CLINICAL UPDATES

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Urinary tract infections account for millions of office visits each year. Unfortunately, patients who have had one infection are at high risk for subsequent episodes, and antibiotic resistance is growing. In this article, the authors review the causes and diagnostic strategies, including self-diagnosis, discuss the current antibiotic therapies, and describe potential prophylactic options to prevent recurrent infections.

Acute, uncomplicated urinary tract infections (UTIs) include episodes of acute cystitis and acute pyelonephritis occurring in otherwise healthy, nonpregnant women with no functional or anatomic abnormalities of the urinary tract. They are among the most commonly encountered bacterial infections. In a survey of 2,000 adult women in the United States,1 10.8% reported having at least one UTI in the past 12 months, with the highest incidence (17.5%) reported by women aged 18 to 24 years. By age 26, one third of women have at least one physician-diagnosed UTI, and the lifetime incidence is 60.4%.1 Prospective studies of young adult women in Seattle, Washington, revealed an incidence of cystitis of 0.5 to 0.7 episodes per person-year.2

The strongest risk factors for cystitis in young women are related to sexual activity. Recent sexual intercourse and spermicide use increase the risk of cystitis several fold. History of UTI is also an important risk factor.2 Early age at the first UTI and a maternal history of UTI are independently associated with having a history of recurrent cystitis, suggesting that some women may have a geneticpredisposition.3

In postmenopausal women, the incidence of UTI is lower and the risk factors are different. In a recent prospective analysis of women aged 55 to 75 years,4 the incidence of acute cystitis was 0.07 per person-year. Sexual activity was less strongly associated than in younger women, whereas insulin-treated diabetes and a higher lifetime number of UTIs were shown to be risk factors. Urinary incontinence and estrogen supplementation have also been associated with UTI in older women, although the reasons for this are incompletely understood.5

Acute uncomplicated pyelo-nephritis is much less common than cystitis. A population-based analysis of South Koreans demonstrated an incidence of 59 diagnoses of pyelonephritis per 10,000 women.6 The incidence increases dramatically after the age of 15 years, and recurrence is not uncommon. The highest incidence of pyelonephritis occurs during the summer months. Risk factors in nonpregnant women are similar to those for cystitis and include frequent sexual intercourse, new sexual partner, spermicide use, history of UTI, and maternal history of UTI.7 Urinary incontinence and diabetes mellitus have also been associated with pyelonephritis.7

Sources and pathway of infection

Escherichia coli causes most epi-sodes of uncomplicated cystitis and pyelonephritis. In a US surveillance database, E coli was recovered from 72% of outpatient urine samples from women aged 15 to 50 years and from 53% of samples from women more than 50 years of age.8 Klebsiella pneumonia, Enterococcus species, and Proteus mirabilis were the next most commonly isolated organisms and were more common in women older than 50. Pseudomonas and other gram-negative rods also were more common in older women, whereas Staphylococcus saprophyticus was common in younger women. Other Staphylococcus species were recovered from 2% to 3% of women.

In the classic model of infection, the uropathogen originates in the fecal flora. Uropathogenic E coli possesses virulence factors, including adhesins such as type 1 fimbriae, that allow the bacteria to colonize the vagina and periurethral area and then ascend into the bladder.9 Mechanical activity, such as sexual intercourse, facilitates ascension of bacteria into the bladder.

Vaginal lactobacilli appear to interfere with this pathway to infection by preventing initial colonization with uropathogens. Lactobacilli interfere with E coli colonization through competitive exclusion and the production of lactic acid, antimicrobial bacteriocins, and hydrogen peroxide.10 An inverse association of H2O2-producing lactobacilli and vaginal E coli colonization has been documented.10 The association of sexual intercourse and spermicide use with UTI is felt to be in part related to reduction of H2O2-producing lactobacilli by the spermicide.

Recent research in mice has revealed another model of infection that may be important in recurrent UTI. E coli has been found to invade the uroepithelial cells, form large intracellular bacterial communities, and persist in a dormant reservoir protected from the host inflammatory response. The bacteria may then reemerge at a later time to cause UTI.11

Diagnosis

The diagnosis of cystitis can often be based on the patient's history alone. Differential diagnostic considerations include vaginitis due to Candida or Trichomonas, bacterial vaginosis, and cervicitis due to Neisseria gonorrhoeae, Chlamydia trachomatis, or herpes simplex.

A woman who presents to a physician for evaluation of cystitis symptoms has a 50% pretest probability of infection based on the prevalence of bacteriuria in symptomatic women. The presence of dysuria, urinary frequency, and hematuria together increases the probability of cystitis to 81%, and this combination of symptoms in the absence of a history of vaginal discharge increases this probability even more.12

Women with fever and back pain suggesting possible pyelo-nephritis or with a history of functional or anatomic abnormal-ities of the urinary tract, immuno-suppression, diabetes mellitus, pregnancy, or recent instrumentation should undergo a physical examination. Findings consistent with pyelonephritis include fever, costovertebral angle tenderness, and the absence of discharge on pelvic examination.12

The ability to accurately diagnose cystitis on the basis of the patient's history allows for the diagnosis and treatment of many episodes of cystitis by means of a telephone conversation with the patient. Success of a telephone management strategy was demonstrated in a population-based, before-and-after study of the treatment of uncomplicated cystitis at Group Health Cooperative in Washington state.13 After the introduction of a telephone-based algorithm, the proportion of patients with cystitis who had urinalysis, urine culture, or an office visit decreased substantially. There were no significant increases in the number of subsequent visits for cystitis or in the incidence of sexually transmitted diseases or pyelonephritis during the intervention period. Patient satisfaction was high.

New evidence also suggests that women with recurrent cystitis may be able to effectively self-diagnose UTI and initiate treatment. In a prospective study,14 female university students with a history of recurrent UTI were instructed to self-initiate anti-microbial therapy after the de-velopment of cystitis symptoms. Eighty-four percent of self-diagnosed UTIs were microbiologically confirmed, and 94% of self-diagnoses overall were felt to represent definite or probable UTI. The investigators concluded that self-diagnosis and self-initiation of therapy may be appropriate for adherent women with a history of recurrent cystitis and low risk for sexually transmitted diseases.

For patients in whom the diagnosis is less certain, urine dipstick analysis for the presence of leukocyte esterase or nitrites may be helpful. Such tests perform better in combination and in UTI associated with higher bacterial colony counts. A combined dipstick test negative for leukocyte esterase and nitrite has a high negative predictive value (84% to 98%) and can be useful in ruling out bacteriuria.15

Women with uncomplicated cystitis generally do not need a pretreatment or posttreatment urine culture. However, women with suspected pyelo-nephritis or evidence of a complicated infection should have a midstream clean-catch urine specimen evaluated for organism culture and antimicrobial susceptibilities. Patients with early recurrent cystitis or cystitis unresponsive to treatment should also have pretreatment cultures performed.15 Growth of a single uropathogen at a quantity as low as 102 colonyforming units per milliliter may indicate a significant infection in a symptomatic woman.15

Antibiotic therapy

In its 1999 guidelines,16 the In-fectious Diseases Society of America (IDSA) recommends a 3-day course of trimethoprim-sulfamethoxazole (TMP-SMZ) as standard therapy for acute cystitis (table 1). TMP-SMZ is an inexpensive antibiotic associated with a greater than 93% eradication rate for susceptible organisms.16 However, E coli resistance to TMP-SMZ has been determined to be as high as 18% in certain parts of the United States,8 and this raises concerns about the usefulness of this antibiotic in empiric treatment of UTI.

Women infected with TMP-SMZ-resistant organisms have been shown to have a much lower rate of microbiologic (42%) and clinical (54%) cure after treatment with TMP-SMZ.17 Therefore, it is important that clinicians learn to identify predictors of resistance in their individual patients, the most prominent of which is recent antibiotic use.

In a study of Michigan women,18 those who had taken TMP-SMZ in the 2 weeks preceding UTI were 17 times more likely to be infected with a TMP-SMZ?|resistant isolate. Use of any other antibiotic during that time was associated with a greater than twofold increase in risk.

In light of this information, TMP-SMZ remains an effective first-line therapy for cystitis in most women, but in areas with a high prevalence of resistance (>10% to 20%)16 or in patients who have had recent antibiotic use or risk factors for recent use, such as hospitalization, another agent may be more appropriate.

Alternatives to TMP-SMZ include nitrofurantoin (Furadantin, Macrobid, Macrodantin), fosfo-mycin (Monurol), and the fluoroquinolones. Resistance among urinary E coli to nitrofurantoin remains low,8 although resistance is higher among some other uro-pathogens. It may be most appropriate for use in women with mild to moderate symptoms in whom treatment failure is likely to have minor consequences. Single-dose fosfomycin is another alternative in women with mild symptoms. It is less effective than first-line agents, more costly than nitrofurantoin, and has significant side effects as well.16 Fluoroquinolones have the highest cure rates and are effective in 3-day regimens.16 Resistance is low but increasing.8 Therefore, fluoroquinolone use in the treatment of cystitis should be reserved for women with more severe symptoms or those with contraindications to other anti-biotics.

New safe and effective fluoroquinolone-sparing alternatives are needed. ??Lactam antibiotics have been studied but have been consistently shown to result in lower bacterial eradication rates and higher recurrence rates than traditional first-line agents.16 One reason is that the prevalence of ??lactam resistance is high.8 ??Lactams have also been proven to be less effective even against susceptible organisms.

In a recent randomized trial of 3-day regimens,19 the rate of clinical cure with amoxicillin-clavulanate was 58% compared with 77% with ciprofloxacin. The inferiority of amoxicillin-clavulanate was most notable within the first 2 weeks of treatment and was apparent even when the analysis was restricted to women infected with suscep-tible uropathogens. The investigators explained this in part by demonstrating the inferior ability of amoxicillin-clavulanate to eradicate E coli colonization of the vagina. Another proposed explanation was that the shorter serum half-life of amoxicillin results in a shorter period of active drug in the urine.

Further research is needed on the use of other extended-spectrum ??lactams, such as oral second- and third-generation cephalosporins. In the meantime, ??lactam antibiotics are not recommended as first-line therapy for cystitis.

For treatment of pyelonephritis, IDSA guidelines recommend a 14-day course of antimicrobial therapy.16 However, women with mild symptoms can be treated empirically on an outpatient basis with a fluoroquinolone; a 7-day regimen is sufficient in most cases. The efficacy and superiority of a 7-day course of oral ciprofloxacin over a 14-day course of oral TMP-SMZ was demonstrated in a multicenter, randomized, double-blind tria1.20 In an efficacy analysis, 96% of subjects receiving ciprofloxacin and 83% of subjects receiving TMP-SMZ had achieved clinical cure by 4 to 11 days after therapy ended. Subjects treated with TMP-SMZ who were infected with resistant organisms had significantly lower cure rates than subjects infected with susceptible organisms. A cost analysis revealed that short-course ciprofloxacin had a significantly lower cost per cure. TMP-SMZ is an alternative for susceptible organisms, and amoxicillin should be added to the empiric regimen if a Gram stain shows gram-positive organisms.

Women with high fever, high white blood cell count, vomiting, dehydration, or sepsis should be hospitalized and treated with a parenteral fluoroquinolone, aminoglycoside with or without ampicillin, or an extended-spectrum cephalosporin with or without an aminoglycoside. Ampicillin-sulbactam (Unasyn) is recommended for gram-positive infections.16 Fortunately, methicillin-resistant Staphylococcus aureus remains a very uncommon cause of uncomplicated cystitis or pyelonephritis. After symptoms improve, patients can complete therapy as outpatients with an oral regimen.

Prophylaxis

Researchers continue to look for nonantibiotic agents that may prevent UTI and subsequent anti-biotic use (table 2). Cranberry juice is one possible option. Cranberries contain proanthocyanadin, a compound that inhibits the adherence of E coli to uroepithelial cells.21 Women who drank cranberry-lingonberry juice daily were found to have a significantly decreased incidence of recurrent UTI.21 Optimal dosing and administration, however, have yet to be defined. Trials are ongoing.

Treatment with intravaginal estrogen has been shown to decrease the incidence of recurrent UTI in postmenopausal women.22 Estrogen use appears to restore the normal vaginal flora and reduce the risk of vaginal colonization by E coli.

Restoration of the vaginal flora through administration of a Lactobacillus probiotic also has the potential to prevent UTI in high-risk women. Candidate lactobacilli would include those H2O2-producing species most commonly found in the normal flora, Lactobacillus crispatus and Lactobacillus jensenii.23 The optimal route of administration of these or other species is yet unknown. Trials are ongoing to determine whether such probiotics can prevent recurrent UTI.

Finally, vaccines against E coli and other uropathogens have been proposed. Mucosal and parenteral vaccines targeted at E coli and other uropathogens are being studied.23 Although these show promise, they are not yet available for clinical use.

Summary

UTI continues to be a common problem for otherwise healthy adult women. Treatment of UTI has become more difficult because of the rising levels of resistance to commonly used antibiotics. Further research is needed to develop new antibiotic therapies and nonantibiotic prevention measures.

Dr Czaja is an infectious diseases fellow of medicine, division of allergy and infectious diseases, department of medicine, University of Washington School of Medicine, Seattle, WA 98195. Dr Hooton is professor of medicine, division of allergy and infectious diseases, department of medicine, University of Washington School of Medicine, Seattle, WA 98195.
Correspondence: Christopher A. Czaja, MD, Division of Allergy and Infectious Diseases, Department of Medicine, BB-1223, University of Washington School of Medicine, Box 356523, Seattle, WA 98195. E-mail: czajac@u.washington.edu.

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