UTIs in Small Animal Patients: Part 1: Etiology and Pathogenesis

Introduction

A urinary tract infection (UTI) is defined as either a temporary or permanent breach in host defense mechanisms that allows microbes to adhere, multiply, and persist within the urinary tract. Development of a UTI is multifactorial, with both bacterial number and virulence and the health status of the patient (e.g., urogenital tract anatomy, physiologic and systemic immunocompetence) playing important roles in determining the outcome. Most UTIs are caused by bacteria, but other etiologies include fungi, viruses, mycoplasmas, and parasites. A UTI can either involve a single site (such as the renal pelvis, ureter, bladder, urethra, prostate, or vagina) or can include multiple sites. Infection of any portion of the urinary tract may increase the likelihood of infection in other locations.

Bacterial UTIs are common. It is currently estimated that 5–27% of dogs will experience infections of the urinary tract at some point during their lifetime.^1–3 Female dogs are more commonly affected than males. A large retrospective study of canine urine cultures reported bacterial growth in 37% of submissions from female dogs and 29% of submissions from male dogs.⁴ In contrast to dogs, bacterial UTIs are relatively rare in cats. In young, otherwise healthy cats with signs of lower urinary tract inflammation, bacterial UTIs are rare (< 2%).^5,6 The incidence of bacterial UTIs in cats increases with age and occur more often in cats > 10 yr.^7–9

Asymptomatic Bacteriuria

Not all species of bacteria will induce clinical signs and cause disease. In some cases, the bacteria present in animals with an asymptomatic bacteriuria may provide protection against colonization of the urinary tract with more pathogenic strains of bacteria (Table 1).^10,11 This is important because some patients that are treated for an asymptomatic bacteriuria may subsequently develop infections of the urinary tract with pathogenic strains of bacteria.¹² Asymptomatic bacteriuria associated with a UTI most often occur secondary to either a systemic disease or immunocompromise. Recommendations for treatment of asymptomatic bacteriuria are provided in part 2 of this review.

Table 1 Commensal Bacterial Genera in the Canine Urogenital Tract¹¹

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Inflammation versus Infection

Evidence of inflammation (e.g., pyuria) in the urine sediment is not synonymous with a UTI. There are several nonbacterial diseases that can result in urinary tract inflammation, and the clinical signs of inflammation may be similar to those of a UTI (e.g., dysuria, pollakiuria, hematuria). Examples of inflammatory conditions include the following: sterile urocystoliths; urethral obstruction; lower urinary tract neoplasia; lower urinary tract trauma; and sterile, polypoid, irritant, and idiopathic cystitis. It is important to perform a urinalysis and urine culture in patients with clinical signs of urinary tract inflammation to confirm the diagnosis of a UTI.

Microbial Isolates

The most common isolate from canine urine is Escherichia coli (E. coli), which accounts for between one-third and one-half of all positive urine cultures.^4,13 The next major group of uropathogens includes the gram-positive cocci (i.e., Staphlyococcus spp., Streptococcus spp., and Enterococcus spp.) Other uropathogens include Proteus spp., Klebsiella spp., Pasteurella spp., Mycoplasma spp., Enterobacter spp., and Pseudomonas spp.^4,13 Those 10 genera account for 95% and 97% of all urinary isolates in male and female dogs, respectively.⁴ One study evaluating bacterial prevalence in an Australian cat population found E. coli to be the most common pathogen (37%), followed by Enterococcus spp. (27%) and Staphlyococcus spp. (20%).^14,15 A retrospective analysis of feline urine cultures submitted to a teaching hospital also found E. coli to be the most common pathogen (47%), followed by Staphlyococcus spp. (18%), Streptococcus spp. (13%), and Klebsiella spp. (4%).¹⁵ In both dogs and cats with bacterial UTIs, a single pathogen is present in most cases (75% of the time). In 20% of the cases there are two pathogens, and ≤ 5% of the time there are three species.¹³ Female dogs most commonly have multiple organisms. ⁴ Infections with less invasive bacteria, such as Pseudomonas spp., can indicate an opportunistic infection secondary to immunocompromise or alterations in host defenses because Pseudomonas spp. are usually not associated with symptomatic UTIs in healthy patients.

Antimicrobial Resistance

Both intrinsic and acquired forms of antimicrobial resistance exist. Intrinsic resistance mechanisms are inherited bacterial properties.¹⁶ For example, penicillinase-producing strains of Staphylococcus spp. have intrinsic resistance to penicillins. Although there is little that can be done about intrinsic resistance, veterinarians play a large role in the acquired forms of resistance because bacterial populations respond to selection pressures subsequent to the use of antimicrobial agents. With increasing use of antimicrobials there is increased risk of resistance. This not only has the potential to affect veterinary patients but also the humans that live with them.

Acquired resistance is created by alterations in bacterial DNA. Bacteria have numerous mechanisms for exchanging genetic material that contribute to acquired antimicrobial resistance. Bacteria have both genomic DNA as well as plasmids. Plasmids, which are small, circular strands of DNA, do not carry genes responsible for essential metabolic function. Instead, the plasmids have genes that are responsible for virulence and resistance. Transposons are another type of mobile genetic element that can contribute to resistance by excising themselves from the donor chromosome and inserting into either recipient chromosomes or plasmids. Plasmids and transposons can be passed between both bacterial strains and across species within a bacterial family by a process known as conjugation.¹⁶ Finally, chromosomal mutations are also possible, which tend to produce resistant modifications in the antibiotic target.

Routes of Infection

Most UTIs are associated with bacterial pathogens from either the gastrointestinal tract or skin surrounding the vulva and prepuce that ascend via the urethra to the urinary bladder. Once the bacteria gains entrance to the urinary tract, it adheres and colonizes the urothelial surface. The ability to establish those colonies depends on both the number and virulence of the ascending microbes and the competence of the host defense mechanisms.

Ascension of bacteria from the lower urinary tract is the primary route of infection of the upper urinary tract (versus either hematogenous or direct extension from surrounding tissues). The most common site of infection in the upper urinary tract is the renal pelvis, but invasion into the renal parenchyma is also possible.¹⁷ Ascension from the lower urinary tract may occur in association with vesicoureteral reflux and/or an obstructive uropathy. Obstruction to urine flow can decrease renal medullary blood flow via increased back pressure and decrease the delivery of antibody, complement, and WBCs to the medulla, increasing the risk of bacterial colonization of the renal pelvis. A small percentage of UTIs are caused by bacteria that have entered the urinary tract through a hematogenous route. The development of an UTI via the hematogenous route is uncommon. When it does occur, it is most frequently affects the kidney. In cases of bacteremia, the high renal blood flow and the extensive filtration surface within the glomeruli exposes the kidney to a relatively large number of bacteria.

Normal Host Defense Mechanisms

Host defense mechanisms are comprised of a combination of anatomic and physiologic factors that have a major role in preventing a UTI. Beyond prevention, the status of host defense mechanisms is one of the most important determinants of the outcome of a UTI. Appropriate antibiotic treatment will, at best, sterilize the urinary tract during the time of administration, but it is the host defense mechanisms that prevent recurrent UTIs (i.e., reinfections) after antibiotic withdrawal. Diagnosis of defense breaches can help identify possible reasons for treatment failures and patients at risk for acquiring a UTI.

Normal Urine Storage and Voiding

Production of a normal amount of urine with frequent and complete voiding helps reduce the number of bacteria ascending through the urethra and adhering to the bladder uroepithelium. Research in rats infected with E. coli identified two phases of bacterial clearance during voiding. The primary phase occurred 0–4 hr after the introduction of bacteria, and the secondary phase occurred 4–24 hr after the introduction of bacteria. During the primary washout phase, 99% of the bacteria were cleared from the bladder. Bacterial numbers continued to be reduced during the secondary washout phase as long as the uroepithelial surface was healthy.¹⁸

Any condition that decreases the frequency of voiding can predispose a patient to a UTI by providing more time for bacterial adherence. For example, dogs with upper motor neuron lesions often have urine retention associated with increased outflow resistance and subsequent bladder atony. Incomplete bladder emptying in those patients subsequently increases the potential for infection. Similarly, retention of urine-associated decreased detrusor contractility (e.g., lower motor neuron lesions and dysautonomia) is also associated with decreased bacterial washout and an increased predisposition to UTI.¹⁹ From a clinical management perspective, prolonged time between voiding opportunities (e.g., owner work schedules) may also make it more difficult to eradicate the UTI.

Although diuresis and increased frequency of voiding in humans reportedly decreases the bacterial colony count in patients diagnosed with UTIs, reduced frequency of voiding in the face of dilute urine (e.g., at night when the patient is asleep) can result in increased urine bacterial counts.²⁰ Dilute urine with low concentrations of urea may predispose dogs and cats to the development of UTIs because bacteria have an increased ability to grow in such conditions compared with the harsher environment of highly concentrated urine (discussed in more detail below). The importance of bladder washout versus antibacterial properties of concentrated urine has not been investigated in dogs; however, it is likely that both factors have clinical significance. In dogs and cats with decreased urine concentrating ability, urine cultures should be part of the longitudinal monitoring recommendations.

Anatomic Structures

There are three anatomic features of the urethra, ureters, and prostate that help prevent infection and/or ascension of bacteria. First, the high pressure zone of the urethral sphincter impedes migration of bacteria. In contrast to urine retention, urethral sphincter mechanism incompetence and lower urethral closure pressures may also compromise host defenses by allowing a greater number of bacteria to more easily ascend through the urethra to the bladder. Second, ureteral peristalsis inhibits ascension of bacteria above the level of the bladder. Third, in male dogs, prostatic secretions that contain zinc and are bacteriostatic, along with increased urethral length, are important defense mechanisms. These factors make UTIs less common in male dogs than in female dogs.^21,22 Congenital and/or acquired anatomic abnormalities of the urogenital system frequently predispose patients to UTIs. Vaginal strictures resulting in either urine pooling or urine retention can increase the time for bacterial adherence/colonization of the lower urinary tract. Ectopic ureters lack the normal vesicoureteral valve; therefore, bacteria from the lower tract can more easily ascend to the upper urinary tract. A recessed vulva and excessive perivulvar skin folds often result in a localized, moist, bacterial dermatitis and increased bacterial ascension through the urethra.

Mucosal Defense Barriers

The urothelium lines the lumen of the urinary tract from the renal pelvis to the urethra and prevents the passage of water, ions, solutes, and macromolecules from the plasma and interstitium into the urinary tract lumen (and vice versa).²³ A healthy uroepithelium also prevents adherence of bacteria. For example, one small study showed that perineal urethrostomy surgery did not increase the risk of UTI in cats with a healthy uroepithelium. However, persistent uroepithelial inflammation combined with surgical alteration in anatomic and functional barriers is associated with a higher incidence of UTIs in cats.²⁴

Within the bladder, the uroepithelium is composed of three layers: basal cells, intermediate polygonal cells, and (the most superficial) umbrella cells. The umbrella cells form a single layer, are separated by cellular tight junctions, and can alter their shape depending on the degree of bladder distention.²³ The apical membranes of the umbrella cells are composed of plaques and hinges that facilitate stretching and bladder filling. The plaques are made up of inner and outer leaflets that form an asymmetric unit membrane, which is composed of transmembrane proteins called uroplakins. One of the main functions of uroplakins is to form a barrier to solutes and water flow across the apical membrane.²³ If ascending bacteria bind to uroplakins, uroepithelial apoptosis can be initiated resulting in washout of the infected cells.

In some cases, the adherence of bacteria to the uroepithelium can lead to the cellular internalization of bacteria. Bacteria within uroepithelial cells are protected from the host’s immune response and have the ability to serve as a reservoir for recurrent infections. Patients that are immunocompromised are predisposed to the internalization of bacteria. This altered immune status can result in the development of recurrent infections.

Glycosaminoglycans (GAGs) and proteoglycans are produced by umbrella cells and are part of the bladder surface mucus layer. GAGs are hydrophilic and bind water to the apical membrane of the transitional cell. That water layer decreases the ability of bacteria and crystals to adhere to the uroepithelium and contributes to the impermeability of the bladder wall.²⁵ Chemical (e.g., cyclophosphamide) and mechanical damage (e.g., presence of uroliths, neoplasia, injury due to urethral catheterization), can disrupt the GAG layer resulting in increased adherence of bacteria to the bladder mucosa.²⁶ Disruption of the GAG layer also increases the permeability of the bladder wall allowing irritating substances to pass through the uroepithelium and cause submucosal inflammation.²⁷

Secretory immunoglobulin A (IgA) is the primary immunoglobulin in mucous secretions from the urogenital tract. It differs from serum IgA by being bound to a secretory protein component.²⁸ The secretory component complexes with polymeric IgA released by the plasma cells in the lamina propria of mucous membranes allowing transport of IgA across the epithelial barrier and into the lumen.²⁹ Widening of the interstitial space between uroepithelial cells associated with inflammation may facilitate secretion of IgA.³⁰ Secretory IgA inhibits attachment of E. coli to human uroepithelial cells by binding to bacteria that enter the mucous layer of the uroepithelium.³¹ Once a bacterium is coated with secretory IgA, its ability to adhere to the uroepithelium is compromised.³⁰

Another mucosal defense mechanism involves normal flora occupying distal uroepithelium receptor sites. Normal flora of the urogenital tract compete with potential pathogens for nutrients and epithelial receptor sites. Bacteriocins are natural antibiotics produced by almost all bacteria.³² Normal flora may produce bacteriocins that are inhibitory and/or bactericidal to potential pathogens.³³ The antibiotic properties of those bacteriocins have a relatively narrow spectrum and are only toxic to closely related strains. Colicin is the most commonly evaluated bacteriocin in E. coli infections.³² Urinary catheters coated with a colicin-producing strain of E. coli have been used to prevent UTIs in humans.³⁴

Antimicrobial Properties of Urine

The antibacterial properties of urine contribute to host defenses via bacteriostatic, and possibly bactericidal effects, depending on urine composition. Potential mechanisms for those antibacterial properties include low pH, high concentrations of urea and weak organic acids, and high urine specific gravity (USG). In children with recurrent UTIs, inhibition of bacterial growth was correlated with increasing USG.³⁵ Urine osmolality and USG have been proposed as a reason why healthy cats have relatively few UTIs; however, because high USG does not always correlate with antimicrobial activity, there are likely other factors or substances in concentrated urine that inhibit bacterial growth.^36,37 Maintaining a patient’s urine pH between 5.0 and 6.5 helps inhibit the growth of bacteria in humans; however, one study examining antibacterial properties of feline urine found no correlation with pH and inhibition of UTI.^36,38 If an acidic urine pH does inhibit bacterial growth in canines, the effect may be more pronounced for bacteria such as Proteus spp. that tend to grow better in an alkaline environment.

Localization

UTIs most commonly colonize the uroepithelial cells of the bladder, but involvement of the kidneys, prostate, and uterus is also possible. If the male dog is intact, colonization of the prostate should be expected. The location of the UTI can be determined in most cases based on the history, physical examination findings, laboratory parameters, and imaging results (Table 2).¹⁷

Table 2 Clinical Features of UTIs Based on Site of Infection¹⁷

CBC, complete blood count; CHEM, serum biochemical panel; CKD chronic kidney disease; UTI, urinary tract infection; WNL, within normal limits.

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Complicating Factors

Conclusion

Bacterial UTIs are common in female dogs and older cats with concurrent systemic disease. Bacteria usually gain entrance to the urinary tract via ascension through the urethra. The ability of bacterial pathogens to adhere and colonize the uroepithelium is determined by the interplay of bacterial virulence factors and normal host defense mechanisms. Understanding those factors should improve a veterinarian’s ability to treat and prevent UTIs.