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Vet Res Forum
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Veterinary Research Forum
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Urmia University Press Urmia, Iran

10.30466/vrf.2024.2018960.4113
Clinical Report
Successful treatment of Candida albicans-induced fungal cystitis in a dog using caspofungin: a case report
Han Sei-Myoung *
Department of Animal Health and Welfare, College of Health and Biotechnology, Semyung University, Jecheon, South Korea.
* Semyung University, Jecheon, South Korea, E-mail: smhan@semyung.ac.kr
2024
15 8 2024
15 8 435438
28 12 2023
7 5 2024
© 2024 Urmia University. All rights reserved
https://creativecommons.org/licenses/by-nc-sa/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0 https://creativecommons.org/licenses/by-nc-sa/4.0/) which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.
A 7-year-old castrated male poodle was brought to the referral Animal Medical Center and diagnosed with diabetes and pancreatitis. One month later, the patient presented with cloudy urine, and ultrasonography revealed a large number of spherical substances. The patient was subsequently diagnosed with fungal cystitis with Candida albicans. Initially, 10.00 mg kg-1 itraconazole was prescribed twice daily for six weeks, and the symptoms of prolonged urination improved; however, the fungal balls persisted in the bladder. The six months later, the patient showed recurrent symptoms, such as dysuria and stranguria; therefore, 5.00 mg kg-1 fluconazole was prescribed twice daily; however, it was not effective. Subsequently, 1.00 mg kg-1 caspofungin once daily was administered for three consecutive days. Finally, the fungal balls in the bladder disappeared. The patient was regularly monitored after completion of treatment and, 17 months later, doing well without recurrence. Few reports exist on the use of caspofungin in veterinary medicine. The recommended dose of caspofungin in dogs remains unknown. In the case of azole-resistant Candida, treatment using caspofungin should be considered; although, additional studies on the established dosing and side effects are needed.

Key Words

Anti-fungal drugs
Azole-resistant candidiasis
Candida albicans
Caspofungin
Fungal cystitis
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pmcIntroduction

Fungal urinary tract infections (UTIs) are caused by the over-growth of fungal yeast. Although fungal bladder or UTIs are uncommon in dogs, Candida spp. account for most fungal infections. Candida spp. are normal flora of the upper respiratory, gastrointestinal, and urogenital tracts of dogs; however, they can cause opportunistic genitourinary fungal infections in dogs.1,2 Several cases of Candida spp. infections and treatment have been reported; particularly, those associated with the long-term use of antibiotics, immunosuppressive drugs, and diabetes mellitus.3-5 In most cases, treatment is attempted and managed successfully using azole drugs; however, resistance to azole-related drugs has been observed.6,7 We report the case of a diabetic dog infected with Candida albicans that was unresponsive to azole-related anti-fungal agents (itraconazole and fluconazole).

Case Description

A 7-year-old castrated male poodle was brought to the referral Animal Medical Center with signs of depression, weight loss, and polydipsia. Routine blood workups, such as complete blood counts, serum biochemistry, urinalysis on the collected urine by cystocentesis, abdominal radio-graphy (AccuRay-603R; DK Medical Systems, Seoul, Korea), and ultrasonography (HD15; Philips, Hamburg, Germany) were conducted. Blood analysis (Dri-Chem NX700; Fujifilm Corp., Tokyo, Japan) revealed abnormal alkaline phosphatase (1,100 U L-1; Reference range: 47.00 - 254 U L-1), and hyperglycemia (glucose level: 539 mg dL-1; Reference range: 75.00 - 128 mg dL-1). Thus, urinalysis with dipstick showed glucosuria (2+) and ketonuria (3+) with a specific gravity of 1.046. The amount of urine sediment was small, and bacteria or cells were not found on microscopic examination. The canine pancreatic lipase test (Canine SNAP cPL; IDEXX Laboratories Inc., West-brook, USA) was also positive. Based on the results, the patient was diagnosed with diabetes mellitus, ketosis, and pancreatitis. While providing supportive care for pancreatitis and ketosis, neutral-protamine-Hagedorn (NPH) insulin (2.00 U, twice daily, Subcutaneously; Humulin N; Eli Lilly and Co., Seoul, Korea) was prescribed for diabetes control at the initial dose. One month later, during a routine checkup, the owner reported that the patient had cloudy urine. Body temperature and other physical examination parameters were normal. Complete blood count, serum chemistry, urinalysis, abdominal radiography, and ultrasonography were performed. Abdominal ultrasonography revealed numerous spherical structures without acoustic shadowing. Urine being collected via cystocentesis was slightly cloudy, and urinalysis revealed concentrated urine (specific gravity: 1.036), aciduria (pH: 6.00), glucosuria (2+), and leuko-cyturia, but no proteinuria or ketonuria. Fungal budding yeast and pseudohyphae were detected in the urine sediment test. A urine sample was submitted to IDEXX Laboratories (Seoul, South Korea) for microbiological culture, which confirmed the presence of C. albicans.

Because it was thought that the fungal ball was partially obstructing urination, treatment for cystitis was initiated with 10.00 mg kg-1 itraconazole (Nelson Pharm Korea, Seoul, South Korea) twice daily,3 to improve the symptoms of prolonged urination. The symptoms of prolonged urination improved somewhat; however, the fungal balls persisted in the bladder. Because the treatment was judged to be ineffective, itraconazole administration for 6 weeks was discontinued, and no further treatment was attempted because the patient was able to urinate.

Six months after the diagnosis of Candida infection, the patient was brought to the hospital as an emergency with symptoms of dysuria, stranguria, abdominal distension, and vomiting. On abdominal palpation, the bladder was distended, and the patient was considered unable to urinate due to urethral obstruction by the fungal ball. Blood tests revealed no significant changes, except for an increase in white blood cells (23,000 µL-1; Reference range: 6,000 -17,000 µL-1) and elevated liver enzymes (alanine aminotransferase: 89.00 U L-1; Reference range: 17.00 - 78.00 U L-1 and alkaline phosphatase: 2,333 U L-1; Reference range: 47.00 - 254 U L-1). Ultrasonography revealed a significant increase in the number of previously identified fungal balls. Fluconazole was prescribed at a dose of 5.00 mg kg-1 twice daily (A Progen Fluconazole cap; Aprogen Biologics Seoul, South Korea).6 Simultaneously, a urinary balloon catheter was inserted through the urethra into the urinary bladder. Bladder lavage was conducted with 0.90% normal saline solution (volume range: 50.00 - 200 mL) without antibiotics, until the retrieved fluid was clear.

Despite continuous fluconazole administration and bladder lavage for 7 days, no improvement was noted in clinical symptoms, and fungal budding yeast and pseudo-hyphae were still detected in the urine (Fig. 1). Therefore, fluconazole was changed to 1.00 mg kg-1 caspofungin (MSD-Korea, Seoul, South Korea) once daily. Caspofungin (50.00 mg) was diluted in 250 mL 0.90% normal saline (final concentration: 0.20 mg mL-1) and intravenously injected for 1 hr for three consecutive days.6,8 On the third day of treatment, the fungal balls in the bladder had disappeared. Thus, caspofungin was administered three times per week and subsequently discontinued and the bladder lavage was discontinued because the substances discharged during bladder lavage were significantly reduced. Fifteen days after the first administration of caspofungin, a urine culture test was requested again and Candida was no longer identified. Figure 2 shows the ultrasound examination of the substances in the bladder from the time of C. albicans diagnosis to the termination of treatment. After completing treatment, the patient was regularly monitored every 2 - 3 months for C. albicans recurrence and diabetes. Seventeen months after treatment, the patient was doing well, with no recurrence, except for the development of bacterial cystitis and calcium oxalate crystalluria.

Fig. 1 A) The arrow indicates sediment in urine after centrifugation; B) Pseudohyphae and budding yeast (arrowheads) are observed under the microscope after Diff-Quik® staining of the urine sediment (400×).

Fig. 2 Ultrasonographic findings of the bladder. A) Ultrasound at the time of diagnosis. B) Worsening of symptoms. A large amount of mobile echogenic ball-shaped matter without acoustic shadowing is observed. C) Ultrasound view before caspofungin administration. D) Bladder ultrasound after the termination of caspofungin administration. The previously seen spherical material is not identified.

Even after caspofungin administration, there was no significant change in blood test results compared to those before administration. Blood test results of the patient before and after caspofungin administration are summarized in Table 1.

Table 1 Changes in blood analysis before and after starting caspofungin treatment. Based on the day of caspofungin administration, the blood test results before (Day –9) and after (Days 2, 16, and 135) treatment are presented.

Parameters	Day –9	Day 2	Day 16	Day 135	Normal range	
White blood cells (×10 3 µL -1 )	23.10	Not available	Not available	7.80	6.00 - 17.00	
Red blood cells (×10 6 µL -1 )	6.93	Not available	Not available	7.48	5.50 - 8.50	
Hematocrit (%)	55.50	Not available	Not available	55.30	37.00 - 55.00	
Platelet (×10 3 µL -1 )	318	Not available	Not available	478	150 - 500	
Alanine aminotransferase (U L -1 )	89.00	31.00	81.00	127	17.00 - 78.00	
Aspartate aminotransferase (U L -1 )	27.00	21.00	37.00	29.00	17.00 - 44.00	
Alkaline phosphatase (U L -1 )	2,333	1,082	1,312	1,386	47.00 - 254	
Gamma-glutamyl transferase (U L -1 )	80.00	25.00	20.00	41.00	0.00 - 11.00	
Blood urine nitrogen (mg dL -1 )	Not available	9.10	12.80	8.50	9.20 - 29.20	
Creatinine (mg dL -1 )	Not available	0.27	0.28	0.29	0.40 - 1.40	
Glucose (mg dL -1 )	506	148	250	329	80.00 - 120	
Total protein (g dL -1 )	Not available	Not available	7.30	6.80	5.40-7.10	
Albumin (g dL -1 )	Not available	Not available	4.10	4.00	2.60-4.00	
Triglyceride (U L -1 )	> 500	Not available	> 500	> 500	30.00 - 133	
Total cholesterol (mg dL -1 )	281	Not available	241	> 450	111 - 312	
C-reactive protein (mg L -1 )	< 9.00	Not available	Not available	< 9.00	0.00 - 9.00	

Discussion

Candida spp. are natural inhabitants of the upper respiratory, gastrointestinal, and urogenital tracts of dogs and can cause opportunistic infections in immunocompromised animals or those undergoing long-term treatment with antibiotics, corticosteroids, and immunosuppressive drugs.2 Moreover, infections in the urinary system of dogs with diabetes have been reported.6,7 Recently, Reagan et al.5 investigated the risk factors for candida UTIs in dogs and indicated that they were related to antibiotic use, among several factors that can cause candidiasis (use of antibiotics and immuno-suppressants, urinary catheterization, diabetes, and hospitalization). Patients with diabetes had an increased susceptibility to Candida spp. owing to an infection being exacerbated in cases of uncontrolled hyperglycemia and immunosuppression.9,10

In human medicine, the necessity for candiduria treatment is uncertain because of the low risk of candidemia. Thus, the concomitant bacterial cystitis should be treated first, and only thereafter should anti-fungal treatment be considered. Because asymptomatic candiduria does not benefit from anti-fungal treatment,11 it should not be treated except in immunocompromised patients. Symptomatic Candida infections (e.g., pyelonephritis, prostatitis, and epididymo-orchitis) must be treated with appropriate anti-fungal agents.12

Azole drugs are primarily used in patients with symptomatic candiduria. Among azole drugs, fluconazole is the first-line anti-fungal drug for candida cystitis treatment. It is usually recommended to prescribe fluconazole for 1 week at a dose of 2.50 - 5.00 mg kg-1, twice daily for dogs and 50.00 mg kg-1, once daily for cats; however, the prescription period varies depending on the infection.13 A 9-year-old dog diagnosed with fungal cystitis caused by C. albicans was managed and successfully treated using itraconazole.3 However, in human medicine, the use of azole agents, such as itraconazole or keto-conazole, is not recommended for patients with Candida UTIs because these drugs are metabolized via the liver. Thus, only small amounts are excreted in the urine.11 In contrast, fluconazole maintains high concentrations in the bladder because the active drug is excreted in the urine.14

In this case, although itraconazole was administered for 6 weeks, the number of fungal balls was not significantly reduced. Itraconazole was ineffective; thus, the drug was discontinued. Then, clinical symptoms such as dysuria and stranguria suddenly appeared, and fluconazole treatment was initiated; however, the symptoms of dysuria and stranguria persisted. Bladder lavage with normal saline was performed simultaneously to reduce the number of fungal balls, but the clinical symptoms did not improve noticeably. Therefore, it was tentatively judged to be an azole-resistant infection, and drug conversion was considered.

Caspofungin is a parenteral anti-fungal drug, and few reports exist on its use in veterinary medicine. It was initially prescribed for invasive aspergillosis or Candida infection.15 The recommended dose of caspofungin in dogs is unknown; however, Schultz et al.8 administered 1.00 mg kg-1 intravenously (every 24 hr) in 250 mL of 0.90% sodium chloride for 1 hr. After the clinical symptoms improved, it was administered three times a week in dogs with systemic aspergillosis. In another study, when caspofungin was administered intravenously at a dose of 1.00 mg kg-1, once daily, for 14 days, the clinical symptoms improved, but the infection persisted.6 In this case, a similar strategy to that used by Schultz et al. was used;8 caspofungin was administered for three consecutive days and then, three times a week. Finally, the fungal balls and clinical symptoms such as pollakiuria, stranguria, and urinary retention were completely disappeared. The side effects of caspofungin in humans include hypersensitivity to the drug (e.g., redness, facial swelling, and itching), pain at the injection site, and hepatic failure; however, it is considered relatively safe. Since the side effects of this drug in companion animals are not well known, the patient's condition was observed throughout drug administration, and no adverse reactions occurred during the treatment period.

Other related studies identified over-expression of the ATP transporter genes, CDR1 and PDH1, in Candida glabrata, causing azole resistance by increasing drug efflux.6 In the present case, a dog with diabetes and UTI was treated using itraconazole and fluconazole, but the clinical symptoms did not improve. Therefore, we tentatively determined that the strain was resistant to azole drugs; however, an anti-fungal susceptibility test or genotyping was not performed. This is a limitation of this case study.

In the present case, caspofungin was successfully administered and no recurrence was observed. Treatment using caspofungin could be considered if there is no improvement in clinical symptoms using fluconazole. However, treatment protocols for Candida infections and the recommended dose of caspofungin have not yet been established in veterinary medicine and additional studies are needed.

Candida albicans is a rare opportunistic infection in veterinary medicine. Clinical symptoms such as dysuria, oliguria, and hematuria may be observed; therefore, if symptoms appear, treatment is necessary. In this case, caspofungin was successfully administered to a patient in whom azole drugs had minimal effect. Therefore, successful treatment with caspofungin is expected in patients with azole-resistant Candida infection. However, further studies on the pharmacological actions of caspofungin and clinical reports are needed to establish the dose and administration methods to be used in veterinary medicine.

Acknowledgments

The author thanks the staff at Animal Medical Center (Gyeonggi-do, South Korea) for their assistance with patient care.

Conflict of interest

No conflict of interest to declare.
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