agar plate media.
Medical records were reviewed for patient signalment, the presence of concurrent bacterial urinary tract infection, species and number of Candida isolated, specific treatments instituted, response to treatment, and outcome. Sensitivity patterns of the isolated Candida spp. were recorded if available. Resolution of candidal urinary tract infection was defined as a negative urine culture after cessation of any specific antifungal therapy. Any concurrent diseases resulting in clinical signs or requiring treatment within the 1 month preceding diagnosis of candidal infection, or any drugs administered within the same time period, were also recorded.
Urine sample handling and cultures at the North Carolina State University College of Veterinary Medicine and the University of Tennessee Veterinary Teaching Hospital were performed in accordance with the National Committee on Clinical Laboratory Standards (NCCLS).19 At the University of California, urine samples were centrifuged and sediment was plated on 5% sheep’s blood and Mac-Conkey’s agar plates. Plates were incubated at 37°C in 5% to 7% carbon dioxide, and observed for growth for a minimum of 5 days prior to being discarded; yeast was identified with a commercial test kit.a
Results
Signalment
Twenty animals (13 dogs, seven cats) with positive Candida spp. urine cultures met the criteria for inclusion. Eleven dogs were purebred; no breed was represented more than once. Two of eight male dogs were sexually intact; all female dogs were spayed. Five of the cats identified were domestic shorthairs, one was Siamese, and one was Himalayan. Six cats were male, and one was female; none were sexually intact. Ages of dogs ranged from 3 to 12 years (median, 9 years; 25th percentile, 3; 75th percentile, 12). Ages of cats ranged from 3 to 15 years (median, 11 years; 25th percentile, 3.5; 75th percentile, 10.5). Excluded animals included one dog with C. albicans peritonitis diagnosed at the time of Candida spp. urinary tract infection, one cat that had yeast noted on urinalysis but did not have a urine culture performed, and two dogs and one cat with C. albicans, C. parapsillosis, or C. glabrata growth in enrichment broth only.
Microbial Isolates
Six species of Candida were identified in affected animals [Table 1]. Eighteen (90%) of 20 animals had a single species of Candida spp. throughout the time of evaluation. A dog with pyelonephritis had C. rugosa initially isolated from the renal pelvis and bladder, but C. rugosa and C. albicans were later isolated simultaneously from a cystocentesis-collected sample; final urine culture from this dog resulted in pure C. albicans growth. A cat with aplastic anemia had C. tropicalis and C. glabrata isolated twice and once, respectively, from different urine samples.
Candida albicans was the most common species isolated, found in 62% (8/13) of dogs and 43% (3/7) of cats. Candida rugosa and C. krusei were isolated only from dogs; C. glabrata and C. parapsillosis were isolated only from cats. When Candida spp. growth occurred on urine count plates, the number of colonies recorded ranged from 3 to >105 colony-forming units per mL of urine. The amount of growth on blood agar plates varied from very few to a large number of organisms; however, this variation did not appear to be related to Candida species.
Antimicrobial susceptibility of Candida spp. was reported for four isolates. One C. albicans isolate was susceptible to fluconazole and amphotericin B. A second isolate was initially susceptible to fluconazole, itraconazole, and ketoconazole; but following 2 months of intermittent treatment with oral fluconazole, it became resistant to those drugs. An isolate of C. parapsillosis was susceptible to 5-fluorourocyl and fluconazole, and a C. glabrata isolate was resistant to ketoconazole, itraconazole, and fluconazole.
Nineteen urine cultures yielded bacterial growth from nine (six dogs, three cats) of the 20 animals during evaluation. Bacterial isolates included Enterococcus spp. (n=8 cultures), Escherichia coli (n=11), Klebsiella pneumoniae (n=2), Proteus vulgaris (n=1), Pseudomonas aeruginosa (n=1), Staphylococcus spp. (n=2), and Streptococcus faecalis (n=1); one cat with candidal and bacterial infections also had a Trichosporone beigelii urinary tract infection. Five of these nine animals (three dogs, two cats) had at least one concurrent bacterial and Candida spp. infection recorded. Three of the five animals with concurrent bacterial and candidal infections had bacteria isolated from urine at the same time that candidal infection was first diagnosed, while one dog and one cat had Candida spp. infections prior to the first documented bacterial infection. A dog with confirmed C. albicans urinary tract infection had yeast identified by Gram’s stain of urine sediment at the time of subsequent bacterial infection, but Candida spp. were not simultaneously isolated by urine culture.
All animals with bacterial urinary tract infections were administered appropriate antibiotics based on microbial susceptibility testing. Only two of the five animals with concurrent bacterial infections had bacterial urine cultures repeated following antibiotic administration; both cultures were negative. One animal had persistent candidal infection following resolution of bacterial infection; two animals had bacterial infection following their final documented positive Candida spp. culture; and two animals had both bacteria and Candida spp. isolated from the final culture of record.
Two dogs had Candida spp. isolated from skin specimens. The site of skin culture was not specified in one dog. In the other dog, regions of chronic, superficial pyoderma on the ventral aspect of the abdomen and medial aspects of the hind limbs were cultured. In this second dog, the candidal species identified was identical to the urinary tract isolate. All other attempts to culture Candida spp. from extra-urinary sites of bacterial infection (e.g., retrobulbar or subcutaneous abscesses; corneal ulcers) did not yield growth of candidal organisms.
Concurrent Diseases and Drug Therapy
Diseases causing clinical signs or requiring drug therapy for the 1 month prior to initial isolation of Candida spp. from the urinary tract are listed in Table 2. Drugs administered during this same time period are listed in Table 3. In all animals, Candida spp. urinary tract infection was documented during diagnosis or treatment of other systemic or urinary tract diseases. Additionally, all animals had received some nonantifungal drug therapy within the previous month. Only animals with concurrent nonCandida spp. lower urinary tract diseases had clinical signs of lower urinary tract disease.
Fourteen animals (70%; nine dogs, five cats) were being managed for noncandidal urogenital tract diseases at the time of diagnosis of Candida spp. urinary tract infection; a number of these animals were diagnosed with multiple urogenital conditions. Five animals (25%; three cats, two dogs) had lower urinary tract stomata formation (e.g., urethrostomy or indwelling cystotomy tube) prior to the initial diagnosis of candidal infection. Uroliths were found in one dog and one cat with recurrent urethral obstruction; analysis of stones showed them to be 100% calcium oxalate in the dog and 90% struvite/10% calcium oxalate in the cat. Of three (15%) dogs with transitional cell carcinoma (TCC), diagnosis occurred concurrently with diagnosis of Candida spp. infection in two dogs.
Of four animals (20%; two dogs, two cats) with diabetes mellitus at the time of Candida spp. infection, three had been diagnosed prior to detection of Candida spp., while one dog was hospitalized for diabetic ketoacidosis at the time of Candida spp. infection. At the time of Candida spp. diagnosis, glycemic control (based on clinical signs and presence of hyperglycemia and glucosuria) was adequate in the nonketotic dog and inadequate in the two cats. Two of these four animals had concurrent noncandidal urological disease.
Nonurogenital neoplasia diagnosed in three (15%) animals with Candida spp. urinary tract infection included grade II mast cell tumor, lingual undifferentiated round cell tumor, and interscapular fibrosarcoma. None of these animals had concurrent nonCandida spp. urogenital diseases.
Six animals (30%; three dogs, three cats) had been administered corticosteroids within 1 month of diagnosis of Candida spp. urinary tract infection. Supraphysiological doses of prednisone (i.e., 0.7 to 2.1 mg/kg body weight per day) were being administered to treat a variety of conditions (e.g., aplastic anemia, immune-mediated hemolytic anemia, grade II mast cell tumor, postoperative subpubic urethrostomy). One cat was given two injections of dexamethasone (unknown dosage) for presumptive allergic rhinitis. A dog was being given fludrocortisone (0.03 mg/kg body weight per day) and prednisone (0.07 mg/kg body weight per day) for treatment of hypoadrenocorticism. Two of the cats had concurrent urological disease.
Sixteen animals (11 dogs, five cats) had been administered antibiotics for treatment of a variety of clinical conditions. The most commonly administered types of antibiotics were β-lactams (amoxicillin-clavulanic acid, n=4; cephalexin, n=3; cefazolin, n=2; amoxicillin, n=2; potassium penicillin G, n=1) and fluoroquinolones (enrofloxacin, n=9).
Five cats were tested for the presence of feline leukemia virus [FeLV] antigen (serum, four cats; bone marrow, one cat). Four cats were tested for presence of feline immunodeficiency virus [FIV] antibodies. The results of all viral tests were negative.
Treatment
Sixteen of 20 animals were treated with antifungal drugs. Fluconazole was the initial therapeutic agent in 12 animals (eight dogs, four cats). Fluconazole was given orally either once daily (dogs, 3.3 to 6.9 mg/kg body weight, n=4; cats, 6.8 mg/kg body weight, n=1) or twice daily (dogs, 4.8 to 8.3 mg/kg body weight, n=3; cats, 3.4 to 5.0 mg/kg body weight, n=2). One cat received fluconazole at an unknown dose and frequency, and one dog received an unknown dose once daily. Fluconazole dosage in one cat was increased to 10 mg/kg body weight, per os [PO], q 12 hours when a cure was not achieved after 1 year of therapy. Two cats initially received ketoconazole (12.5 mg/kg body weight, PO, q 12 hours for 30 days, or unknown dose and duration, PO, q 12 hours). Following persistent Candida spp. urinary tract infection, these cats were switched to either fluconazole (6.1 mg/kg body weight, PO, q 12 hours) or itraconazole (6.25 mg/kg body weight, PO, q 12 hours). The final two dogs received either flucytosine (35.7 mg/kg body weight, PO, q 8 hours for 28 days) or methenamine (28.2 mg/kg body weight, PO, q 12 hours) and ascorbic acid (28.2 mg/kg body weight, PO, q 24 hours) for urine acidification.
Case Outcomes
Thirteen animals (eight dogs, five cats) had repeat urine cultures performed following initial diagnosis of Candida spp. urinary tract infection; seven animals were euthanized or lost to follow-up. Resolution of candidal urinary tract infection occurred in five animals, including two dogs and one cat that did not receive any specific antifungal therapy, and one dog treated with fluconazole (5.4 mg/kg body weight, PO, q 24 hours for 2 weeks, then increased to q 12 hours for 5 weeks). Resolution occurred in the cat initially treated with ketoconazole followed by itraconazole, but a urine culture was not repeated when stranguria and hematuria recurred 2 months following the last negative urine culture. None of these five animals had definitive resolution of their concurrent noncandidal diseases. Five animals treated with fluconazole had no candidal growth during antifungal therapy; of these, three dogs did not have urine culture repeated after therapy was discontinued, and two cats had recurrence of Candida spp. urinary tract infection following cessation of treatment. The remaining three animals continued to have candidal infection during fluconazole (one dog, one cat) or methenamine and ascorbic acid (one dog) therapy.
Discussion
In this study, the authors identified 13 dogs and seven cats with Candida spp. urinary tract infections. In all cases, candidal infection occurred in the presence of other diseases and nonantifungal drug therapy. Definitive cure occurred in only three dogs and two cats, of which three animals did not receive specific antifungal therapy.
Organisms of the genus Candida spp. are part of the normal gastrointestinal, upper respiratory, and genital mucosal flora of humans, dogs, and cats.12 Although C. glabrata has historically been separated out as a distinct genus (Torulopsis glabrata), it is now considered to be part of the Candida genus.2 In dogs and cats, initial colonization by Candida spp. occurs when the neonate is exposed during birth to the dam’s genital mucosa.1 Candida albicans and C. parapsillosis are the most common isolates from normal dogs.1 Although no studies have described the types or relative numbers of Candida spp. isolates in healthy cats, one study demonstrated C. albicans in 23% of oropharyngeal swabs of FIV-infected cats versus 4% of noninfected cats; all FIV-infected cats with positive candidal swabs were clinically ill but were asymptomatic for candidal infection.20 A more recent study demonstrated no significant difference in ability to isolate C. albicans from cats with or without retroviral infection.21 In the authors’ study, all that can be said is that negative retroviral status does not appear to protect against Candida spp. urinary tract infection.
Six different species of Candida were isolated from urinary tract samples in the animals of this report. Candida albicans was the most common species identified, likely because of its increased prevalence compared to other species in normal animals. Likewise, C. albicans is the predominant isolate from urine samples from humans;4822 however, there are recent rises in nonCandida albicans candidal urinary tract infections, particularly C. glabrata.22 In a recent review, the relative occurrence of various candidal species in human urinary tract infections was similar to the findings of this study.4
The authors defined Candida spp. urinary tract infection as isolation of any amount of Candida spp. by routine microbiological culture of urine, regardless of the number of colony-forming units per mL of urine. Likewise, in humans, the criteria for diagnosis of candidal urinary tract infections have not been well established, but investigators have recommended that identification of any yeast organisms in two properly collected urine samples is diagnostic and that quantitative colony counts serve no purpose.8 Attempts to correlate pyuria or clinical signs with infection have been unsuccessful.822
The conversion of Candida spp. from a commensal organism to a pathogen is presumed to be secondary to impairment of the normal immune response or host defense mechanisms.12 In the 20 cases of this report, candidal urinary tract infections consistently occurred in the presence of concurrent disease processes or drug therapy that may have compromised one or more of these defenses. Local defense mechanisms of the canine and feline urinary tract include normal anatomical structures, urothelial defenses, antimicrobial properties of normal urine, and the act of micturition itself.23 Additionally, innate, cell-mediated, and humoral immunity all likely play a role in urinary tract defense.23 In humans, numerous risk factors that impair immunity and predispose to candidal urinary tract infections are repeatedly cited, including certain drugs (e.g., antibiotics, immunosuppressives, antineoplastics), diseases (e.g., diabetes mellitus, anatomical urinary tract abnormalities, neoplasia), and iatrogenic factors (e.g., indwelling urinary catheters, urinary tract manipulation).34822 However, statistical analysis supporting the relative risk of these factors is scant. Likewise, although other factors such as the presence of virulence factors (including production of proteases and integrin-like molecules that promote tissue invasion, phenotypic switching, and variations in surface structure) in some C. albicans have been identified, their contribution to infection is unknown.2
Local defenses of the urinary tract were most obviously compromised in those animals managed for nonneoplastic urogenital disease. The creation of artificial stomata in five of these animals may have bypassed the urethral high-pressure zones, decreased normal urethral peristalsis, and shortened the urethral length—all of which contribute to urinary tract protection.23 Surgical formation of these stomata usually occurs with diseases that interfere with normal micturition, which is needed for local defense of the lower urinary tract. Additionally, urocystoliths, TCC, previous bladder or urethral surgery, and recurrent bacterial cystitis compromise the bladder mucosa, and the impaired concentrating ability associated with pyelonephritis and renal failure alters the antimicrobial properties of urine.
Increased exposure of the lower urinary tract to candidal organisms via alterations in normal cutaneous or gastrointestinal flora may have predisposed some animals to candidal urinary tract infection following contact of feces with urogenital mucosa or following mechanical transfer of organisms from the skin. Seven animals (35%; four dogs, three cats) were receiving antibiotics that have good in vivo efficacy against obligate anaerobic bacteria. This spectrum of activity has been associated with C. albicans gastrointestinal proliferation in mice.24 Other factors that may lead to alterations in intestinal flora (such as gastrotomy tubes or drugs such as gastric-acid pH modifiers, prokinetic agents, and laxatives) were also present in this study’s population. Three animals had dermatological diseases that may have contributed to cutaneous candidal overgrowth. This increase in Candida spp. colonization of the skin may have led to candidal urinary tract infection through oral transfer by the animal or through iatrogenic introduction by cystocentesis.
Other animals had identifiable sources of systemic defense impairment. In addition to altering local defense mechanisms via polyuria and glucosuria, diabetes mellitus is known to alter innate immunity by decreasing leukocyte phagocytosis, chemotaxis, adherence, and bactericidal activity in humans.5 Similar effects may occur in dogs.25 Endogenous or exogenous hypercortisolemia, which interferes with local immunity via polyuria, also blunts host cell-mediated and humoral immune response. Nonurogenital neoplasia may interfere with host systemic immunocompetence; extensive hospitalization, chemotherapeutics, radiation therapy, and surgery in these patients also may have contributed to decreased host immunity. Candida spp. infections diagnosed in hospitalized humans are considered to be nosocomial, thus supporting the roles of indwelling urinary catheters and urinary tract manipulation as likely risk factors for infection.34822 Dogs with TCC had multi-factorial compromise of local immunity, both via disruption of mucosal integrity and protective mechanisms, as well as the systemic immunosuppression of neoplasia.
In the 20 animals of this study, 45% were diagnosed with bacterial infections at some point during clinical evaluation, with concurrent bacterial and fungal infections occurring in 25%; isolates included an approximately equal number of Gram-positive cocci and Gram-negative bacilli. Although increased susceptibility to bacterial and candidal urinary tract infections may occur in the same animals, the role of bacteria in the establishment and maintenance of Candida spp. urinary tract infection is unclear. In previously published case reports, dogs and cats with Candida spp. urinary tract infections did not have concurrent bacterial infections, but four of five animals had historical bacterial infections.12–17 Any compromise of host defenses could predispose animals to bacterial as well as fungal infections. Additionally, bacterial cystitis may further compromise local protective mechanisms, providing a more favorable environment for candidal infection. It is possible that animals with recurrent bacterial urinary tract infections may be at increased risk for Candida spp. urinary tract infection. Successful management of candidal infections should likely include treatment of concurrent bacterial infections.
For the purpose of determining treatment modality, candidal urinary tract infections in humans are classified as asymptomatic (patients that present without previously diagnosed predisposing causes) or symptomatic (patients with known risk factors).3 Using this scheme, one patient in this study would have been classified as asymptomatic and 19 as symptomatic. However, this delineation is based on risk factors in humans, and it is unknown if these factors can be applied to veterinary patients.
Spontaneous resolution of candidal infection was seen in 15% (three animals) of the cases in this series, all of which were classified as symptomatic. However, it was impossible to determine from record review whether timing of infection resolution correlated with correction or abatement of potentially predisposing factors. The treatment of asymptomatic human patients is controversial. Identification and elimination of undiagnosed risk factors is the first recommended step.3 Spontaneous resolution of candidal urinary tract infection has been documented in 23% to 65% of asymptomatic cases; however, resolution may take several months to years.48 Fewer than 10% of humans with candiduria progress to candidemia, and candiduria can be identified as the source of candidemia in approximately 10% of cases.2226 In the present study, candidemia was suspected by the attending clinician in one cat that eventually died of unknown causes. This cat had chronic renal failure and diabetes mellitus, which are not risk factors for progression of candiduria to candidemia in humans.26 Further long-term studies are needed with larger numbers of dogs and cats to determine if antifungal therapy should be given to or withheld from dogs and cats that have Candida spp. urinary tract infections without known risk factors.
The most common antifungal drugs used in symptomatic humans with Candida spp. urinary tract infections are intravenous or intravesicular amphotericin B, oral azoles, and oral flucytosine.348 The preferred agent, dose, and dosing regimen are not established. Intravenous amphotericin B has clear efficacy and is the drug of choice for systemic candidiasis.3 Flucytosine clears Candida spp. urinary infections in 40% to 70% of cases, but toxicity in humans has precluded its routine use.3 Currently, intravesicular amphotericin B or oral fluconazole are the most widely used treatments for candidal urinary tract infections in humans.4 The former induces more rapid resolution of candidal urinary tract infection but requires hospitalization and urinary catheterization, is expensive, and may be associated with poorer long-term survival.482728 With fluconazole, resolution of candidal infection occurs more slowly, distribution of drug to tissue is affected by various urinary tract factors such as pH, and optimal dose and duration of treatment are unknown; however, fluconazole provides longer fungicidal effect (i.e., time until reinfection).3428–30 Treatment with ketoconazole or itraconazole is not recommended, because therapeutic concentrations are not achieved in urine.383031
An optimal treatment regimen is difficult to infer from the animals of this report. Azole drugs were the most commonly chosen antimycotic agents in this case series, most likely because of safety margin, ease of administration, and lower cost than alternative agents. However, definitive cures were documented in only five of 20 animals. Fluconazole should probably be considered the azole of choice, but the need for routine and repeated sensitivity testing is unknown. Two isolates in this study’s series were resistant against all tested azoles, and there are reports of fluconazole resistance in nonurogenital human candidiasis, particularly with prolonged azole administration.29–31 Other authors have reported success with intravesicular clotrimazole13 and failure with intravesicular amphotericin B.16 Intravenous liposome-encapsulated amphotericin B may also prove to be a safe alternative.332
Conclusion
The clinical presentation, diagnosis, treatment, and outcome of candidal urinary tract infection in dogs and cats are inconsistent. Based on the patient population of this study, the authors suspect that as with humans, concurrent alterations in local and systemic immunity play a role in development and maintenance of Candida spp. urinary tract infection. Identification and correction of these patient risk factors are critical for management, but specific antimycotic treatment regimens have yet to be established. Fluconazole may provide effective therapy when other factors are effectively managed, but long-term treatment and follow-up are likely required.
API 20C AUX; bioMerieux, Hazelwood, MO
Contributor Notes
