Introduction

Alkaline-encrusted cystitis is a rarely reported condition in the human and veterinary literature. It is defined by the unique intramucosal mineralization, alkaline urine pH, and concurrent urea-splitting bacterial infection of the urinary tract. The most common isolate is Corynebacterium urealyticum; however, other pathogens have also been reported.¹ Human reports have acknowledged several predisposing factors for development of encrusted cystitis, including past bladder trauma, micturition disorders, local neoplasia, systemic immune suppression, or urogenital manipulation such as catheterization, cystoscopy, or surgery.^2–7 Prior antibiotic use is a common finding in these cases but a direct cause-and-effect relationship has not been established. There have been few reports of encrusted cystitis in the veterinary literature over the past 15 yr with similar predisposing factors such as prior urinary catheterization, bladder surgery, neurologic deficits, prior antibiotic use, or trauma reported.^1,8–13

Cystoscopic-guided laser ablation (CLA) is a newly described method for diagnosis and treatment of certain urogenital conditions in dogs, most notably ectopic ureters (EU).¹⁴ Reported complications of CLA of EU (CLA-EU) include urethral inflammation, persistent incontinence, urethral tears, ureteral tears, uroabdomen, lymphoplasmacytic cystitis, and stricture formation leading to ureteral obstruction.^14–16 To the authors’ knowledge, this is the first reported case of encrusted cystitis following CLA-EU in a dog.

Case Presentation

A 1 yr old 30 kg spayed female Labrador retriever was referred to the University of Florida Small Animal Hospital for treatment of EU and recurrent urinary tract infections. The dog was adopted at 7 mo old and urinary incontinence was noted at that time. The dog was evaluated by the primary veterinarian and treated with phenylpropanolamine (1.5 mg/kg per os [PO] q 8 hr) without resolution of incontinence. A urinalysis and urine culture were performed, revealing bacteriuria and growth of Klebsiella pneumonia. The dog was treated with cefpodoxime (10 mg/kg PO q 24 hr) for 10 days. The owner noted improvement in the incontinence, but not resolution.

Four mo after adoption, the dog presented to a specialty referral practice for further evaluation. Complete blood count and serum biochemistry were normal. Urinalysis revealed urine specific gravity (USG) 1.035, pH 8.0, rods 26–50 per high-power field (HPF), struvite crystals 4–10 per HPF, but no pyuria or hematuria. Urine culture via cystocentesis revealed growth of Enterococcus faecalis. Abdominal ultrasound showed the left ureter entering the trigone at the papilla and then coursing intramurally distally consistent with ureteral ectopia. No abnormalities were noted with the right ureter or either kidney. Because there was neither an active sediment nor clinical signs of cystitis, the Enterococcus infection was not treated and the dog was referred for CLA-EU.

At presentation to the University of Florida Small Animal Hospital on day 0, physical examination revealed vulval involution with moist perivulvar dermatitis. Urinalysis revealed a USG 1.035, pH 8.0, occasional struvite crystals, and moderate cocci chains. Urine culture was submitted. Marbofloxacin (3.3 mg/kg PO q 24 hr) was started based on previous culture results as recommended in human guidelines for urological interventions in patients with asymptomatic bacteriuria.¹⁷ The next day, cystoscopy revealed multifocal 1–2 mm, raised mucosal lesions suggestive of lymphoid hyperplasia in the vestibule and persistent paramesonephric remnant with a dual vagina. Bilateral EUs were identified, with the left having a proximal urethral opening and the right a mid-urethral opening (Figures 1A, B). The rest of the exam was unremarkable. For each ureter, a 0.038” hydrophilic guidewire was advanced into the proximal ureter under cystoscopic and fluoroscopic guidance. A 5-french open-ended ureteral catheter was placed over the guidewire and a retrograde pyeloureterogram performed in conjunction with a cystogram via the cystoscope. After confirming the intramural tract of the EUs, CLA was performed as previously described using a holmium:yttrium-aluminum-garnet laser.¹⁴ The vaginal septum was also ablated. Marbofloxacin was continued until culture results were available on day 3, which showed growth of >1,000,000 colony-forming units (CFU) per mL of Enterococcus faecalis. The reported minimum inhibitory concentration for marbofloxacin was 2 µg/dL, but no interpretation was provided because Clinical and Laboratory Standards Institute standards did not exist. For this reason, antibiotic therapy was changed to amoxicillin-clavulanic acid (14 mg/kg PO q 12 hr) on day 4 for 7 days.

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Following the procedure, the dog’s clinical signs completely resolved. On day 20, 9 days after stopping antibiotics, the dog developed pollakiuria and hematuria. A urine culture via cystocentesis was obtained by the primary care veterinarian and therapy with amoxicillin-clavulanic acid (14 mg/kg PO q 12 hr) was restarted pending results. The culture revealed growth of Enterococcus faecalis >100,000 CFU/mL sensitive to amoxicillin-clavulanic acid. Because there was no resolution of clinical signs after 7 days of antibiotic treatment, the dog was again seen by the specialty referral practice. Urinalysis showed pH 8.5, USG 1.025, 11–20 red blood cells/HPF, 11–20 struvite crystals/HPF, 26–50 rods/HPF, and 3+ protein. Urine culture showed no growth after 72 hr. Abdominal ultrasound revealed left hydronephrosis (1.13 cm) and hydroureter. The bladder wall was diffusely thickened with irregular contour and nodular thickening at the left ureteral papilla. Ureteral obstruction secondary to severe inflammation and possible granuloma formation was suspected and the dog was referred for further evaluation and treatment.

The dog re-presented to the University of Florida Small Animal Hospital on day 35. Physical exam revealed vulval involution but was otherwise unremarkable. Ultrasound revealed left hydronephrosis (1.2 cm), moderate left ureteral dilation, and a diffusely thickened bladder wall. The bladder wall had a diffusely irregular, hyperechoic mucosa with areas of distal acoustic shadowing consistent with mineralization. A urine sample was obtained for aerobic bacterial culture and sensitivity via cystocentesis. Cystoscopy revealed a moderate amount of white, fibrinous to mucoid material adhered to the urethral mucosa (Figure 2A). In some locations, the material formed plaque-like lesions. Similar findings were seen in the urinary bladder. The cranial bladder wall had several small polypoid masses with white plaques adhered (Figure 2B). The right ureteral opening was identified by visualization of urine jets, but the papilla was obscured by plaque lesions. The left ureteral opening could not be identified because of plaque lesions (Figure 2C). After gently probing the area with a closed 2.0 mm flexible biopsy forceps to dislodge plaque material, left urine jets were visualized but the left ureteral opening and papilla were not identified. Debridement of other plaque lesions was not performed. Biopsy samples from the bladder wall were obtained for histopathology, fungal culture, aerobic bacterial culture, and Mycoplasma culture.

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Because of the appearance of the plaque-like lesions, recent negative urine culture, and lack of response to antibiotic therapy, there was concern for fungal infection, such as Candida sp., and antifungal therapy was started pending culture results. During days 35–37, the patient received fluconazole (5 mg/kg PO q 12 hr) and clotrimazole bladder infusions. Clotrimazole infusions were performed via cystocentesis under ultrasound guidance with 1% solution diluted 1:1 with 0.9% NaCl as previously reported.¹⁸ Amoxicillin-clavulanic acid (15 mg/kg PO q 12 hr) was continued for the previous Enterococcus growth. Clinical signs were unchanged during the first 2 days of treatment. Repeat abdominal ultrasound on day 37 (2 days after re-presentation) revealed improvement in the left hydronephrosis (0.8 cm) and left hydroureter. Histopathology revealed mineralized, eosinophilic, granular cellular debris mixed with fibrin and aggregates of neutrophils and gram-positive short rods.

On day 38 (3 days after re-presentation), preliminary aerobic culture results were suggestive of Corynebacterium infection. Given the histopathologic, ultrasonographic, and cystoscopic findings, a diagnosis of encrusted cystitis was made. Antifungals and amoxicillin-clavulanic acid were discontinued. Empiric treatment with chloramphenicol (35 mg/kg PO q 8 hr) was started pending final culture results based on human study of Corynebacterium sensitivities showing 25% of isolates are susceptible to chloramphenicol.¹⁹ Ammonium chloride (100 mg/kg PO q 12 hr) was also started to decrease urine pH and aid in dissolution of mineralized lesions. Ultrasound on day 39 (4 days after re-presentation) revealed resolution of left hydroureter and improved hydronephrosis (0.5 cm). The bladder appeared unchanged. The patient was discharged with instructions to continue chloramphenicol and ammonium chloride pending final sensitivity results.

Fungal and Mycoplasma cultures were negative for growth. On day 40 (5 days after re-presentation), final aerobic bacterial cultures from both urine and bladder tissue were positive for a slow-growing, gram-positive rod consistent with Corynebacterium sp at >1,000,000 CFU/mL, but a definitive identification could not be made. Bacterial 16S polymerase chain reaction was performed and confirmed Corynebacterium urealyticum. Sensitivity testing revealed multidrug resistance with susceptibility to amikacin, doxycycline, and gentamicin, and intermediate susceptibility to chloramphenicol. Because of a lack of established Clinical and Laboratory Standards Institute standards, there was no available interpretation for amoxicillin-clavulanic acid for treatment of this organism.

Amikacin (15 mg/kg subcutaneously q 24 hr) therapy was chosen based on sensitivity results and bactericidal properties, but due to potential renal toxicity and cost of monitoring was only given for 8 days. Amikacin was started on day 45 (10 days after re-presentation). Because plaque lesions in the bladder mucosa may potentiate bacterial colonization, make antimicrobial penetration difficult, and release organisms as plaques dissolve, long-term therapy was recommended using chloramphenicol. Although chloramphenicol had intermediate susceptibility with a minimum inhibitory concentration of 16 µg/mL, it reaches mean urine concentrations of 124 µg/mL, which should be 90–95% effective in vivo.²⁰

Due to distance, treatment and follow-up monitoring were performed through the primary veterinarian and the specialty referral practice. Urinalysis, blood urea nitrogen, and creatinine were monitored every 2 days during the 8 days of amikacin treatment (days 45–53). The pH of the urine was 7.0 on the third day of amikacin therapy. On day 53 (18 days after re-presentation), ultrasound showed resolution of both left hydroureter and hydronephrosis but persistent thickening of the bladder wall without evidence of shadowing. Serum chemistry analysis was unremarkable. Urinalysis via cystocentesis showed USG 1.024, pH 6.5, 1+ protein, 4–10 red blood cells/HPF, and no crystals or bacteria. Urine culture on day 60, 7 days after amikacin was discontinued, showed no bacterial growth after 72 hr. On day 95 (60 days after re-presentation), ultrasound revealed a normal bladder wall, no hydronephrosis, and mild distal dilation of the left ureter. Chloramphenicol and ammonium chloride were continued until day 145 (110 days after re-presentation). Repeat urinalysis and urine culture were performed on day 180 (145 days after re-presentation) and revealed no growth after 5 days with an inactive urine sediment.

The dog was reported to have infrequent episodes of incontinence since discontinuing urinary acidification and antibiotics. Pollakiuria and odorous urine was noted and the dog was seen by the primary care veterinarian on day 270 (235 days after re-presentation and 125 days after antibiotics were discontinued). Urinalysis revealed a pH 9.0, presence of rods, and 30 WBC/HPF. Minocycline (6.7 mg/kg PO q 12 hr) was started pending results of the urine culture, which revealed >100,000 CFU/mL of Proteus mirabilis. Therapy was changed to cefpodoxime (6.7 mg/kg PO q 24 hr) for 10 days based on sensitivity. Clinical signs resolved within 2 days of cefpodoxime therapy. Repeat urine culture 5 days after antibiotics were discontinued was negative for bacterial growth after 72 hr. The dog continued to have infrequent incontinence that completely resolved with phenylpropanolamine (1.5 mg/kg PO q 12 hr) treatment. Repeated urine cultures on days 345 and 400 were negative for bacterial growth after 72 hr. Urinalysis at day 400 showed a pH of 7.0 with an inactive sediment. At last follow-up by telephone on day 580, the dog was reported to have no urinary incontinence on twice daily phenylpropanolamine therapy.

Discussion

Encrusted cystitis is characterized by urease-producing bacterial infection of the urinary tract leading to struvite-based mineral deposition on the mucosal wall of the bladder. In veterinary cases, infection has been attributed largely to C. urealyticum, although a recent report found Staphylococcus pseudintermedius as a causative pathogen.^1,8–13 Corynebacterium urealyticum is a fastidious gram-positive rod with marked tropism for uroepithelial cells.²¹ Proper diagnosis can be difficult because it is a slow-growing organism and often requires a minimum of 3–5 days of incubation time. Unlike other urease-producing bacteria, this organism results in deposition of mineral onto the mucosal wall instead of struvite urolithiasis. It is suspected that encrusted cystitis results from a combination of an opportunistic bacterial infection in conjunction with disruption of normal bladder defenses. Certain predisposing factors have been noted in veterinary medicine, including prior trauma, micturition disorders, prior bladder surgery, or urinary catheterization.^1,8–13 Cystoscopy, systemic immune suppression, and local neoplasia are predisposing factors documented in human cases that have not yet been noted in veterinary medicine, although they exhibit similar mechanisms to other factors. Prior antibiotic use is a common finding in cases of encrusted cystitis in both human and veterinary cases; however, no causative relationship has been established.

There are several possible factors that predisposed to the development of encrusted cystitis in this case. First, the dog had a history of prior antibiotic use for documented urinary tract infections. Prior antibiotic use is a common finding in veterinary and human cases. It is unclear if antibiotic use changes the microbiota predisposing to C. urealyticum colonization. Second, this dog had a history of urogenital manipulation, which is commonly reported as a predisposing factor for development of encrusted cystitis. Only two cases of encrusted cystitis reported in veterinary literature lack prior urogenital manipulation.¹¹ In both of those cases, the dogs had previous urinary tract infections with other organisms treated with antibiotics and chronic urinary incontinence.¹¹ The dog in this report had a history of urinary incontinence, urinary tract infections, and prior antibiotic use that may have predisposed to encrusted cystitis even without urogenital manipulation. Cystoscopy without additional urologic procedures has been reported as a predisposing factor for encrusted cystitis in human cases. It is suspected that cystoscopy disrupts local bladder defenses and predisposes to opportunistic infection. Cystoscopy has not yet been associated with veterinary cases of encrusted cystitis even though other instrumentation (such as urinary catheterization) has been reported. Finally, there is the possibility that the CLA-EU procedure specifically predisposed to development of encrusted cystitis beyond cystoscopy alone. Cystoscopic-guided laser ablation of ectopic ureters causes inflammation and damage to tissue, reducing local defense mechanisms, which may lead to bacterial colonization and proliferation.

Corynebacterium urealyticum is an opportunistic pathogen and has been isolated from preputial and vaginal swabs in 1–2% of normal dogs.^22,23 Although it is possible that cystoscopy introduced this opportunistic pathogen to the urinary bladder, there is also evidence that C. urealyticum infection was likely present before the initial procedure. The urinalysis and culture done before the CLA-EU procedure revealed Enterococcus growth without evidence of pyuria. The urine was alkaline with a pH of 8.0 and had occasional struvite crystals. Although rare species of Enterococcus have been shown to be urease-producing, these species have not been reported as urinary pathogens and the finding of Enterococcus did not reasonably explain the alkaline urine pH.²⁴ Furthermore, the urinalysis from the primary veterinarian revealed rods that would not correlate with the Enterococcus grown from that sample. The culture was grown under standard microbiology technique for 48 hr. C. urealyticum can take 3–5 days to exhibit growth and therefore its presence was likely missed on initial culture. It is probable that the bacteria was already present in the urinary tract before the procedure and is a more reasonable explanation for the alkaline urine pH and struvite crystalluria. Performing CLA-EU likely worsened the infection by causing inflammation, hindering local bladder defense, and allowing for bacterial colonization. Alternatively, it is possible that the reported morphology of the original urine sediment was inaccurate. There is variable correlation between morphologic identification of bacteria on unstained urine sediment compared with final culture results, with only 38% agreement in cats and 76% agreement in canines.^25,26

In humans, urologic procedures done during active infections may predispose to complications.¹⁷ The most common complications include fevers, bacteremia, septicemia, and upper urinary tract infections.^27–29 Use of preprocedural antibiotics can reduce those complications.^27–29 There are fewer human reports of antibiotics reducing localized tissue complications such as strictures.²⁹ Screening for asymptomatic bacteriuria and therapy with antimicrobials is recommended in human patients prior to urologic procedures likely to result in mucosal bleeding based on expert opinion.¹⁷ Protocols for antibiotic use prior to urologic procedures in cases of asymptomatic bacteriuria remain variable. The ideal time of initiating therapy or duration of therapy surrounding the urologic procedure is unknown. There is some concern that treatment with antibiotics too early or too prolonged beyond the procedure may predispose to more resistant superinfections.¹⁷ Typical preprocedure antibiotic treatments are 1–4 hr prior to the procedure, but some reports treat up to 24 hr before the procedure. Treatment with a single dose of an antibiotic immediately before a procedure was equally successful at reducing human complications compared with prolonged treatment (5 days) post procedure.³⁰ In this case, the original CLA-EU was performed with the presence of Enterococcus without evidence of pyuria. There are no defined standards regarding treatment of asymptomatic bacteriuria prior to urologic procedures in veterinary patients.³¹ Based on human guidelines, the dog in this report was treated with marbofloxacin 16 hr prior to the procedure. It is possible that therapy this early before the procedure or the prolonged therapy following the procedure may have reduced asymptomatic bacteriuria (Enterococcus) and made a more suitable environment for Corynebacterium growth. As noted previously, it is likely that Corynebacterium was present but missed at the time of the initial urinalysis and culture. Because the preprocedure antibiotics in this case were not a class of antibiotics that successfully treats Corynebacterium, it is likely that the bacteria were still present at the time of CLA-EU. The procedure could have exacerbated the infection by causing tissue damage and providing an ideal environment for Corynebacterium colonization.

Diagnostic imaging for encrusted cystitis often includes radiographs, ultrasound, and cystoscopy. Common radiographic findings include radiopaque mineralization in the region of the urinary bladder. Ultrasound findings include thickening of the bladder wall with hyperechoic mucosa and areas of acoustic shadowing denoting dystrophic mineralization in the bladder mucosa, which was seen in this case. There are rare reports of hydroureter and hydronephrosis associated with encrusted cystitis in the veterinary literature.¹¹ It is not clear whether dilation is the result of ureteritis, pyelitis, or ureteral obstruction, or whether these lesions resolve with proper antibiotic therapy alone. In the current case, the dilation of the left ureter and renal pelvis was likely secondary to obstruction. The hydronephrosis and hydroureter resolved quickly after cystoscopic debridement of focal plaques at the left ureteral papilla and before appropriate therapy for the encrusted cystitis was started, suggesting that obstruction was the most likely explanation for ureteral and renal pelvic dilation rather than inflammation or infection. However, contrast studies were not performed to provide a definitive diagnosis. Obstructive disease has been documented in human cases.^32,33 Hydronephrosis in some human cases improves without plaque debulking; however, urinary acidification and proper antibiotic therapy were instituted before improvement was appreciated.³³

In people, treatment for encrusted cystitis includes a multimodal approach with proper antibiotic therapy, acidification of urine, and surgical or cystoscopic debridement of plaque lesions. Plaque debridement is strongly recommended because lesions promote colonization of bacteria, reduce local host defenses, and may hinder antimicrobial penetration. Veterinary cases have been successfully managed with and without debridement.^1,11 Therefore, case selection criteria would be helpful to determine which cases require debridement. Guidelines cannot be determined based on this case alone. However, monitoring hydroureter or hydronephrosis after initiation of proper therapy is strongly suggested. Persistence or progression of hydroureter or hydronephrosis would suggest the need for contrast studies followed by surgical or cystoscopic-guided plaque debridement. Full debridement was not performed in this case; however, the plaque lesions in the area of the left ureteral papilla were probed until urine jets were clearly visualized and this may have played a role in resolution of the hydronephrosis and hydroureter. This is the third report of cystoscopic debridement of plaque lesions in canine patients, which encourages a less invasive and successful route of plaque debridement.¹¹

In retrospect, portions of this case could have been managed differently. Given the disparity between the original culture and urinalysis results, repeat urine culture prior to the CLA-EU procedure could have been considered, although the dog was asymptomatic and no evidence of infection was noted at the time of cystoscopy. Fungal cystitis was suspected due to the appearance of the plaque lesions, negative bacterial culture, and lack of prior response to antibiotics. Due to concern of worsening disease, antifungal therapy was started pending results of histopathology and fungal culture. In retrospect, it would have been better to examine samples cytologically to try and confirm fungal disease prior to starting therapy.³⁴ Additionally, the hypothesis of fungal cystitis would not have explained the alkaline urine pH and instead alternative organisms should have been considered. The follow-up urinalysis and cultures were performed at a different facility due to distance. Although it was strongly recommended to perform prolonged 5-day urine cultures, only a selected few cultures were held for this recommended time. A normal urinary pH and inactive urine sediment after 1 yr suggests clearance of the bacteria. However, without prolonged urine cultures during the follow-up period, full clearance of the Corynebacterium cannot be ensured.

Conclusion

Encrusted cystitis is a rare condition in veterinary medicine that has been previously associated with prior antibiotic use, urogenital catheterization, surgery, and trauma, but has not been reported as a complication following CLA-EU. Although a ureteral obstruction was not proven in this case, the improvement in hydronephrosis and hydroureter after cystoscopic debridement of lesions suggests this may be a minimally invasive technique for management of ureteral obstructions in cases of encrusted cystitis when combined with medical management including urinary acidification and long-term antibiotic therapy.