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Update on Trimethoprim-Sulfamethoxazole, its side effects and current evidence for its use in uncomplicated urinary tract infections.

By Virginia Sinnott-Stutzman, DVM, DACVECC
angell.org/emergency
617-522-7282

Trimethoprim‑Sulfamethoxazole (TMP-SMX) was widely prescribed in the 1970s, 1980s and 1990s. The side effect profile was limited to gastrointestinal (GI) upset or diarrhea until after market idiosyncratic drug reactions were identified. Some of the reactions reported were so unexpected and severe that many veterinarians stopped using the drug altogether in favor of drugs with more predictable side effects such as amoxicillin. This has led to widespread use of beta-lactam antibiotics, such that in some regions of the country organisms isolated in uncomplicated urinary tract infections (UTI) are likely to be sensitive to amoxicillin only 68% of the time.1 While not an unreasonable probability of success for a non-life threatening infection, the trend of increasing resistance is concerning and has inspired researchers to re-evaluate TMP-SMX as a treatment for uncomplicated UTI. While the idea of this may inspire fear in some veterinarians due to memories of reactions in bygone days, TMP-SMX may actually be singularly suited to be used for uncomplicated, often first-time UTI. This is because there is evidence that uncomplicated UTI may be cleared with short courses of antibiotics and it is likely that the most worrisome side effects may only occur with exposures to TMP-SMX longer than the recommended UTI course.

There are two types of drug reactions, dose-dependent and idiosyncratic. The dose-dependent reactions associated with TMP-SMX are thyroid suppression, hematuria and non-regenerative anemia. These reactions are thought to be due to folate depletion and are nearly always associated with either supra-therapeutic dosing (i.e. >30mg/kg/day) or prolonged courses of therapy and thus should be avoided by using TMP-SMX for only short-course therapy at recommended dosages. 2

The most famous side effect of TMP-SMX use is keratoconjunctivitis sicca (KCS), and it somewhat blurs the line between dose-dependent and idiosyncratic reactions. Blepharospasm and mucoid ocular discharge are thought to occur as a result of a hypersensitivity reaction resulting from lymphoplasmacytic infiltration of lacrimal acinar cells which can occur during or after therapy. If KCS occurs during therapy, it may be reversible with prompt drug withdrawal since this side-effect may be in part attributable to direct cytotoxic effects to lacrimal gland tissue.2  It is reasonable to check a Schirmer tear test in at-risk dogs before starting therapy, and avoid treatment in dogs with borderline values (i.e. 15mm in 60 seconds) or in dogs with excessive corneal exposure (i.e. brachycephalic breeds) or a prior diagnosis of KCS. While KCS is not uncommon, it has not been reported in dogs on TMP-SMX for less than 5 days, again making the short courses recommended for uncomplicated UTI attractive when considering this side effect.

Figure 1: E. coli from a urinary specimen growing at the Angell Clinical Microbiology lab on MacConkey agar (left) and sheep’s blood agar (right). Note that lactose fermentation by E. coli causes the MacConkey agar to turn pink.

True idiosyncratic reactions to the sulfamethoxazole component of TMP-SMX are associated with type 2 and 3 immune-mediated reactions of various types in dogs and humans. Dogs are theorized to be at increased risk (as compared to cats) due to reduced N-acetylation of the parent sulfonamide which may reduce clearance and lead to build-up of cytotoxic metabolites that undergo oxidation by cytochrome P450 enzymes. Specifically hydroxylamines may result in neutrophil apoptosis and be phagocytosed and presented by antigen-presenting cells along with major histocompatibility proteins, priming an immune-mediated response.2 Again, these reactions are associated with at least five days of therapy. The most commonly reported reactions since use was reduced in the early 1990s (1993-2003) are fever, thrombocytopenia and hepatopathy.3 It was estimated that 0.25% of dogs prescribed TMP-SMX developed reactions in one investigation, which is equivalent to 1 idiosyncratic reaction for every 400 patients treated, however again, no dog in this investigation was on TMP-SMX for less than 7 days of therapy.4

Uncomplicated urinary tract infection (UTI) is defined as, “a sporadic bacterial infection of the bladder in an otherwise healthy individual with normal urinary tract anatomy and function.”5 Additionally, the animal should have clinical signs referable to UTI such as hematuria, pollakiuria or behavioral signs of dysuria. Normal urinary tract anatomy and function refers to an animal that concentrates its urine adequately, has no other systemic illness and has no obvious or extreme conformational abnormalities on physical examination. As such, a urinalysis is required to make a diagnosis of uncomplicated urinary tract infection since urine concentrating ability must be evaluated.

Uncomplicated urinary tract infections result in the majority of veterinary antimicrobial prescriptions and are a good candidate for short-course therapy. The International Society for Companion Animal Infectious Disease recently published guidelines for the treatment of UTI in dogs and cats and “acknowledged the likelihood that a shorter treatment time (≤ 7 days) may be effective” despite the fact that most vets typically treat uncomplicated UTI for 7-14 days.5 Recently, two investigations showed equivalent cure rates to standard course antibiotics with three days of therapy of either TMP-SMX or enrofloxacin.6,7 Since enrofloxacin is a drug commonly used to treat life-threatening infections and has a side effect profile that makes it a more favorable candidate for the multiple days of therapy needed to treat serious infections, I don’t recommend using it to treat uncomplicated UTI. TMP-SMX, however, has been shown to be problematic for some dogs for 5 days or longer therapy, making it less ideal for life-threatening infections and long and short term cure rates were equivalent between TMP-SMX 15mg/kg PO twice a day for 3 days of therapy and Cephalexin 20mg/kg PO twice a day for 10 days.6 It is important to note that the long-term cure rate (recurrence at one month) was high for BOTH groups (about 50%) suggesting either that neither treatment was effective for long term cure or that the UTIs being treated were not truly uncomplicated. Since long-term cure rates are rarely evaluated in UTI in dogs and cats, we don’t know what “good” looks like, and most clinicians will tell you that you can’t know with the first UTI whether a dog will be a “frequent flier.” The significance of the high recurrence rate shouldn’t be interpreted beyond saying that a traditional UTI therapy and the short course treatment were equivalent. Of note, in a select few dogs in the TMP-SMX group of this investigation were evaluated for anti-TMP-SMX antibodies (n=8) and for drug-specific T-cell proliferation (n=9), and none of the dogs had either anti-TMP-SMX antibodies or drug-specific T-cells.6 While I consider this pilot data given the low numbers, it suggests that 3 days of TMP-SMX exposure may not be enough to generate an immune response that would result in the worrisome side-effects seen with longer courses of therapy.

Finally, TMP-SMX has been shown time and time again to be one of the single most effective oral antibiotics to treat UTI. A recent investigation evaluating susceptibility of UTI to various antibiotics found isolates from  uncomplicated UTI to be susceptible to TMP-SMX 90% of the time, the highest frequency of all oral antibiotics evaluated.1 Investigations looking at E. coli specifically (the most common cause of UTI in dogs), found that isolates were sensitive to TMP-SMX 82-83% of the time.8,9

In summary, uncomplicated UTI uniquely lends itself to short courses of antibiotic therapy due to the ability to deliver antibiotics in high concentrations to the urine, the rich blood supply to the urinary bladder, the ability to obtain microbiologic samples, and the non-life threatening nature of the infection. TMP-SMX, on the other hand, is an antibiotic best used for short course therapy (3 days or less) in dogs to reduce the likelihood of antigenic exposure. Recent evidence suggests that short antibiotic courses are a reasonable approach to treat UTI, offering support to the clinician wanting to increase compliance and reduce the client headache of treating animals with oral medications without increasing the likelihood of resistance of critically important drugs commonly used to treat life-threatening infections.

References:

  1. Wong C, Epstein SE, Westropp JL. Antimicrobial Susceptibility Patterns in Urinary Tract Infections in Dogs (2010-2013). J Vet Intern Med. 2015 Jul;29(4):1045–52.
  2. Trepanier LA. Idiosyncratic toxicity associated with potentiated sulfonamides in the dog. J Vet Pharmacol Ther. 2004;27(3):129–138.
  3. Trepanier LA, Danhof R, Toll J, Watrous D. Clinical findings in 40 dogs with hypersensitivity associated with administration of potentiated sulfonamides. J Vet Intern Med. 2003;17(5):647–652.
  4. Noli C, Koeman JP, Willemse T. A retrospective evaluation of adverse reactions to trimethoprim‐sulphonamide combinations in dogs and cats. Vet Q. 1995 Dec;17(4):123–8.
  5. Weese JS, Blondeau JM, Boothe D, Breitschwerdt EB, Guardabassi L, Hillier A, et al. Antimicrobial Use Guidelines for Treatment of Urinary Tract Disease in Dogs and Cats: Antimicrobial Guidelines Working Group of the International Society for Companion Animal Infectious Diseases. Vet Med Int. 2011;2011:1–9.
  6. Clare S, Hartmann FA, Jooss M, Bachar E, Wong YY, Trepanier LA, et al. Short- and Long-Term Cure Rates of Short-Duration Trimethoprim-Sulfamethoxazole Treatment in Female Dogs with Uncomplicated Bacterial Cystitis. J Vet Intern Med. 2014 May;28(3):818–26.
  7. Westropp JL, Sykes JE, Irom S, Daniels JB, Smith A, Keil D, et al. Evaluation of the Efficacy and Safety of High Dose Short Duration Enrofloxacin Treatment Regimen for Uncomplicated Urinary Tract Infections in Dogs. J Vet Intern Med. 2012 May;26(3):506–12.
  8. Boothe D, Smaha T, Carpenter M, Shaheen B, Hatchcock T. Antimicrobial resistance and pharmacodynamics of canine and feline pathogenic E. coli in the united states. J Am Anim Hosp Assoc. 2012;49:379–89.
  9. Cummings KJ, Aprea VA, Altier C. Antimicrobial resistance trends among canine Escherichia coli isolates obtained from clinical samples in the northeastern USA, 2004–2011. Ca
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