In female dogs, as in women, a clinical diagnosis of uncomplicated bacterial cystitis is relatively common and is based on consistent clinical signs of acute dysuria in an otherwise healthy patient. Empirical antimicrobial selection is the cornerstone of treatment and is based on the predictability of common uropathogens. Resolution of clinical signs typically is used as a marker for successful treatment in both dogs and women. Documentation of a positive urine culture at diagnosis and confirmation of resolution of bacteriuria after treatment are not routinely performed for first time infections in dogs or women.
For decades, short-duration antibiotic treatment has been the standard of care for uncomplicated bacterial cystitis in healthy women. This approach arose from evidence that antibiotic administration for a week or more was not necessary to cure superficial infections of the bladder.[2-5] In women, 3-day regimes of potentiated sulfonamides[6, 7] or fluoroquinolones[7, 8] show equal clinical efficacy when compared with longer courses.[9, 10] Advantages of short-duration treatment include lower cost, better compliance, fewer adverse effects, and decreased antimicrobial resistance.[2, 4, 11] To avoid unnecessary fluoroquinolone use, a 3-day course of trimethoprim-sulfamethoxazole (TMP-SMX) is the recommended empirical treatment for bacterial cystitis in women with no known history of previous TMP-SMX sensitization and when the local prevalence of Escherichia coli resistance to sulfonamides is <20%.[12, 13] Beta-lactam antibiotics are not recommended for empirical treatment in women because they result in lower bacterial eradication rates and higher recurrence rates, even with extended durations of treatment.[4, 9, 12, 14]
In contrast to the treatments recommended in women, empirical long-duration (7–14 days) beta-lactams are a common first-line treatment in female dogs with uncomplicated cystitis.[15, 16] The routine clinical use of potentiated sulfonamide antibiotics in dogs is limited by the potential for hypersensitivity reactions that include blood dyscrasias, hepatotoxicity, polyarthropathy, and cutaneous skin eruptions.[17, 18] However, sulfonamide hypersensitivity reactions occur ≥5 days after beginning drug treatment in both humans and dogs,[17-19] and clinically relevant reactions have not been reported in women in association with widespread use of short-duration TMP-SMX regimens.
The purpose of our study was to compare the efficacy of 3 days of treatment using a potentiated sulfonamide antibiotic (TMP-SMX) with 10 days of treatment using a first-generation beta-lactam (cephalexin) in female dogs with uncomplicated bacterial cystitis. We hypothesized that short-duration sulfonamide (SDS), the standard of care for uncomplicated cystitis in women, would be more efficacious than long-duration beta-lactam (LDBL), the historical first-line treatment for female dogs, in achieving clinical and microbiological cures. Our primary outcomes were clinical and microbiological cure rates, both short term (4 days after antibiotic discontinuation) and long term (>30 days after antibiotic discontinuation). A secondary objective was to determine whether there was any evidence of immunologic sensitization to SMX in dogs treated for 3 days with TMP-SMX.
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- Materials and Methods
This study evaluated the clinical and microbiological cure rates of SDS and LDBL antibiotic treatment in female dogs with a clinical diagnosis of uncomplicated bacterial cystitis. Most dogs in both treatment groups had resolution of clinical signs by treatment day 3 (89% in SDS group, 94% in LDBL group). Clinical cure rates 4 days after discontinuation of antibiotics also were comparably high in both groups (85% in SDS group, 72% in LDBL group). However, durable clinical remission rates were lower (only 50% in SDS group and 65% in LDBL group) when evaluated >30 days after completing antibiotics. This demonstrates a relatively high rate of recurrence of clinical infections in this population of female dogs.
Microbiological cure rates were relatively low in both treatment groups. Only 59% of SDS and 36% of LDBL group dogs had microbiological cures 4 days after completion of antibiotics, and only 44% of SDS and 20% of LDBL dogs had microbiological cures >30 days after completing treatment. All 7 dogs that had clinical relapse between short-term (4 days after treatment was completed) and long-term (>30 days after treatment was completed) follow-up also had evidence of recurrent infection. However, some dogs had ABU (positive cultures at follow-up without clinical signs); specifically, 35% of dogs in the SDS group and 43% in LDBL group, which contributed to the lower microbiological cure rates as compared with clinical cure rates. Most of these ABU dogs (9 of 12) did not develop a recurrence of clinical signs during the study observation period.
The relative importance of clinical versus microbiological cure for bacterial cystitis in dogs is not clear. Clinical cure rather than microbiological cure is the primary outcome for short-duration antibiotic treatment in women with uncomplicated lower urinary tract infections. Short-duration antibiotic treatment is aimed at decreasing the bacterial load to a level that allows clinical signs of the infection to be controlled, while the patient's immune system eradicates the remaining bacterial organisms from tissues (ie, bladder, vagina, and rectal reservoirs).
The clinical cure rates reported in women treated for uncomplicated cystitis are 90% (SDS) and 85% (LDBL) at short-term follow-up and 85% (SDS) and 70% (LDBL) at long-term follow-up.[7, 9, 10] The microbiological short- and long-term cure rates reported for SDS and LDBL in women are similar to their reported clinical cure rates. The lower long-term clinical and microbiological cure rates in the dogs reported in this study may be attributable to differences in anatomy, endogenous estrogen concentrations, gut flora, perineal hygiene, degree of involvement of the upper urinary tract, or other factors between the 2 species.
Treatment failures occur most commonly in women with occult upper urinary tract infections. Although upper urinary tract involvement in the dogs in our study could not be completely ruled out, dogs with polyuria and polydipsia or azotemia and concurrent dilute urine were not eligible. Nine of 11 dogs in this study with clinical recurrence had concurrent bacteriuria. In this study, there was a subjective difference in the timing of clinical recurrence relative to completion of treatment between the 2 treatment groups, but in each case, the organism cultured at recurrence was the same bacterial species cultured at enrollment. This is in contrast to women with recurrent infections restricted to the bladder, which typically are caused by an organism different from the original isolate (ie, reinfection). However, without genotyping, discernment between a relapsing infection and reinfection is not possible in this group of dogs.
Factors that may contribute to antibiotic treatment failure in dogs with bacterial cystitis include antibiotic choice, duration of treatment, owner compliance, superficial versus deep bladder wall involvement, dysbiosis of the vaginal vault, or concurrent illness, even if subclinical. At study enrollment, all dogs in this study were screened for common complicating factors, and all bacterial isolates cultured had in vitro susceptibility to the study antibiotics. The high long-term failure rates of both treatment groups suggest that in some female dogs, “uncomplicated” bacterial cystitis, diagnosed on the basis of acute onset of clinical signs in the absence of predisposing factors, may be more complicated than previously recognized.
The clinical use of and published reports describing short-duration antimicrobial treatment for the treatment of cystitis in dogs are limited to a single experimental study and recently reported clinical study. In the small experimental study, bacterial cystitis was induced with pathogenic E. coli in dogs and after development of clinical signs, a 3-day antimicrobial regimen was evaluated in 8 female dogs using either trimethoprim-sulfadiazine (TMP-SDZ) or amikacin. The 4 female dogs treated with TMP-SDZ achieved microbiologic cures at 48 hours and 14 days after 3 days of treatment. A recent clinical study, published after initiation of this study, compared long-duration beta-lactam treatment to short-duration enrofloxacin. The study found that high-dose short-duration enrofloxacin (20 mg/kg for 3 days) was not inferior to a 14-day course of amoxicillin-clavulanic acid in the treatment of male and female dogs with bacterial cystitis. Clinical cure rates of 77% (short-duration enrofloxacin) versus 81% (long-duration amoxicillin-clavulanate) were based on short-term follow-up only (7 days after completion of treatment). Microbiological cure rates at the 7-day follow-up were 81% versus 80% for the short-duration enrofloxacin and long-duration amoxicillin-clavulanate groups, respectively. Long-term assessment of the clinical and microbiological cure rates of high-dose short-duration enrofloxacin is needed because long-term cure also is a relevant clinical outcome, as demonstrated in this study.
Although short-term clinical cure rates are comparable between the 2 short-duration therapies (77% in the high-dose short-duration enrofloxacin group 7 days after treatment versus 85% in the SDS group 4 days after treatment reported here), the short-term microbiological cure rate appears higher for short-duration enrofloxacin than for SDS in this study (81% versus 59%, respectively). However, 76% (13 of 17) of the SDS dogs had microbiological cure 11 days after discontinuation of treatment (data not shown, but available because of the double-blinded design of this study).
Fluoroquinolones are only considered first-line treatment in women with uncomplicated bacterial cystitis in regions where bacterial sulfonamide resistance is high (eg, ≥20%), in women with known sulfonamide hypersensitivity, or in women in whom lower urinary tract signs persist or recur within a week or two of antibiotic treatment. In this study, dogs considered treatment failures that had positive bacterial urine culture were rescued with antibiotic treatment. Because these dogs were considered treatment failures, additional treatment for “uncomplicated” bacterial cystitis was not pursued. Eight of the 9 treatment failure culture-positive dogs were treated with a 2-week course of fluoroquinolone treatment. This treatment was thought to be a logical second-tier intervention in the dogs in this study that failed traditional long-duration beta-lactam treatment or short-duration sulfonamide treatment (treatment group was unknown to investigators and owners at the time of dispensing rescue antibiotics).
The strengths of this study include the double-blinded, placebo-controlled experimental design and long-term follow-up. One limitation was the use of abdominal radiographs and not a complete ultrasound examination to rule out complicating factors at enrollment. However, full abdominal ultrasound examination is not performed routinely for first time or isolated urinary tract infections in dogs, and the study was designed to evaluate the efficacy of the 2 treatments in a clinically relevant setting.
Additional limitations of this study were single-center recruitment and smaller than planned study population. Based on an interim analysis of clinical cure rates 2 years into enrollment, we closed the study because the results failed to show superior efficacy of TMP-SMX at 4 or >30 days after discontinuation of treatment and our hypothesis was that clinical cure would be 20% higher for SDS. In addition, the rates of microbiological cure, which were higher in the SDS group at both short- and long-term follow-up, did not reach significance in this population of dogs. If present, this would be a clinically relevant difference, but based on a post hoc sample size calculation using our actual data, 80 dogs would have been needed in each treatment group to detect these differences, if real, as significant.
This relatively small canine patient population limited our ability to adequately evaluate the SDS-treated dogs for sulfonamide immunoreactivity. In women, longer durations (eg, ≥5 days) of sulfonamide treatment are associated with more adverse effects compared with short-duration (ie, single dose or 3-day) protocols. However, published studies did not specifically evaluate the sulfonamide-treated patients for a sulfonamide-specific immune response.[12, 40, 41] In this study, none of the dogs (n = 20) treated with TMP-SMX for 3 days developed clinical signs consistent with a sulfonamide hypersensitivity reaction, and the subpopulation of dogs (n = 8) tested for antisulfonamide antibodies and sulfonamide-specific T cells after 3 days of TMP-SMX did not develop a sulfonamide-specific immune response. These data only provide a pilot assessment of immunoreactivity in dogs treated with short-duration sulfonamide treatment. Larger studies are needed to adequately determine if limiting a sulfonamide naive dog's exposure to 3 days is safe and avoids immune sensitization associated with longer duration protocols.
In summary, this study did not demonstrate a difference in cure rates between SDS and long-duration beta-lactam treatment regimens for uncomplicated cystitis in female dogs. No serious clinical or biochemical adverse events were noted during the study in either treatment group. Given the increasing rates of fluoroquinolone resistance and the potential for interspecies spread of multi-drug resistance among bacteria, future studies of adequate power are needed to determine if short-duration potentiated sulfonamides and high-dose short-duration fluoroquinolones are comparable in safety outcomes and equivalent for long-term clinical and microbiological cure of bacterial cystitis in female dogs.