d,l-Methionine in combination with amoxicillin–clavulanic acid successfully dissolves spontaneously occurring infection-induced struvite urocystoliths in dogs: a pilot study

Amber S. M. Harris College of Veterinary Medicine, University of Georgia, Athens, GA

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Joseph W. Bartges College of Veterinary Medicine, University of Georgia, Athens, GA
College of Veterinary Medicine, University of Tennessee, Knoxville, TN

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 DVM, PhD, DACVIM, ACVNU
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Tamberlyn D. Moyers College of Veterinary Medicine, University of Tennessee, Knoxville, TN

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Abstract

OBJECTIVE

To determine the efficacy and safety of a urinary acidifier (d,l-methionine [Methio-Form]) and an antimicrobial agent (amoxicillin–clavulanic acid [Clavamox]) without changing diet for dissolving infection-induced struvite urocystoliths in dogs.

ANIMALS

14 dogs were recruited for this prospective study; 11 completed it and 3 dogs withdrew due to inability of the owners to administer the treatment (n = 2) or refusal of treatment by the dog (1).

PROCEDURES

All dogs were administered d,l-methionine (approx initial dose of 75 mg/kg, PO, q 12 h) and amoxicillin–clavulanic acid (22 mg/kg, PO, q 12 h) based on urine culture and sensitivity. Urine pH, urinalysis, urine culture, venous blood gas and serum biochemical analysis, and lateral survey abdominal radiographic images were evaluated initially and every 4 weeks until urolith dissolution (success) or lack of change in size and/or shape of urocystoliths on 2 consecutive reevaluation points (failure) occurred.

RESULTS

Uroliths dissolved in 8 of 11 dogs in a median of 2 months (range, 1 to 4 months) with a final effective dosage of d,l-methionine of approximately 100 mg/kg, PO, every 12 hours. In 3 dogs, uroliths failed to dissolve and were removed surgically; they contained variable amounts of calcium oxalate. No adverse events occurred.

CLINICAL RELEVANCE

Infection-induced struvite urolithiasis is 1 of the 2 most common minerals occurring in canine uroliths. Results of this study supported the use of d,l-methionine and amoxicillin–clavulanic acid without changing diet for dissolution of infection-induced struvite urocystoliths in dogs.

Abstract

OBJECTIVE

To determine the efficacy and safety of a urinary acidifier (d,l-methionine [Methio-Form]) and an antimicrobial agent (amoxicillin–clavulanic acid [Clavamox]) without changing diet for dissolving infection-induced struvite urocystoliths in dogs.

ANIMALS

14 dogs were recruited for this prospective study; 11 completed it and 3 dogs withdrew due to inability of the owners to administer the treatment (n = 2) or refusal of treatment by the dog (1).

PROCEDURES

All dogs were administered d,l-methionine (approx initial dose of 75 mg/kg, PO, q 12 h) and amoxicillin–clavulanic acid (22 mg/kg, PO, q 12 h) based on urine culture and sensitivity. Urine pH, urinalysis, urine culture, venous blood gas and serum biochemical analysis, and lateral survey abdominal radiographic images were evaluated initially and every 4 weeks until urolith dissolution (success) or lack of change in size and/or shape of urocystoliths on 2 consecutive reevaluation points (failure) occurred.

RESULTS

Uroliths dissolved in 8 of 11 dogs in a median of 2 months (range, 1 to 4 months) with a final effective dosage of d,l-methionine of approximately 100 mg/kg, PO, every 12 hours. In 3 dogs, uroliths failed to dissolve and were removed surgically; they contained variable amounts of calcium oxalate. No adverse events occurred.

CLINICAL RELEVANCE

Infection-induced struvite urolithiasis is 1 of the 2 most common minerals occurring in canine uroliths. Results of this study supported the use of d,l-methionine and amoxicillin–clavulanic acid without changing diet for dissolution of infection-induced struvite urocystoliths in dogs.

Introduction

Struvite uroliths are composed of magnesium ammonium phosphate hexahydrate, (Mg2+NH4+PO43-*6H2O). An important driving force for urolith formation is supersaturation of urine with calculogenic substances. For struvite uroliths to form, urine must contain increased concentrations of magnesium, ammonium, and phosphate ions and the urine pH must be alkaline, as struvite is more soluble in acidic urine and tends to precipitate in alkaline urine. In dogs, this is usually associated with a bacterial urinary tract infection with urease-producing bacteria such as Staphylococcus spp or Proteus spp.1,2

Although the relative prevalence of different types of canine uroliths has changed over the last 20 years, struvite remains one of the most common canine urolith types encountered, comprising 36% to 43% of canine urolith submissions encountered at urolith analysis centers, including the Minnesota Urolith Center.2,3,4 The majority (95%) of struvite uroliths occur in the lower urinary tract.1

Most infection-induced struvite uroliths are amenable to medical treatment for dissolution using a diet change to decrease urine concentrations of struvite calculogenic compounds and an antimicrobial agent.5 Antimicrobial agents are an essential component of treatment for infection-induced struvite uroliths. Treatment should include a therapeutic dose of an antimicrobial agent selected with the aid of susceptibility testing. Antimicrobial treatment is continued as long as uroliths remain in the urinary tract. Even if the urine quickly becomes sterile, bacteria may remain viable within the matrix of a urolith and become exposed to the urine as the urolith dissolves. Struvitolytic diets and antimicrobial agents need to be continued at least 1 month beyond survey abdominal radiographic evidence of urolith dissolution. This reduces the likelihood of recurrence due to small (< 3-mm-diameter) uroliths not detectable radiographically.1,5,6

Although cases have been reported in which antimicrobial treatment alone induced dissolution of infection-induced struvite urocystoliths in dogs,7,8 the recommendation has been to administer an antimicrobial agent and change diet. Dietary treatment may aid dissolution by increasing urine volume and decreasing urine concentrations of urea, phosphorus, magnesium, and pH. A high-moisture struvitolytic diet (Prescription Diet Canine s/d; Hill’s Pet Nutrition Inc) and therapeutic urinary diets (Purina Pro Plan Veterinary Diets UR Urinary Ox/St Canine Formula dry/canned; Nestlé Purina) have been specially formulated to contain low quantities of high-quality protein, phosphorus, and magnesium. Use of these diets in combination with an antimicrobial agent have been reported to induce dissolution in an average time of 8 to 10 weeks and a median time of 31 days, respectively, although this varies depending on the size, location, and surface area of the uroliths.1,5,9,10

Despite the apparent success of medical dissolution of infection-induced struvite uroliths in dogs using struvitolytic or urinary diets and antimicrobial agents, this treatment may not be an option for some patients. Some dogs will not eat the struvitolytic diet or cannot tolerate the high fat and/or high sodium chloride content. This is of particular concern with Miniature Schnauzers that are predisposed to struvite urolithiasis,11,12 abnormalities in lipid metabolism, and pancreatitis. The low protein content of the struvitolytic diet may also produce a catabolic state in animals, particularly if given for a prolonged period of time.1,13 The use of urinary diets circumvents many of these concerns and patient selection limitations; however, these diets may still be contraindicated for certain disease processes, such as hyperlipidemia. Furthermore, the struvitolytic diet is not a maintenance diet, which requires the owner to change the dog’s diet during treatment and then back again once the uroliths are dissolved. This may impart an additional expense as the therapeutic diet may be more expensive than over-the-counter dog foods. For this reason, an alternative treatment would benefit many dogs.

We hypothesized that utilization of a urinary acidifier (Methio-Form) and an appropriate antimicrobial agent (to treat the urease-producing bacterial urinary tract infection) without changing diet would be effective and safe in dissolving spontaneously occurring, infection-induced struvite urocystoliths in dogs. We further hypothesized that dissolution would take 8 to 12 weeks. The objective of this study was to determine the efficacy and safety of a urinary acidifier and an antimicrobial agent (Clavamox) without changing diet for dissolving infection-induced struvite urocystoliths in dogs.

Materials and Methods

Dogs

All dogs in this study were client-owned, and owners gave informed consent to include their dog in the study. No dog was fed a diet designed to dissolve struvite uroliths or one considered a urinary diet; instead, dogs were continued on their current maintenance diet. Owners were asked to not give additional foods or treats. Dogs were housed in their home environments for the duration of the study. Fourteen dogs were evaluated and selected on the basis of clinical signs of lower urinary tract disease, positive radiographic findings (radiodense urocystoliths of homogeneous density and variably sized), supportive urinalysis results (alkaluria, struvite crystalluria, and pyuria), and a positive aerobic urine culture with a urease-producing microbe. Exclusion criteria included the following: presence of comorbidities that may predispose to recurrent bacterial cystitis and/or otherwise be considered a “complicated” urinary tract infection (eg, bladder or urinary tract neoplasia, endocrinopathies, kidney disease/failure, etc),14 presence of a disease in which intolerance to an orally administered acidifier might occur (eg, renal failure, etc), evidence that the stone(s) may not be composed completely of struvite (eg, stones appear more typical for calcium oxalate or there is mixed mineral density to the stones radiographically implying presence of 2 different minerals, etc),2,15 and unwillingness or inability of the owner or dog to comply with the protocol established in this study. This study was approved by the University of Tennessee IACUC (protocol No. 1448).

Baseline data included CBC (ADVIA 2120i; Siemens Medical Solutions), serum biochemical analysis (Hitachi 911; Boehringer Mannheim; including concentrations of albumin, bicarbonate, calcium, chloride, creatinine, globulins, glucose, phosphorous, potassium, sodium, total bilirubin, total protein, and urea nitrogen; calculated anion gap; and activities of ALT and ALP), complete urinalysis, aerobic bacteriological culture of urine collected by cystocentesis, survey abdominal radiography, and venous blood gas analysis (Stat Profile Prime Plus VET; Nova Biomedical; including blood pH). Urine pH was determined using a pH meter (Orion pH Meter; Thermo Fisher Scientific Inc).

Treatment

Dogs were maintained on their regular diet. The bacterial urinary tract infection was treated with an appropriate antimicrobial on the basis of culture and sensitivity results. Based on clinical experience, both antimicrobial treatment and the urinary acidifier were administered during medical dissolution and for 2 weeks beyond radiographic evidence of urocystolith dissolution. An attempt was made to administer an approximate initial dose of 75 mg/kg, PO, every 12 hours based on dosage recommendations by the manufacturer.16 Some dogs were started on a lower or higher dose due to the fact that the urinary acidifier was supplied as 500-mg tablets. Dosage of the urinary acidifier was adjusted based on monitoring urine pH with the goal of achieving a urine pH < 6.8.

Monitoring

A free-catch urine sample was collected between approximately 6:00 AM and 8:00 AM by the owner prior to administration of the urinary acidifier and preprandial 5 to 7 days after beginning the urinary acidifier and brought to the clinic by 9:00 AM. Urine pH was determined by meter immediately upon delivery. Dogs were reevaluated every 4 weeks until urocystoliths were inapparent radiographically or until they did not change in size and/or shape for 2 consecutive reexaminations. Owners were queried about adherence to dietary recommendations and administration of additional foods or snacks. Urine was collected by cystocentesis for urinalysis and aerobic bacteriological culture at approximately 8:00 AM prior to administration of the urinary acidifier and preprandial. A venous blood sample was collected for blood gas analysis to monitor systemic acid-base status and for serum biochemical analysis to monitor drug safety. Lateral survey abdominal radiography was performed to monitor urocystolith dissolution every 4 weeks. Radiography was used to determine urolith location, number, size, and volume. Urolith volume was calculated using the following formula: V = 4/3πr3, where V is the volume of a sphere and r is the radius of the sphere for individual uroliths.17 A best fit circle was applied to individual uroliths using digital radiographic software (Vue PACS version 12.1.6; Philips). If multiple uroliths (usually > 10) prevented delineation of urolith borders, urolith volume was estimated by combining the pool of uroliths into single or more often multiple best fit circles by use of digital radiographic software (Vue PACS version 12.1.6; Philips). Urolith volume for each pool was then calculated on the basis of the diameter of the circles. The total urolith volume for each dog was the sum of all of the individual uroliths and pool volumes.

Definition of success

Success was defined as radiographic evidence of urocystolith dissolution and resolution of clinical signs. Following evidence of radiographic dissolution of urocystoliths, appropriate antimicrobial treatment and the urinary acidifier were continued for 2 additional weeks. Dogs were maintained on their regular maintenance diet and any other medications required for other conditions.

Definition and management of failure

Failure was defined as lack of evidence of change in size and/or shape of urocystoliths for 2 consecutive reevaluation points. At that point, urocystoliths were removed surgically and analyzed quantitatively (Minnesota Urolith Center, University of Minnesota).

Statistical analysis

This was a descriptive study without a control group. Data were determined to be normally distributed using the Shapiro-Wilk test. If data were normally distributed, means and SDs were reported and repeated-measures ANOVA was performed. If data were not normally distributed, data were reported as median and range and Kruskal-Wallis was performed. A P < .05 was considered significant. Statistical analysis was performed with available software (Analyse-it version 2.20; Analyse-it Software Ltd).

Results

Dogs

Fourteen dogs met inclusion criteria and were included in the study; however, 3 dropped out due to inability of the owners to administer the treatment (n = 2) or refusal of treatment by the dog (1). Data from the 11 dogs are included. Ten dogs were spayed females, and 1 was a castrated male. Four dogs were of mixed breed, 2 were Miniature Schnauzers, and the remaining were 1 each of Beagle, English Bulldog, Pekingese, Pug, and Shih Tzu. Average age was 5.7 ± 2.1 years (range, 3 to 9 years). Average body weight was 15.8 ± 11.8 kg (range, 4.3 to 43.0 kg). Body weight did not change over the course of treatment for any dog (P = .7). Nine of 11 dogs were considered to be healthy other than a bacterial urinary tract infection and urocystoliths. One dog was recovering from acute gastroenteritis. Urocystoliths were found by abdominal radiography. The dog was receiving famotidine and metoclopramide. One dog was being treated for immune-mediated hemolytic anemia and thrombocytopenia with immunosuppressive drugs (prednisone; azathioprine [Imuran]). This dog developed a bacterial urinary tract infection and urocystoliths while receiving immunosuppressive therapy; however, at the time of enrollment in this study, anemia and thrombocytopenia were resolved and immunosuppressive treatment was tapered and eventually discontinued.

Diets

No dog consumed a “struvite dissolution” diet or “urinary” diet; 9 dogs were eating over-the-counter adult maintenance dry dog food, 1 dog was eating over-the-counter adult maintenance canned dog food, and 1 dog was consuming an “enteric diet” for a resolving nonspecific enteritis episode (Prescription Diet Canine i/d; Hill’s Pet Nutrition Inc). No owner admitted to deviating from dietary recommendations or administering additional foods or treats.

Urocystoliths

Urocystoliths dissolved in 8 of 11 dogs with a median time of 2 months (range, 1 to 4 months). Average baseline urolith volume for all dogs was 74,704 ± 98,220 mm3 (range, 431 to 274,254 mm3). Urolith dissolution time was not associated with baseline urolith volume (P = .8) or with percent change in urolith volumes at 4 weeks (P = .4). In 3 dogs, urolith dissolution failure occurred at 3, 4, and 6 months. In 1 dog, the stone was composed of 80% struvite and 20% calcium phosphate carbonate form with a shell of 100% calcium oxalate monohydrate. In 1 dog, the nidus was composed of 70% struvite, 15% calcium phosphate carbonate form, and 15% calcium oxalate monohydrate; the stone was composed of 75% struvite and 25% calcium phosphate carbonate form; and the shell was composed of 55% calcium oxalate dihydrate, 40% calcium oxalate monohydrate, and 5% calcium phosphate apatite form. In 1 dog, the stone was composed of 45% calcium phosphate carbonate form, 40% calcium oxalate monohydrate, and 15% calcium hydrogen phosphate; the shell was composed of 70% calcium oxalate dihydrate and 30% calcium oxalate monohydrate; and the surface was composed of 55% calcium phosphate carbonate and 45% calcium oxalate monohydrate.

Dosage of acidifier

The mean ± SD starting dose of d,l-methionine was 78.6 ± 28.5 mg/kg, PO, every 12 hours (range, 31.4 to 115.7 mg/kg, PO, q 12 h). The average starting dosage was variable due to the fact that the urinary acidifier was supplied as 500-mg tablets. Average final dosage of acidifier at time of dissolution or time of surgery if urocystoliths did not dissolve was 113.7 ± 35.8 mg/kg, PO, every 12 hours (range, 56.8 to 166.7 mg/kg, PO, q 12 h). Average final dosage for dogs in which urocystoliths dissolved was significantly lower than for dogs in which urocystoliths did not dissolve (P = .01). Average final dosage for dogs in which urocystoliths dissolved (n = 8) was 97.3 ± 25.6 mg/kg, PO, every 12 hours (range, 56.8 to 125.0 mg/kg, PO, q 12 h), and average final dosage for dogs in which urocystoliths did not dissolve (3) was 157.5 ± 12.8 mg/kg, PO, every 12 hours (range, 142.9 to 166.7 mg/kg, PO, q 12 h). During the study, 6 of 11 dogs had the dosage of acidifier increased more than 25%; in 3 dogs urocystolith dissolution was successful, and in 3 dogs urocystolith dissolution was unsuccessful. The decision to increase dosage was based on radiographic appearance of uroliths not decreasing in size and/or number by at least 25% to 50% from previous reevaluation.

Aerobic bacteriologic culture and antimicrobial treatment

All 11 dogs had positive aerobic bacteriological cultures at baseline. All urinary tract infections were considered sporadic. Seven dogs had Staphylococcus spp that were susceptible to all antimicrobials tested. One dog had Enterococcus spp that was susceptible to all antimicrobials tested.18 Two dogs had Staphylococcus spp and Escherichia coli that were susceptible to amoxicillin–clavulanic acid combination. One dog had Staphylococcus spp and Enterococcus spp that were susceptible to amoxicillin–clavulanic acid. Amoxicillin–clavulanic acid was administered to all dogs in the study at an average dose of 23.5 ± 3.1 mg/kg, PO, every 12 hours (range, 17.4 to 27.8 mg/kg, PO, q 12 h). One dog had been given cephalothin at 22 mg/kg, PO, every 12 hours for 7 days prior to collection of baseline data; however, Staphylococcus spp was cultured from this dog that was susceptible to all antimicrobials tested. In all dogs, urine cultures were negative at all reevaluation time points regardless of success of urocystolith dissolution. There was not a significant difference (P = .9) in antimicrobial dosage between baseline and end of study defined as success or failure to induce dissolution of urocystoliths. In 3 dogs for which urocystolith dissolution was unsuccessful, 1 dog had Staphylococcus spp, 1 dog had Enterococcus spp, and 1 dog had Staphylococcus spp and E coli.

Urine pH

Average urine pH was significantly higher at baseline (P < .0001) than at reevaluations, and it was not significantly different between other time points. Average baseline (n = 11) urine pH was 7.79 ± 0.45 (range, 7.02 to 8.43); average 5- to 7-day reevaluation (11) urine pH was 6.82 ± 0.98 (range, 5.62 to 8.42); average 4-week reevaluation (11) urine pH was 6.76 ± 1.12 (range, 5.45 to 8.96); average 8-week reevaluation (10) urine pH was 6.42 ± 0.62 (range, 5.55 to 7.45); average 12-week reevaluation (5) was 7.25 ± 1.08 (range, 6.42 to 8.45); and average 16-week reevaluation (3) urine pH was 6.97 ± 1.34 (range, 6.11 to 8.51). Average urine pH at baseline was higher than average pH at last reevaluation (P = .01). Average urine pH at final reevaluation was 6.68 ± 1.01 (range, 5.55 to 8.51). There was no significant difference (P = .8) in urine pH at baseline between dogs in which urocystoliths dissolved and dogs in which urocystoliths did not dissolve. Average urine pH at baseline from dogs in which urocystoliths dissolved (n = 8) was 7.87 ± 0.42 (range, 7.32 to 8.43) and average urine pH at baseline from dogs in which urocystoliths did not dissolve (3) was 7.57 ± 0.55 (range, 7.02 to 8.12). There was no significant difference (P = .13) in urine pH at final reevaluation between dogs in which urocystoliths dissolved and dogs in which urocystoliths did not dissolve. Average urine pH at final reevaluation for dogs in which urocystoliths dissolved was 6.24 ± 0.62 (range, 5.55 to 6.74), and average urine pH at final reevaluation for dogs in which urocystoliths did not dissolve was 7.75 ± 1.27 (range, 6.28 to 8.51).

Complete blood cell counts and serum biochemical analyses

Results of CBC and serum biochemical analyses were within normal reference ranges for all dogs at all time points and did not change significantly over the course of the study.

Acid-base evaluation

No dog experienced metabolic acidemia (reference range for venous blood gas pH, 7.205 to 7.457) while receiving the acidifier. Average venous blood pH at baseline (n = 11) was 7.356 ± 0.045 (range, 7.218 to 7.402); average venous blood pH at 4 weeks (11) was 7.369 ± 0.059 (range, 7.305 to 7.501); average venous blood pH at 8 weeks (10) was 7.362 ± 0.025 (range, 7.332 to 7.415); average venous blood pH at 12 weeks (5) was 7.365 ± 0.027 (range, 7.327 to 7.397); and average venous blood pH at 16 weeks (3) was 7.375 ± 0.057 (range, 7.315 to 7.427). Venous blood pH did not change significantly (P = .5) over the course of the study. Average venous blood pH was not significantly different (P = .3) between baseline and last reevaluation. Average baseline venous blood pH was 7.356 ± 0.045 (range, 7.218 to 7.402), and average venous blood pH at last reevaluation was 7.366 ± 0.036 (range, 7.305 to 7.427). Venous bicarbonate concentration was within reference range for all dogs at all time points in the study and did not change significantly during the course of the study (P = .2). Average venous bicarbonate concentration at baseline (n = 11) was 21.0 ± 1.4 mEq/L (range, 18.9 to 22.6 mEq/L); average venous bicarbonate concentration at 4 weeks (11) was 21.3 ± 1.7 mEq/L (range, 18.7 to 24.2 mEq/L); average venous bicarbonate concentration at 8 weeks (10) was 20.0 ± 2.0 mEq/L (range, 17.4 to 24.1 mEq/L); average venous bicarbonate concentration at 12 weeks (5) was 20.7 ± 1.2 mEq/L (range, 19.4 to 22.2 mEq/L); and average venous bicarbonate concentration at 16 weeks (3) was 22.3 ± 0.6 mEq/L (range, 21.7 to 22.9 mEq/L). Venous bicarbonate concentration was not significantly different (P = .7) between baseline and last reevaluation. Average venous bicarbonate concentration at baseline (n = 11) was 21.0 ± 1.4 mEq/L (range, 18.9 to 22.6 mEq/L), and average venous bicarbonate concentration at last reevaluation was 21.4 ± 1.9 mEq/L (range, 18.7 to 24.2 mEq/L).

Discussion

Struvite (magnesium ammonium phosphate hexahydrate) is 1 of the 2 most common minerals found in canine uroliths.1931 In dogs, it occurs most commonly from a bacterial urinary tract infection with a urease-producing organism,1,32,33 although sterile struvite urocystoliths have been reported to occur in dogs.13 The role of bacterial infection inducing struvite formation is documented in human beings,32,34-38 experimentally in dogs,39,40 and clinically in dogs.7,8,11,39,41,42 Unfortunately, the exact association of infection with struvite urolith formation is not known for several reasons, including the following: (1) inconsistent collection and submission of urine for aerobic bacteriologic culture by veterinarians, (2) treatment of the canine patient with antimicrobial agents prior to removal of struvite uroliths, (3) inconsistent provision of information to veterinary urolith analysis centers concerning bacterial urinary tract infections, (4) lack of consistency of performing aerobic bacteriologic culture of submitted uroliths by veterinary urolith analysis centers, and (5) the observation that some canine patients may have negative aerobic bacteriologic urine cultures but positive aerobic bacteriologic urine cultures of uroliths and vice versa.42,43

For infection-induced struvite uroliths to form, urine must be supersaturated with magnesium, ammonia, and phosphorous and alkaluria must be present. Normally, urine ammonium (NH4+) concentration rises only when acid catabolites are excreted renally in high concentration. The rise in urine concentration of NH4+ in this situation represents a normal compensatory response by renal tubular cells to secrete ammonia (NH3) into tubular lumens to reduce acidity by subsequent formation of NH4+. Ammonia is lipid soluble and penetrates tubular cell walls; NH4+ is lipid insoluble and cannot penetrate cell walls (ion trapping). Likewise, excretion of alkaline urine under physiologic conditions is associated with reduced renal production of NH3 and thus reduced quantities of NH4+ in urine. When urinary tract infection with urease-producing microbes occurs in urine with a sufficient quantity of urea, the unique combination of elevation in concentrations of NH4+ and carbonate (CO3-2) in an alkaline environment may develop. These conditions favor formation of uroliths containing struvite (Mg NH4 P04-6H20), calcium apatite (Ca10[PO4]6[OH]2), and carbonate apatite (Ca10[PO4•CCO3O4]6[OH]2). Both urea and urease are required for ammonia production, alkalinization, supersaturation, and subsequent precipitation of struvite, calcium apatite, and carbonate apatite. The majority of urea in urine originates from dietary protein, whereas urease is derived from microbes (some bacteria, particularly Gram-positive cocci and Proteus spp; some yeasts; and ureaplasmas). In dogs, Staphylococcus spp are the most common urease-producing microbes associated with infection-induced struvite urolith formation.5,32,42

Recommended management of infection-induced urocystoliths in dogs involves physical removal (surgery, laser lithotripsy, or voiding urohydropropulsion) or feeding a struvite dissolution diet or urinary diet with administration of an appropriate antimicrobial agent.10,44 Medical dissolution is the preferred recommendation followed by minimally invasive procedures when surgery is necessary.45 There is a commercially available “struvite dissolution” diet and urinary diets that “aid in the dissolution” of struvite. Compared with an average adult canine maintenance diet, the struvite dissolution diet is lower in protein, higher in fat, and acidifying; this diet may not be tolerated by some dogs. The urinary diets are lower in fat, less protein restricted, and considered maintenance diets but are also not appropriate for all dogs depending on their comorbidities. Despite the recommendation44 and use of the struvite dissolution diet and urinary diet with antimicrobial agents for medical dissolution of infection-induced struvite uroliths in dogs, there are no published controlled studies evaluating their efficacy when used in combination with an antimicrobial agent when compared with dietary treatment alone or antimicrobial treatment alone.7,10

In the current study, medical dissolution was effective in 8 of 11 dogs using an appropriate antimicrobial agent based on aerobic bacteriologic culture of urine (amoxicillin–clavulanic acid) and a urinary acidifier (d,l-methionine) but without a struvite calculolytic diet; however, 3 dogs of the original 14 that entered into the study did not complete the study. Median time for dissolution was 2 months (range, 1 to 4 months), which is similar to dissolution times reported with combination of struvite dissolution diet and antimicrobial agent or with antimicrobial agent alone.4,7,44 d,l-Methionine was tolerated in 11 of 14 dogs; however, in 3 dogs, either owners were unable to administer it or the dog refused it. The dosage of d,l-methionine that was effective was approximately 100 mg/kg, PO, every 12 hours. No dog experienced metabolic acidosis or any major adverse effects due to administration of d,l-methionine other than the 3 dogs that were withdrawn from the study. The main side effect reported by owners was vomiting and/or anorexia, which can often be controlled by concurrent administration with food. Urinary acidifiers such as d,l-methionine should be used cautiously or not at all in dogs with diseases associated with metabolic acidosis, such as chronic kidney disease, or in conditions for which inducing aciduria would be contraindicated, such as ammonium urate or calcium oxalate urolithiasis. Successful dissolution of presumed infection-induced struvite urocystoliths required adequate control of the bacterial urinary tract infections. All dogs had confirmed bacterial urinary tract infections with urease-producing microbes: 10 had Staphylococcus spp and 1 had Enterococcus spp18; 1 dog had a combination of Staphylococcus spp and Enterococcus spp.

In dogs for which successful urolith dissolution was achieved, uroliths decreased in size on average by at least 50% at the 1-month reevaluation. In the 3 dogs for which dissolution was unsuccessful, percent change at 1 month was < 50% (successful dissolution, 76.3 ± 31.7%; unsuccessful dissolution, 43.5 ± 47.7% at 1-month reevaluation); however, this observation involved only 3 dogs and interpretation of this result should be made cautiously. This result was in line with a recent study4 that found that if no reduction in urolith size or number occurs by 1 month into a dissolution trial, a nonstruvite composition is likely. Increasing the dosage was successful in 3 dogs; however, in the 3 dogs for which successful dissolution was not achieved, 1 dog had uroliths composed of calcium (combination of calcium oxalate and calcium phosphate and therefore not a struvite urolith), in 1 dog calcium oxalate was present in the stone, and in the remaining dog calcium oxalate was present in the shell and surface of the uroliths. These data were again supported by the previously mentioned recent study that found that uroliths containing > 10% nonstruvite mineral were common in the group of dogs that did not successfully undergo medical dissolution.4 For the 1 dog whose uroliths contained calcium oxalate in its shell, it is possible that these uroliths contained calcium oxalate at the beginning of the study. For the other 2 dogs that failed dissolution, it seemed most likely that their uroliths contained calcium oxalate within the stones themselves. It may also be possible that administering a higher dosage of d,l-methionine due to apparent lack of response resulted in calcium deposition. The dog with the calcium oxalate shell was a Miniature Schnauzer. Its stone volume decreased from initial evaluation to the 3-month evaluation, then remained static in size. It is possible that the initial decrease in size was due to struvite dissolution, but the ultimate failure to dissolve occurred as a result of calcium oxalate deposition around a struvite nidus. Although metabolic acidosis did not occur, it is possible that administering a higher dosage of d,l-methionine resulted in calcium mobilization from bone and hypercalciuria or administering a higher dosage of d,l-methionine promoted oversaturation of urine with calcium oxalate (due to either increased calciuresis or decreased calcium urolith inhibitor amount or activity or combinations).4648 Though the urine calcium concentration and urine calcium-to-creatinine ratio were not measured in this study, Miniature Schnauzers are a breed prone to calcium oxalate stone formation, have a higher urine calcium-to-creatinine ratio, and have hypercalciuria associated with calcium oxalate stone status.49,50 It should also be noted that the 3 dogs that failed dissolution were Miniature Schnauzers (n = 2) and a Shih Tzu (1), both of which are breeds associated with hypercalciuria and calcium oxalate stone formation.50 Further studies are warranted to evaluate this observation specifically looking at the efficacy of d,l-methionine and dissolution of struvite uroliths in breeds prone to calcium oxalate stone formation, as well as the possible risk of deposition of calcium oxalate on a struvite nidus with prolonged use of d,l-methionine in these breeds.

As with any study, there were limitations. Though this was a pilot study, the small sample size was a limitation and warrants cautious interpretation of results. There was also no control group that was on the currently recommended management protocol of a dissolution diet and appropriate antimicrobial treatment for comparison.45 Owners were asked to not feed treats or table scraps during the study, but no strict monitoring protocol was in place to ensure this happened. Though this was a limitation, the fact that 73% (8/11) of the dogs that completed the study achieved dissolution, despite this dietary uncertainty, lends support to the use of d,l-methionine for dissolution. Lastly, all dogs received amoxicillin–clavulanic acid at a therapeutic dose for treatment of their UTIs on the basis of culture and sensitivity results. This can be seen as a limitation, as the efficacy of d,l-methionine with other antimicrobials remains unknown. However, choosing the most appropriate antimicrobial as part of the dissolution protocol for infection-induced struvite uroliths is of utmost importance in promoting antimicrobial stewardship.14 Future prospective studies using d,l-methionine as part of the dissolution protocol with dogs on different antimicrobials are needed to help determine whether d,l-methionine efficacy is altered by the antimicrobial used.

In conclusion, d,l-methionine was safe and effective in dissolving presumed infection-induced struvite uroliths in dogs in combination with amoxicillin–clavulanic acid in this small study of 14 dogs. Of 14 dogs that began the treatment, 3 dogs (21%) did not complete the study. Of 11 dogs that completed the study, dissolution was achieved in 8 (73%) dogs, while failure occurred in 3 of 11 (27%) dogs. In these 3 dogs, calcium oxalate was found to be incorporated into or onto the stone, which may have occurred due to urinary acidification. The apparent effective dosage of d,l-methionine was approximately 100 mg/kg, PO, every 12 hours when used with amoxicillin–clavulanic acid. Successful dissolution occurred when uroliths decreased in size by at least 50% at the 1-month reevaluation. If uroliths do not decrease in size by at least 50% at the 1-month reevaluation, consideration should be given to (1) lack of compliance, (2) inappropriate dosage, (3) difficulty in controlling the bacterial urinary tract infection, or (4) uroliths being composed of other minerals, most likely calcium oxalate, in addition to or instead of struvite.

Acknowledgments

This study was supported by Lloyd, Inc.

The authors declare that there were no conflicts of interest.

The authors declare no extralabel use of medications.

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