Chapter 86 URINARY TRACT INFECTIONS IN WOMEN

EPIDEMIOLOGY

Urinary tract infections (UTIs) are the most common bacterial infections and account for a substantial number of office and emergency room visits as well as hospital admissions each year. Additionally, UTI is the most common cause of nosocomial infection.¹ The morbidity of UTIs varies widely, from self-limited to life-threatening conditions. The focus of this chapter is on UTI in women, who make up a significant proportion of UTI suf-ferers. The annual incidence among women is 12.1%. Peak incidence in women occurs between the ages of 20 to 24 years.² Health care costs attributed to UTIs are substantial. The estimated overall costs of UTI among ambulatory women in the United States exceeds $1 billion annually.³

Pathogenesis

The interaction between bacterial virulence and host defense factors can ultimately result in UTI. More virulent bacteria are necessary to infect healthy hosts with a normal urinary tract, whereas less virulent bacteria may easily infect compromised hosts.

Laboratory studies of uropathogenic strains of Escherichia coli (UPEC) have helped to obtain a better understanding of the pathogenesis of UTIs. The initial step is bacterial adherence to the urothelium. Type 1 pili are filamentous adhesive organelles encoded by almost all UPEC, and they are significant virulence factors associated with UTIs. FimH is an adhesin molecule at the tip of type 1 pili that specifically binds to the luminal surface of the bladder.⁴ Bacterial colonization then precipitates a host inflammatory response, which includes neutrophil influx followed by apoptosis and exfoliation of the bladder’s epithelial cells in an effort to rid the bladder of bacteria. Despite the host’s response, however, high titers of UPEC persist in the bladder for several days.⁵

How are the bacteria able to elude the host defenses? Recent research has shown that UPEC avoids clearance by invading and replicating within the epithelial cells. They form “bacterial factories” that are refuges in which bacteria may persist and form biofilms. Bacteria within a biofilm are resistant not only to host defenses but also to typical courses of antimicrobials.⁵ These bacteria may subsequently reemerge and cause recurrent acute infections.⁶ Historically, the vagina and intestine have been accepted as UPEC reservoirs; however, this new paradigm demonstrates that the bladder itself may be a reservoir for UPEC.

Host Factors

Host factors include genetic, anatomic, functional, and behavioral factors that affect the host’s susceptibility to uropathogens and its ability to overcome them (Table 86-1).

Table 86-1 Host Factors

Genetic	Anatomic/Functional	Behavioral
Blood group antigen	Congenital abnormalities	Sexual activity
Nonsecretor status	Urinary obstruction	Diaphragm use
Density of adhesin receptors	Urinary incontinence	Spermicide use
Maternal history of UTI	Calculi	Antimicrobial use
	Residual urine
	Catheters or foreign bodies
	Atrophic vaginitis

UTI, urinary tract infection.

Modified from Ronald A: The etiology of urinary tract infection: Traditional and emerging pathogens. Am J Med 113(Suppl 1A):14S-9S, 2002.

In order for a UTI to occur, the infecting organism must first obtain access to the urinary tract. In the 1960s, Stamey hypothesized that bacteria that cause UTIs originate in the rectal flora and colonize the vaginal and urethral mucosa before ascending to the bladder.⁷ Vaginal colonization has proved to be a crucial step in the pathogenesis of UTI. Many factors that increase the risk of UTI do so by facilitating vaginal colonization with uropathogens.⁸ Women (in comparison to men) are particularly at risk based simply on differences in anatomy. Women have a moist periurethral space, a shorter distance between the anus and urethral opening, and a shorter urethra. These factors increase exposure to uropathogens and enhance the ability of these pathogens to colonize the urinary tract.²

Why are some women more susceptible to vaginal colonization, and therefore recurrent UTI, than others? There is substantial evidence that vaginal colonization is determined by genetic factors. In 1977, Fowler and Stamey discovered that E. coli adhered more avidly to vaginal epithelial cells of women with recurrent UTI.⁹ Follow-up studies by Schaeffer showed that high vaginal cell receptivity was correlated with high buccal cell receptivity, suggesting that epithelial cell receptivity is actually a genotypic trait.¹⁰ The concept of hereditary susceptibility was further investigated by Schaeffer and associates, who demonstrated that the prevalence of the human leukocyte antigen (HLA) A3 subtype was greater in women with recurrent UTIs.¹¹ In addition, carbohydrate structures bound to cell membranes known as blood group antigens make up a significant component of the uroepithelial cell membrane. Certain blood group antigens have been associated with susceptibility to UTI. Sheinfeld and colleagues determined that women with Lewis blood group Le(a⁻b⁻) or Le(a⁺b⁻) (nonsecretor) had a significantly higher incidence of recurrent UTIs than women with the Le(a⁻b⁺) (secretor) phenotype.¹² E. coli bind to mannose residues, which are more available in nonsecretor mucosa.¹³

Sexual Activity

Vaginal and oral intercourse help to propagate potential pathogens into the vagina and urinary tract. Additionally, vaginal intercourse may cause trauma of the vaginal epithelium, rendering it more susceptible to bacterial adherence and vaginal colonization.¹⁴ Several studies have linked sexual activity with vaginal colonization and UTI. Foxman and colleagues found that vaginal colonization with E. coli was inversely associated with the number of days since sexual activity.¹⁵ Hooton and coworkers reported that urine cultures in the immediate postcoital period show a transient bacteriuria.¹⁶ It has been proposed that voiding immediately after intercourse is protective, although there are no current data that support this conjecture.¹

DIAGNOSTIC TOOLS

History

A thorough history is an essential component of obtaining the proper diagnosis. It is important to clarify the onset and the presence or absence of symptoms including dysuria, urinary frequency, hematuria, suprapubic tenderness, flank pain, fever, and nausea/vomiting. Has the patient had previous UTIs as a child or as an adult? If so, were her previous UTIs associated with fever?

A complete medical and surgical history is also important. Does the patient have a history of nephrolithiasis or previous urinary tract surgery? Is the patient pregnant? Does the patient diabetic? The answers to these questions will direct further workup and management.

Physical Examination

The physical examination is not considered diagnostic of UTI but can be helpful in certain cases. The findings may assist in differentiating between lower urinary tract (cystitis) and upper urinary tract (pyelonephritis) infection. Is the patient febrile? Is there costovertebral tenderness? Findings such as a urethral diverticulum may occasionally reveal a potential source of recurrent UTI. The physical examination may also help to rule out other causes of patient symptomatology. For example, the presence of vaginal discharge has a strong association with vaginal infection rather than a UTI.²⁰

Urinalysis

Women should provide a midstream voided urine for analysis after spreading the labia and wiping from front to back with a clean sponge.⁷ The urinalysis provides information about pyuria, bacteriuria, and hematuria. Urine dipstick analysis is a quick and inexpensive test that is often used in the clinical setting. Testing for leukocyte esterase, an enzyme produced by polymorphonuclear cells, and nitrite, a byproduct of bacterial growth, it provides an indirect measurement of both pyuria and bacteriuria.²¹ If either the nitrite assay or the leukocyte esterase test is positive, the dipstick test has a sensitivity of 75% and a specificity of 82%.²² False-negative results can occur when the infecting organism does not produce nitrites.²³ It is important to note that, although the dipstick test can be useful for screening, it is not as sensitive as microscopic examination.⁷ Pyuria on microscopic examination has a high sensitivity (95%) and a relatively low specificity (71%).²⁴ The presence of bacteria on microscopic examination has a lower sensitivity (40% to 50%) yet a higher specificity (85% to 95%).²⁴

Urine Culture

The Infectious Diseases Society of America (ISDA) defines cystitis as greater than or equal to 10⁵ cfu/mL of midstream urine. However, studies by Stamm and Hooton demonstrated that greater than or equal to 10² cfu/mL for a catheterized urine specimen in a symptomatic patient is significant.²⁵ It is not necessary to obtain a urine culture in all patients. Appropriate patient selection for urine culture is addressed in a later section.

Imaging Techniques

Multiple radiographic techniques are available for imaging the urinary tract. Plain abdominal films may demonstrate radiopaque calculi. Intravenous pyelography, although not typically used in the setting of UTI, can be useful to determine the site of an obstruction.⁷ Renal ultrasonography may demonstrate stone, hydronephrosis, or perirenal abscess. Advantages of ultrasound are that it does not expose the patient to radiation or contrast material; however, ultrasound results are dependent on operator experience.⁷ Computed tomography (CT) and magnetic resonance imaging (MRI) demonstrate excellent anatomic detail and are more sensitive than intravenous pyelography and ultrasonography.⁷ Although numerous imaging techniques are available, most UTIs do not warrant radiologic evaluation. The appropriateness of imaging in the setting of a UTI is discussed later.

TREATMENT

Antimicrobial Principles

The successful treatment of a UTI depends on two important principles. First, the treatment should result in elimination of bacteriuria. This typically occurs hours after initiation of treatment.⁷ Second, the urine concentration of the antimicrobials must exceed the minimal inhibitory concentration (MIC) of the bacteria.²⁶ It is important to keep in mind that hospital micro-biology laboratories typically report bacterial sensitivities based on serum levels that may be several-fold lower than the urine levels of a particular agent.

Antimicrobial Resistance

The most common reason for unresolved bacteriuria is bacterial resistance to the chosen antimicrobial agent. There are several ways in which bacteria may be resistant. In natural resistance, certain bacteria simply lack a drug-susceptible substrate, rendering an entire species of bacteria resistant to a particular antimicrobial. Examples include Proteus resistance to nitrofurantoin and Enterococcus faecalis resistance to cephalexin.⁷ Resistance can also occur when the antimicrobial therapy actually selects for resistant mutants. This mode of resistance occurs within the urinary tract and can typically be avoided by choosing an agent with a urine concentration that exceeds the MIC by the greatest margin, adequate dosing, and stressing the importance of compliance with therapy.⁷ The third mechanism of resistance is extrachromosomal plasmid-mediated resistance, also known as transferable resistance. This mode of resistance takes place within the bowel and produces multiple resistant strains. To date, transferable resistance has not been demonstrated with nitrofurantoin or fluoroquinolones, and therefore these two drugs are good options for patients exposed to other antimicrobials.²⁷

Antimicrobial Selection

In selecting an antimicrobial agent, it is necessary to understand the efficacy, spectrum of activity, resistance patterns, side effects, dosing, and cost.²⁸ Individual antimicrobials are discussed later. Costs for a complete course of therapy of the antimicrobials based on 2001 wholesale prices are listed in Table 86-2.

Table 86-2 Antimicrobial Cost

Antimicrobial	Dose (mg)	Cost ($)
Sulfonamides
TMP-SMX	160/800 two times daily × 3 days	6.30-8.80
TMP	100 two times daily × 3 days	0.90-1.40
Fluoroquinolones
Ciprofloxacin	100-250 two times daily × 3 days	17.20-25.00
Levofloxacin	250-500 daily × 3 days	21.90-25.60
Nitrofurantoin macrocrystals
Macrodantin	100 four times daily × 7 days	47.00
Macrobid	100 two times daily × 7 days	23.00
β-lactams
Amoxicillin	250-500 three times daily × 3 days	6.40-11.50
Cefixime	400 daily × 3 days	23.20
Cefpodoxime	100 two times daily × 3 days	18.30

SMX, sulfamethoxazole; TMP, trimethoprim.

Modified from Jancel T, Dudas V: Management of uncomplicated urinary tract infections. West J Med 176:51-55, 2002.

Trimethoprim-sulfamethoxazole

Trimethoprim-sulfamethoxazole (TMP-SMX) blocks folic acid metabolism of bacteria, thereby preventing bacterial growth. TMP is effective as a single agent in uncomplicated UTI, has fewer side effects, and is safe for patients with sulfa allergies.²⁹ SMX has a synergistic bactericidal effect that improves the efficacy of the treatment of upper tract infections.³⁰ The combination of TMP-SMX is active against most aerobic gram-positive and gram-negative organisms. It is not active against enterococci or Pseudomonas aeruginosa.²³ Dosage is one double-strength tablet twice daily for 3 days for uncomplicated cystitis. Side effects may include rash, gastrointestinal upset, and photosensitivity.³¹ Serious adverse events may include Stevens-Johnson syndrome.²³ TMP-SMX should be avoided in pregnant patients as well as those taking warfarin.⁷

TMP-SMX has historically been the most widely used anti-microbial in the treatment of uncomplicated UTI, which may account for its high resistance rates. A recent study by Gupta and colleagues highlighted the fact that antimicrobial susceptibility patterns are dependent on geographic distribution. E. coli resistance to TMP-SMX ranged from 10% in the northeastern United States to 22% in the western United States.³² Risk factors for resistance to TMP-SMX include previous use of TMP-SMX and current use of other antimicrobials, as well as diabetes and recent hospitalization.²³

Nitrofurantoin

Nitrofurantoin inhibits several bacterial enzyme systems and is bactericidal. It is active against E. coli and most species of Klebsiella, Enterobacter, Staphylococcus, and Enterococcus. It is not effective against Pseudomonas or Proteus species.³³ A 7-day course of therapy is recommended for uncomplicated UTI, and it is also frequently used for UTI prophylaxis.²³ The agent does not penetrate urinary tract tissue or achieve bactericidal levels in blood and therefore is not recommended for complicated UTIs or pyelonephritis.³⁴ It also should not be used in patients with poor renal function, because adequate urine concentration levels will not be achieved.⁷ Side effects may include gastrointestinal upset, peripheral polyneuropathy, hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency, and pulmonary reactions ranging from cough to fibrosis.⁷ Nitrofurantoin exhibits very low levels of resistance.²³