Intravesical instillation of amikacin for treatment of a lower urinary tract infection caused by Pseudomonas aeruginosa in a dog

Ahmira R. Torres Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610.

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Kirsten Cooke Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610.

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Abstract

Case Description—A 9-year-old neutered male Golden Retriever was evaluated because of recurrent lower urinary tract infection subsequent to placement of a permanent cystostomy tube.

Clinical Findings—The dog was clinically normal except for the presence of malodorous urine. Bacteriologic culture of a urine sample obtained by cystocentesis yielded growth of Pseudomonas aeruginosa, which was susceptible to amikacin, gentamicin, imipenemcilastatin, and ticarcillin–clavulanic acid.

Treatment and Outcome—The dog was administered amikacin sulfate (15 mg/kg [6.8 mg/lb], SC, q 24 h) for 14 days before treatment was discontinued because of the presence of casts in the urine. The cystostomy tube was replaced, and intravesical instillation of amikacin (15 mg/kg diluted in 30 mL of saline [0.9% NaCl] solution, q 12 h) was initiated. On day 25 of instillation treatment, bacterial culture of a urine sample yielded no growth, urinalysis revealed no casts, and SUN and creatinine concentrations were within reference intervals. On day 27 of instillation treatment, gross hematuria was observed, which resolved following discontinuation of amikacin instillation.

Clinical Relevance—In this dog, treatment of a lower urinary tract infection caused by a multidrug-resistant strain of P aeruginosa was successfully achieved with intravesical instillation of amikacin. Results of serial serum biochemical analyses remained within reference limits, and urine casts were not identified on urinalyses during the treatment period, which suggested that systemic absorption of amikacin was minimal. Intravesical instillation of antimicrobials may be a viable treatment option for dogs with lower urinary tract infections caused by multidrug-resistant bacteria.

Abstract

Case Description—A 9-year-old neutered male Golden Retriever was evaluated because of recurrent lower urinary tract infection subsequent to placement of a permanent cystostomy tube.

Clinical Findings—The dog was clinically normal except for the presence of malodorous urine. Bacteriologic culture of a urine sample obtained by cystocentesis yielded growth of Pseudomonas aeruginosa, which was susceptible to amikacin, gentamicin, imipenemcilastatin, and ticarcillin–clavulanic acid.

Treatment and Outcome—The dog was administered amikacin sulfate (15 mg/kg [6.8 mg/lb], SC, q 24 h) for 14 days before treatment was discontinued because of the presence of casts in the urine. The cystostomy tube was replaced, and intravesical instillation of amikacin (15 mg/kg diluted in 30 mL of saline [0.9% NaCl] solution, q 12 h) was initiated. On day 25 of instillation treatment, bacterial culture of a urine sample yielded no growth, urinalysis revealed no casts, and SUN and creatinine concentrations were within reference intervals. On day 27 of instillation treatment, gross hematuria was observed, which resolved following discontinuation of amikacin instillation.

Clinical Relevance—In this dog, treatment of a lower urinary tract infection caused by a multidrug-resistant strain of P aeruginosa was successfully achieved with intravesical instillation of amikacin. Results of serial serum biochemical analyses remained within reference limits, and urine casts were not identified on urinalyses during the treatment period, which suggested that systemic absorption of amikacin was minimal. Intravesical instillation of antimicrobials may be a viable treatment option for dogs with lower urinary tract infections caused by multidrug-resistant bacteria.

A 9-year-old 31-kg (68.2-lb) neutered male Golden Retriever was examined because of recurrent lower UTI subsequent to placement of a permanent cystostomy tube. The dog had a history of being unable to completely void its bladder. At that time, a neurologic examination, abdominal radiography and ultrasonography, fluoroscopic urethrocystography, and cystoscopy were performed. The most remarkable findings were urethral spasms at the level of the prostatic urethra when the dog tried to void urine during the fluoroscopic evaluation. With the dog anesthetized, those spasms resolved and the urinary bladder was easily expressed manually. Urethral pressure profilometry was not performed, and a functional urethral obstruction was presumptively diagnosed. Attempts to resolve the functional urethral obstruction with several muscle relaxants (specific drugs and doses unavailable) were unsuccessful. Consequently, parasympathomimetics and antispasmodic medications, including prazosin, phenoxybenzamine, tamsulosin, bethanechol, and baclofen, were administered (doses and frequencies unknown), and a permanent cystostomy tubea was surgically placed. The owner was instructed to empty the dog's bladder 3 to 4 times daily. After placement of the cystostomy tube, the dog developed multiple lower UTIs. Because the dog was unable to urinate voluntarily, typical signs of bacterial cystitis, such as pollakiuria and stranguria, were impossible to assess; the only indications that the dog had a UTI were malodorous urine and changes in urine color. When those signs became apparent, the dog was examined and a urine sample obtained by ultrasound-guided cystocentesis was submitted for bacteriologic culture. Antimicrobial treatment was initiated on the basis of results of bacterial cultures of urine and subsequent bacterial susceptibility testing and was continued for 4 to 6 weeks. For each incidence of UTI, additional urine samples were obtained by ultrasound-guided cystocentesis and submitted for bacteriologic culture 2 to 3 weeks after initiation of antimicrobial treatment and 4 to 5 days after completion of treatment.

Following 8 bouts of lower UTI and subsequent antimicrobial treatment, the dog again developed malodorous urine. The dog was examined at the veterinary teaching hospital at the University of Florida. Results of a physical examination, CBC, and serum biochemical analysis were unremarkable. Urine obtained by ultrasound-guided cystocentesis was malodorous and brown in color. Bacteriologic culture of the urine yielded growth of Pseudomonas aeruginosa (38,000 CFUs/mL), which subsequent testing revealed was susceptible only to amikacin, gentamicin, imipenemcilastatin, and ticarcillin–clavulanic acid. Results of a urinalysis revealed an absence of protein and urine sediment that did not contain WBCS or RBCs (ie, inactive sediment).

A lower UTI was diagnosed, and antimicrobial treatment with amikacin sulfateb (15 mg/kg [6.8 mg/lb], SC, q 24 h) was initiated. Treatment was continued for 14 days, at which time urinalysis revealed urine casts and SC administration of amikacin was discontinued. The cystotomy tube was then replaced, and intravesical instillation of amikacin was initiated. The intravesical instillation process consisted of emptying the urinary bladder, infusion of a diluted amikacinb solution (15 mg/kg diluted in 30 mL of saline [0.9% NaCl] solution) into the bladder via the cystostomy tube, retention of the amikacin solution in the bladder for 2 hours, and then removal of the amikacin solution from the bladder. The intravesical instillation of amikacin was repeated every 12 hours.

Ten days after initiation of intravesical instillation of amikacin, a urine sample was obtained by ultrasound-guided cystocentesis for bacteriologic culture and urinalysis. Culture yielded growth of P aeruginosa (65,000 CFUs/mL; 60% of bacterial isolates) and β-hemolytic staphylococci (40% of bacterial isolates). Susceptibility testing revealed that P aeruginosa was susceptible to amikacin, whereas Staphylococcus organisms were not susceptible to amikacin. Results of the urinalysis revealed sediment with 6 to 9 WBCs/hpf and 4 to 6 RBCs/hpf (ie, active sediment) and an absence of protein. Serum urea nitrogen and creatinine concentrations were within reference limits.

Twenty-five days after initiation of intravesical instillation of amikacin, another urine sample was obtained by ultrasound-guided cystocentesis for bacteriologic culture and urinalysis and a blood sample was obtained for determination of SUN and creatinine concentrations to evaluate the dog for evidence of amikacin toxicosis. The culture yielded no growth. Urinalysis results were within reference limits with no urine casts identified. Serum urea nitrogen and creatinine concentrations were within reference limits.

On day 27 of intravesical instillation treatment, the dog's owner noticed gross pigmenturia, which was confirmed to be hematuria by urinalysis. Intravesical instillation of amikacin was discontinued, and the urine returned to its normal color within 7 days. Bacteriologic culture of a urine sample obtained 2 weeks after discontinuation of amikacin instillation yielded growth of Escherichia coli (> 1,000,000 CFU/mL), which was susceptible to multiple antimicrobials that could be administered orally.

Discussion

Urinary tract infections caused by bacteria that are resistant to multiple antimicrobials are a common problem in veterinary medicine. The mainstay for treatment of UTIs is orally administered antimicrobials. In some patients, UTI is secondary to detrusor muscle dysfunction or functional or mechanical urethral obstruction, which causes incomplete voiding of urine and may necessitate alternative methods for removal of urine from the bladder such as the use of indwelling or intermittent transurethral catheterization, urethral stents, or cystostomy tubes. Use of any of those alternatives predisposes the patient to persistent or recurrent UTIs, and over time, the bacteria that cause those infections can become resistant to multiple antimicrobials, thereby limiting treatment options.

Intravesical instillation of antimicrobials has been described for the safe and effective treatment of human patients with UTIs caused by multidrug-resistant bacteria,1–3 but there is a paucity of descriptions of the use of intravesical instillation in veterinary patients. To our knowledge, prior to the present report, there was only a single case report4 that described the use of intravesical instillation in a veterinary patient; intravesical instillation of an antifungal was used to successfully treat a dog with candiduria.

A lower UTI that is left untreated or unsuccessfully treated can spread to the renal parenchyma. Urinary tract infections caused by multidrug-resistant organisms can be especially difficult to treat in patients with intrinsic urinary problems, such as the dog of this report, and cause secondary pyelonephritis, which can contribute to the morbidity and death of affected patients. Intravesical instillation is a novel method for antimicrobial administration that may be beneficial for patients with UTIs in which oral antimicrobials are likely to be ineffective and injectable antimicrobials are not an option because of toxicoses or cost. Amikacin was chosen for intravesical instillation in the dog of the present report on the basis of results of susceptibility testing on the P aeruginosa isolated from dog's urine and because most reports1–3 that describe this route of drug administration in human patients involve aminoglycosides. For the dog of the present report, the dose of amikacin used in the intravesical instillation was the same as that recommended for IV administration because, in human patients, consensus regarding the appropriate dose of aminoglycosides for intravesical instillation is lacking, and in most instances, the antimicrobial is instilled once daily and left in the bladder overnight.1–3 For the dog of this report, the amikacin was removed from the bladder 2 hours after instillation because of concerns about the effect it might have on the bladder mucosa if it was retained for a longer period; therefore, we chose to instill the amikacin twice daily. Given that the entire dose of amikacin was administered directly into the bladder, the dose used might have been higher than was necessary. We believe that the hematuria observed on day 27 of treatment was the result of amikacin toxicosis because it resolved within 7 days after amikacin instillation was discontinued, although we were unable to find reference to hematuria as a complication of amikacin administration in the literature. A potential risk associated with intravesical instillation of aminoglycosides into an inflamed or otherwise compromised bladder is absorption of the drug across the bladder epithelium and into the systemic circulation.3 Investigators of a study2 in which healthy dogs were administered gentamicin sulfate by intravesical instillation report that the drug was undetectable in serum at 0 and 30 minutes after instillation and the serum creatinine concentration did not change significantly between instillation and 3 days after instillation. Because aminoglycosides are cationic, they are unlikely to cross the uroepithelium,3 which may be the reason why serum or plasma concentrations of aminoglycosides or other evidence of their systemic absorption was undetectable in patients following intravesical instillation.1–3 For the dog of the present report, the serum amikacin concentration was not determined at any time during intravesical instillation treatment; however, results of serial serum biochemical analyses remained within reference limits and urine casts were not identified on urinalyses throughout the treatment period, which suggested that systemic absorption of amikacin was minimal.

The protocol for intravesical instillation of antimicrobials is not standardized for human patients with UTIs, and successful treatment has been achieved with once-daily or twice-daily intravesical instillation of various doses of an antimicrobial.1–3 A human patient with a UTI caused by a multidrug-resistant strain of E coli who was treated with intravesical instillation of 80 mg of gentamicin once daily for 8 months had undetectable serum gentamicin concentrations throughout the duration of treatment.3 Additionally, bacteriologic cultures of urine performed every 3 months during treatment of that patient yielded no growth.3 Shortly after treatment was discontinued, that patient developed another UTI, which was caused by a different bacterial isolate that was susceptible to antimicrobials that could be orally administered,3 much like the dog of the present report. Ideally, the purpose of intravesical instillation of an antimicrobial is to cure an infection. However, for the dog of the present report, the cystostomy tube will remain a nidus for infection such that permanent resolution of the UTI is unlikely. Our goal for the treatment of that dog with intravesical instillation of amikacin was to eliminate the multidrug-resistant P aeruginosa with the hope that the next pathogen that colonized the urinary tract would be susceptible to antimicrobials that could be orally administered.

On the basis of the results of the urinalysis performed immediately before initiation of the intravesical instillation of amikacin, the urine sediment was inactive (ie, contained no WBCs or RBCs), which might be considered indicative of subclinical bacteruria. Treatment of subclinical bacteruria with antimicrobials is controversial. We decided to initiate antimicrobial treatment to the dog of this report because it had a permanent cystostomy tube that served as a nidus for infection and obviated the dog's ability to develop pollakiuria and stranguria, clinical signs commonly associated with bacterial cystitis, and there was concern that failure to initiate antimicrobial treatment might contribute to the development ascending pyelonephritis.

All of the urine samples from the dog of the present report were obtained by ultrasound-guided cystocentesis; therefore, we believe it is unlikely that the P aeruginosa isolated from the urine was a contaminant resulting from contact of the needle with the cystostomy tube during cystocentesis. Replacement of the cystostomy tube just prior to initiation of intravesical instillation of amikacin might have contributed to the elimination of the P aeruginosa infection; however, it is unlikely that it was the sole reason the infection was cleared because bacteriologic culture of a urine sample obtained 10 days after the cystostomy tube was replaced still yielded growth of P aeruginosa. When the cystostomy tube was replaced, the bladder was emptied but not flushed, and the tube that was removed was not swabbed for bacteriologic culture. The culture of P aeruginosa and Staphylococcus spp from and the presence of active sediment in the urine sample obtained 10 days after initiation of intravesical instillation of amikacin might be considered a treatment failure by some. However, the median duration of intravesical instillation of gentamicin in human patients with UTIs was 90 days in 1 study1 and 9 months in another study,3 with urine samples obtained for bacteriologic culture every 3 months. Given the seemingly arbitrary dose selection and treatment durations of those studies1,3 and the fact that the dog of this report had an indwelling cystostomy tube that served as a nidus for infection, our plan was to continue intravesical instillation of amikacin (15 mg/kg) twice daily for 30 days. The times chosen for patient monitoring were arbitrary and dependent on the owner's schedule and ability to bring the dog to the hospital. The development of hematuria after 27 days of treatment caused us to discontinue the intravesical instillation, and the hematuria resolved within 7 days.

The obvious limitation of drug administration by intravesical instillation is the requirement for an indwelling cystostomy tube. Intermittent transurethral catheterization for intravesical instillation of drugs might be feasible for male dogs but not for female dogs. Although intravesical instillation of antimicrobials will not be a practical treatment option for many patients with UTIs caused by multidrug-resistant bacteria, it might be a treatment option for patients with physical urethral obstruction because of neoplasia or those with functional urethral obstructions because of neurologic disease that require a cystostomy tube. For patients without a permanent cystostomy tube, placement of an indwelling catheter and hospitalization for a period of treatment with intravesical instillation of antimicrobials might be an option. However, this option might be too expensive or labor-intensive for many owners because of the prolonged duration of treatment required for most patients. For example, the dog of this report still had P aeruginosa cultured from its urine after 10 days of treatment and had intravesical instillation of amikacin performed twice daily for 27 days.

Intravesical instillation of amikacin (15 mg/kg diluted in 30 mL of saline solution; q 12 h) to a dog that developed a UTI caused by a multidrug-resistant strain of P aeruginosa subsequent to placement of a permanent cystostomy tube effectively eliminated the infection with no evidence of adverse systemic effects. The dog developed hematuria after 27 days of treatment that resolved within 7 days after discontinuation of treatment. Additional investigation is necessary to determine the optimal protocol (ie, dose, frequency, and duration) for antimicrobial administration by means of intravesical instillation for the treatment of dogs with UTIs caused by multidrug-resistant bacteria.

ABBREVIATION

UTI

Urinary tract infection

a.

Low-profile gastrostomy device, Wilson-Cook Medical, Winston-Salem, NC.

b.

Amiglyde-V, Fort Dodge Animal Health, Fort Dodge, Iowa.

References

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  • 4. Forward ZA, Legendre AM, Khalsa Singh HD. Use of intermittent bladder infusion with clotrimazole for treatment of candiduria in a dog. J Am Vet Med Assoc 2002; 220: 14961498.

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