Urinary Tract Infection: Risk Stratification, Clinical Evaluation, and Evidence-Based Antibiotic Therapy

Part I: Epidemiology, Emerging Resistance Patterns, and Patient-Specific Treatment Strategies

Authors: Romolo Gaspari, MD, FACEP, Research Director, Assistant Professor, Department of Emergency Medicine, University of Massachusetts School of Medicine, Worcester, MA; and Gideon Bosker, MD, FACEP, Assistant Clinical Professor, Yale University School of Medicine, New Haven, CT.

Peer Reviewers: David S. Howes, MD, FACEP, Program Director and Chairman, Residency Program, Department of Emergency Medicine, University of Chicago Hospitals and Clinics, Associate Professor, Pritzker School of Medicine, Chicago, IL; and Ralph J. Riviello, MD, FACEP, Assistant Professor, Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA.

In the constantly shifting landscape of drug resistance, antibiotic options, and pharmacoeconomic considerations, urinary tract infection (UTI) continues to be one of the most frequently diagnosed conditions in patients presenting to the emergency department.

It is estimated that practitioners manage 7 million new cases of cystitis in the United States each year and that, overall, UTIs account for approximately 1 million hospitalizations annually.1,2 Moreover, UTIs are the leading cause of gram-negative bacteremia in patients of all ages, and are associated with a high risk of morbidity and mortality, especially in the elderly.3 The total annual cost of treatment is in the billions of dollars.4

Among common infections managed in the outpatient setting, few conditions have treatment guidelines, antibiotic selection strategies, or diagnostic protocols that have changed or evolved as rapidly as those used for UTI. Despite a general consensus that empiric treatment of UTI in adult women requires, at the very least, mandatory coverage of Escherichia coli and other gram-negative organisms, antibiotic selection strategies—including initial choice of therapy and duration of treatment—vary widely among practitioners and institutions.

There are many reasons for inconsistencies in the current approach to UTI management among hospital-based physicians. Unfortunately, deciphering the strengths and weaknesses of recommendations issued by different authoritative sources can be problematic and confusing, especially since resistance patterns of infecting uropathogens may vary among geographic regions, and because outcome-effectiveness, medication compliance, failure rates, total-resource costs to achieve clinical cure, the risk of recurrent infection, and evolving bacterial resistance issues are not always entered into the drug selection equation.

Because no single set of guidelines is applicable to every patient or hospital practice environment, management guidelines for UTI must be "customized" for the local practice setting and, as always, clinical judgment must prevail. This means taking into account local antibiotic resistance patterns, epidemiological and infection incidence data, and patient demographic features.

Important, new therapeutic options that have been introduced into the antimicrobial armamentarium for uncomplicated UTI offer clinicians compliance-enhancing strategies that can improve clinical outcomes. In this regard, recent introduction of extended release ciprofloxacin (Cipro XR®) has made it possible to enhance medication compliance through once-daily administration of what has been considered to be the "gold standard" antibiotic (ciprofloxacin) for uncomplicated UTI, while at the same time making available a preparation that achieves an area under the curve (AUC) that is equivalent to conventional BID ciprofloxacin and achieving a Cmax that is 40% higher than the conventional BID formulation.

From a practical clinical perspective, because of its potentially compliance-enhancing properties (once-daily dosing and a well-tolerated side effect profile), extended release delivery system, and clinically effective urine concentrations, the extended-release formulation represents a risk-management upgrade from BID ciprofloxacin; therefore, it should replace the older formulation as the clinical standard for treatment of uncomplicated UTI when indicated. A well-designed clinical trial comparing the new and conventional formulations supports this shift to the once-daily, extended-release formulation and is described in this review.

Even when these factors are considered, a number of important questions about drug selection issues for UTI still remain: 1) What is the appropriate initial, empiric choice for uncomplicated UTI? Once-daily (QD) extended-release ciprofloxacin (Cipro XR®) or trimethoprim-sulfamethoxazole (TMP-SMX)? 2) What are the specific "intensification and treatment trigger" criteria that support amplifying initial spectrum of coverage from TMP-SMX to a fluoroquinolone such as extended release ciprofloxacin? 3) How should evolving resistance of E. coli to TMP-SMX affect initial antimicrobial therapy? 4) What is the optimal duration of therapy for uncomplicated and complicated UTIs? 5) Which antibiotic currently provides correct spectrum coverage, safety, and reliability for outpatient treatment of uncomplicated UTI?

Although optimizing cure rates with so-called convenient, dose- and duration-friendly branded agents that provide appropriate and predictable coverage with a low risk of antimicrobial resistance may be perceived as costly on a drug-acquisition basis, it is important to stress the following point: Antimicrobial agents with more predictable coverage against pathogens implicated in UTI can help avoid the unnecessary costs of treatment failures, disease progression, patient re-evaluations, return visits, patient dissatisfaction, and the pharmacological reservicing costs associated with initiating a second course of antibiotics.5

In this sense, antibiotics that lower barriers to clinical cure and provide a predictable spectrum of coverage can be seen as "productivity tools" that improve efficiency of clinical care and potentially reduce the overall costs associated with inpatient and acute outpatient management of UTI.

In light of the important advances, changes, and refinements that have occurred in the area of UTI treatment during the past year, this comprehensive, state-of-the-art review presents a revised and updated set of guidelines outlining UTI epidemiology and management in outpatient and hospital-based settings. Special emphasis has been given to both epidemiological data demonstrating the importance of correct spectrum coverage with specific fluoroquinolones, such as ciprofloxacin, and the selection of initial antibiotics for patients deemed suitable for discharge.

In addition, detailed evidence-based analysis comparing ciprofloxacin to TMP-SMX is presented to guide antibiotic selection in patients with uncomplicated UTI and pyelonephritis.5 Cautionary notes about the overuse of extended spectrum fluoroquinolones are outlined, and evidence-based studies confirming ciprofloxacin’s workhorse role in hospital-based treatment of UTI is discussed. Drawing upon consensus panels, expert opinion, and clinical trials, this clinical consensus report presents antimicrobial protocols and treatment guidelines linked to, and driven by, risk-stratification criteria, evidence-based trials, and specific clinical profiles of patients presenting to the hospital with symptoms and signs suggestive of UTI.The Editor


Introduction

Changing resistance patterns observed with common urinary pathogens have altered the empirical approach to antibiotic selection for both upper and lower UTIs. Previously, decisions regarding antimicrobial therapy have been made based on patient characteristics and the anticipated spectrum of urinary flora. However, increasing levels of resistance to beta-lactams during the past decade has decreased the utility of this drug class for treatment of UTIs. In addition, emerging resistance among E. coli species to TMP-SMX also is affecting initial drug selection choices for UTI, a change characterized by the acceptance of fluoroquinolones such as extended release ciprofloxacin as the initial agent of choice for greater than 90% of uncomplicated UTIs seen in the outpatient setting.

Epidemiology

Acute UTI is one of the most common illnesses encountered in adult women, resulting in as many as 8 million office visits per year6 and at least 100,000 hospital admissions.7,8 Although the exact frequency of UTI is not known, based on current evidence accumulated from office and hospital surveys, it is estimated that there are approximately 7 million episodes of cystitis9 and 250,000 episodes of pyelonephritis10 annually in the United States. One prospective study determined the annual incidence of cystitis to be 0.5-0.7% per person-year.11

Although many cases of uncomplicated UTI resolve with only transient, mild symptoms, studies suggest considerable morbidity and mortality are associated with all forms of UTI. Two independent studies12,13 found that asymptomatic bacteriuria in the elderly was associated with an increased mortality rate; however, this is not a universal finding.14,15 Certain patient populations, in particular those with diabetes and pregnancy, have been found to have a higher level of morbidity.16,17 Studies reviewing simple cystitis also have revealed substantial morbidity, with limited activity lasting for more than two days.18 As many as 60% of elderly patients with pyelonephritis will develop bacteremia, and 20% of these cases will result in septic shock.19 Life-threatening bacteremia as a complication of UTI also has been documented by a number of other investigators.20-24

UTIs in women vastly outnumber those in men.25 This may be related to such factors as the length of the urethra, distance of the urogenital meatus from the anus, and the antibacterial properties of prostatic fluid.26 Regardless of the reason, the fact that male UTIs are so uncommon has led many authors to classify them as complicated. This is supported by the high degree of virulence found in male UTI isolates, and the high prevalence of non-E. coli UTIs.27

Microbiology and Emerging Resistance Patterns

For many years, pathogens associated with uncomplicated UTIs remained constant, with E. coli identified as the etiologic agent in about 75-90% of infections.25 Five to 15% of uncomplicated UTIs are caused by Staphylococcus saprophyticus,28,29 with Klebsiella, Proteus, Enterococcus, and Pseudomonas species seen in much smaller percentages.30-32

The emergence of E. coli isolates demonstrating resistance to commonly used antibiotics, especially to TMP-SMX, is changing initial drug selection patterns in patients with both uncomplicated and complicated UTIs. The most common uropathogens identified in adult patients with UTI include enteric gram-negative bacteria, with E. coli being the most common. (See Table 1.) The remainder of infections are caused by coagulase-negative Staphylococcus saprophyticus (10-20%), while Proteus mirabilis, Klebsiella, and Enterococcus account for less than 5%.3,33,34 Other aerobic gram-negative bacteria of the Enterobacteriacea family include Citrobacter, Enterobacter, Serratia, and Salmonella.35-37 Non-enteric aerobic gram-negative rods such as Pseudomonas and aerobic gram-positive cocci such as Enterococcus are less prevalent in immunocompetent hosts. (See Table 1). Group B streptococci infection is observed in neonates secondary to inoculation from a colonized mother during delivery through the vaginal canal.

Anaerobic bacteria rarely are pathogenic despite their prevalence in fecal flora. The Lactobacillus species, coagulase-negative staphylococci, and Corynebacterium are not considered clinically significant isolates in the urine of healthy children between 2 months and 2 years of age.1,38 Corynebacterium, Lactobacillus, and Streptococcus species are identified only rarely; when present in this age group, they nearly always represent contamination of the specimen rather than a true pathogen. In complicated UTI, in addition to E. coli, there is a higher prevalence of Pseudomonas, Enterobacter species, Serratia, Acinetobacter, Klebsiella, and enterococci.39 There are anecdotal reports of treatment for Gardnerella vaginalis, lactobacilli, Chlamydia trachomatis, and Ureaplasma urealyticum in pregnant women, but it is unclear whether these organisms represent true pathogens in this population.40,41 Candidal species now are emerging in greater numbers, especially in catheterized patients and those who received previous treatment for enterococcal UTIs.39

The high incidence of UTIs in the general population; the potential for complications, especially in high-risk subgroups; and the associated costs of treatment emphasize the importance of appropriate antibiotic therapy. Microbial resistance to nearly all classes of antimicrobials continues to rise despite increasing awareness and concerns worldwide. European studies have shown E. coli resistance rates to multiple antibiotics, specifically TMP-SMX, in as many as one-third of patients.42,43 Similar trends in the United States have prompted a shift to fluoroquinolones such as ciprofloxacin as preferred initial agents for empiric intravenous and/or oral therapy of UTI in both hospital and emergency department settings.44

In a cross-sectional survey of urine cultures obtained in the emergency departments of urban tertiary care centers in the United States, microbial resistance was as high as 48% to ampicillin, 25% to tetracycline, 14-28% to TMP-SMX, and 13% to nitrofurantoin.45 Similar studies have shown that the resistance to ciprofloxacin among common uropathogens, including E. coli, frequently encountered in hospital-managed UTI is as low as 1-2%.46-50

These epidemiological data have important treatment implications, since recent studies also already are demonstrating outcome differences in clinical efficacy and patient cure rates between UTI patients managed on TMP-SMX and those managed on ciprofloxacin.51 As would be expected, maintenance of predictable antimicrobial activity by ciprofloxacin against the anticipated spectrum of uropathogens has solidified the role of this antibiotic in treatment pathways for UTI among all institutional settings.

Surveillance and Sensitivity. Hospitals affiliated with managed care organizations also have been prompted to re-evaluate their initial approach to antibiotic selection for UTI. A cross-sectional survey of 4000 urine cultures obtained from women ages 18-50 in an HMO setting between 1992 and 1996 showed E. coli prevalence to be 86%, with the resistance rate to TMP-SMX increasing during this period from 9% to 18%. Recent data suggest that in some regions of the country, especially the West, Southwest, and in most major urban centers, the resistance rate to TMP-SMX has risen to as high as 35%.5,42,43,52-55 The overall resistance to multiple groups of antimicrobials, including the penicillins, cephalosporins, and sulfa drugs, doubled from 8% to 16%.56 In pregnant patients, E. coli resistance to ampicillin, which at one time was a drug of choice for UTI in this population, is now about 20-30%.41

Fortunately, one class of antimicrobials to which sensitivity rates have remained consistently high is the fluoroquinolone group, of which ciprofloxacin is the most frequently used in the adult population. A two-tiered study from 1989 to 1991 and 1996 to 1997 at an urban sexually transmitted disease clinic evaluated young, sexually active females diagnosed with a UTI and found E. coli resistance rates to ampicillin, cephalosporins, or tetracycline in as many as 25% of patients. There was very little change in the low prevalence of organisms resistant to fluoroquinolones.57

Additional studies at student health clinics in California during a five-year period demonstrated significant increases in the resistance of E. coli to ampicillin (30-45%), tetracycline (29-40%), and TMP-SMX (15-32%), with resistance to fluoroquinolones in fewer than 5% of organisms.34 In a recent analysis of young women with uncomplicated pyelonephritis, E. coli was isolated in more than 90% of cultures and was resistant to TMP-SMX in 18%, compared with a 0.4% resistance to ciprofloxacin. A significant variance in resistance patterns existed in different geographic regions, with resistance to TMP-SMX as high as 35% on the West Coast of the United States as opposed to 14% in the Midwest and 7% on the East Coast.51 One caveat regarding bacterial resistance is that in vitro sensitivity results may not correlate with clinical cure rates and in vivo sensitivity. Eradication of a uropathogen depends on the concentration of antibiotics in the urine as opposed to serum, which may be higher than the levels used in in vitro studies.39

Recent studies have noted a subtle shift in etiologic agents associated with UTIs. A survey of all UTI pathogens in 1997 found the top four isolates to be E. coli (48.6%), Enterococcus spp (13.7%), Klebsiella spp (12.0%), and Pseudomonas aeruginosa (6.2%).58 More current data from 1998 support these trends.59 This shift in pathogens may be related to factors such as bladder catheterization or antibiotic use. Another study reported a similar mix of uropathogens in catheter-associated UTIs.60 Not surprisingly, bacterial isolates found in complicated UTIs follow a similar pattern.61,62 (See Table 2.)

Although there are fewer data on patients with pyelonephritis, recently published surveys indicate a similar mix of pathogens, with about 90% of patients with pyelonephritis manifesting infection with E. coli.64,65 Other isolates included those found in lower UTIs. Urethritis usually is caused by Chlamydia trachomatis, Neisseria gonorrhoeae, or herpes simplex virus.

Escherichia coli (E. coli) Resistance. The sensitivity of a urinary tract pathogen to a specific antimicrobial agent is defined by measuring the bacteria’s ability to grow in the presence of that antibiotic. In the case of E. coli, if the strain under evaluation can grow in media containing 2 mcg/mL or greater (mean inhibitory concentration or MIC) of the antibiotic, the strain is considered resistant to that antibiotic. Potential confusion arises when the reported resistance levels are related to the blood concentration of antibiotic and not the urine concentration. As a rule, antibiotics used for UTIs are concentrated in the urine and have higher urine levels than blood levels. Therefore, isolates that are reported resistant to an antibiotic by laboratory testing actually may be eradicated by the antibiotic in the in vivo environment. This concept is clinically relevant and has been demonstrated in a number of studies.28,66,67

Due to the consistent, relatively predictable spectrum of pathogens encountered in UTIs, empiric therapy represents an appropriate strategy for the majority of patients, whether they present in the outpatient, emergency department, or in-hospital setting. Historically, empiric therapy using any one of a wide range of agents has proven clinically successful for UTI. Until recently, high cure rates could be expected because a predictable group of urinary pathogens have manifested a low degree of resistance to most antibiotics selected on an empiric basis. However, a number of recent studies have highlighted evolving changes in antimicrobial resistance patterns to E. coli. In particular, clinically and microbiologically significant changes in resistance to TMP-SMX among E. coli species, and in a small percentage of cases, to fluoroquinolones have been reported in Europe68,69 and the United States.30-32,59,70

Resistance and Implications for Antibiotic Therapy—Fluoroquinolones Emerge as Initial Agents of Choice. Evolving changes in drug resistance dramatically have altered the approach to empiric therapy of UTI. Although beta-lactams, sulfa-based antibiotics, and fluoroquinolones each have their place in the treatment of UTI, their roles are changing, with fluoroquinolones emerging as initial agents of choice, even for uncomplicated UTI. Penicillin-based antibiotics once were a mainstay of UTI treatment, but current resistance rates among E. coli (approaching 40% in many regions) have limited their effectiveness.30,71,72 Although E. coli resistance to fluoroquinolones in the United States has not reached the levels encountered with other antibiotics,25,28,72 the level of resistance in other countries is alarming.73,74 In the United States, however, increasing E. coli resistance to TMP-SMX has been accompanied by a paradigm shift in the initial treatment of choice for UTI (please see below).31,75-78

The level of E. coli resistance to TMP-SMX has more than doubled during the past 12 years and now exceeds 25% in some areas of the country.79-81 One group of investigators examined a cross-section of urinary isolates from 1992 to 1996 and found an increase of TMP-SMX resistance from 9% to more than 18%.72 Subsequent, larger studies have shown similar results.79-81 Resistance rates in the United States vary from region to region, and knowledge of local resistance rates are important factors when determining initial antibiotic therapy.31

Most experts and national association panels concur that sequential selection strategies for antibiotic therapy in UTI, to a significant degree, should depend on the degree of E. coli resistance to TMP-SMX in a particular community. In this regard, the Infectious Disease Society of America (IDSA) recommends that alternative antibiotics (i.e., agents other than TMP-SMX) should be used as first-line therapy in areas of the country where TMP-SMX resistance is greater than 10-20%.78 More specifically, the clinical outcome and pharmacoeconomic implications of fluoroquinolones vs. TMP-SMX therapy have been linked to a 20% E. coli drug resistance cut-off point.

With this antibiotic preference issue in mind, two published studies have examined the effect of E. coli resistance rates on patient outcomes75 and economic parameters.82 One study concluded that the clinical effectiveness of fluoroquinolones such as ciprofloxacin was superior to TMP-SMX when more than 10% of the E. coli isolates were resistant to TMP-SMX.75 At a 20% resistance rate, nitrofurantoin also was superior to TMP-SMX. Another study, using a cost-analytical model, approached the issue of antimicrobial selection from a different angle. Performing a cost analysis of first-line UTI antibiotic options—examining the desirability of one agent vs. another through the prism of increasing antibiotic resistance rates—these investigators found progressive cost savings to the community when a fluoroquinolone was substituted for TMP-SMX as initial agents of choice in areas characterized by a 20% or greater resistance rate among E. coli to TMP-SMX.82 Although authorities identify different resistance rate breakpoints that would favor a shift to a fluoroquinolone as first-line therapy, there is general agreement that the greater the resistance rate, the greater the clinical and pharmacoeconomic benefits to fluoroquinolone use.

It should be stressed that the fluoroquinolones are not immune to the selective pressures causing antibiotic resistance in UTI isolates. Studies in some foreign countries, where there has been heavy use of this class of antibiotics, have shown increasing rates of resistance. A multi-center study found E. coli resistance to ciprofloxacin in 36% and 20% of urinary isolates from Portugal and Spain, respectively.30 However, most studies of urinary isolates in the United States show only a 1-4% resistance rate to fluoroquinolones.31,59

Multi-drug resistant uropathogens are becoming increasingly common across the United States. One retrospective study found that 37% of UTI isolates from emergency department patients were multi-drug resistant.32 A larger national study of inpatients as well as outpatients looked at almost 39,000 urinary isolates from patients with UTIs and found the number of multi-drug resistant isolates to be 7.1%. Among the resistant strains, 98% were resistant to ampicillin and 93% were resistant to TMP-SMX. The resistance to ciprofloxacin and nitrofurantoin was 39% and 8%, respectively.79

Urinary Tract Infections in Women—Principles of Management

Asymptomatic Bacteriuria. Asymptomatic bacteriuria is a well-documented entity that affects women of all ages. A number of large-scale population studies have shown the prevalence of asymptomatic bacteriuria to be directly related to age, with a 1-2% rate in young women, 6-10% in women older than age 60,83 and 15-20% in women ages 65 and older.15,84,85 These rates only represent a "snapshot in time," inasmuch as studies have demonstrated a "turnover" of bacteriuria from positive to negative and back again during sequential six-month urine cultures.86,87

As a rule, asymptomatic bacteriuria (ASB) should not treated in most patients, since multiple studies have shown that antibiotic therapy does not make a significant impact on long-term outcomes in an otherwise healthy adult population.88 A recent prospective study of asymptomatic bacteriuria in sexually active young women found prevalence rates of approximately 5%, with 8% of those women developing symptomatic UTI within one week.89 Specific groups benefiting from antibiotic treatment include pregnant women, neutropenic patients, patients with abnormal renal function, renal transplant recipients in the early post-transplantation period, and men and women planning to undergo urologic procedures.3,89

Infants with ASB represent a low-risk population for the development of UTIs, with a tendency toward spontaneous abacteriuria within a few months, and do not generally require antibiotic treatment.90 School-age children usually are left untreated; however, patients with underlying voiding disorders should be referred appropriately for further evaluation and treatment.

Pregnant women with ASB should be treated with a three- to seven-day course of antibiotics, followed by a subsequent culture to ensure sterilization of urine. Despite increasing resistance rates to ampicillin, amoxicillin and cephalosporins remain a first-line choice in these patients. Ceftriaxone is the preferred agent in pregnant women. Nitrofurantoin is becoming a first-line drug, because it is efficacious, inexpensive, and well-tolerated. The only contraindication to using this drug is in patients with G6PD deficiency, in whom hemolysis can occur. TMP-SMX remains a first-line agent in areas of low resistance, but should be avoided in the first and third trimesters secondary to possible teratogenic effects and the risk of kernicterus from competitive binding of TMP-SMX to bilirubin binding sites. At this time there is no clear evidence to support a single-dose regimen over a typical three- to seven-day course.40,91 A properly sized, randomly controlled trial is recommended for comparison of these regimens, as a single dose has lower cost, fewer adverse effects, and increased compliance compared with longer treatment regimens.91

Initial evidence in the elderly population had suggested an increased risk of morbidity and mortality in patients with ASB. More recent studies have challenged these reports, but have failed to identify a connection between ASB and an increase in long-term sequelae such as hypertension or end-stage renal disease. Up to 40% of the elderly will have ASB at some time. Aggressive screening and treatment have little effect on decreasing symptomatic or clinically significant infection and associated complications.3 Catheterized patients, including those with neurologic disorders or spinal cord injuries, rarely require aggressive work-up and treatment unless symptoms intervene.93 Interestingly, a recent study of catheterized patients found that catheter-associated UTIs are rarely symptomatic and infrequently cause bacteremia (< 1%). No significant differences were noted between symptomatic and asymptomatic bacteriuria groups with regard to signs and symptoms commonly associated with infection (i.e., fever, dysuria, urgency, or flank pain) or leukocytosis.94 Investigations have noted that both groups are a major reservoir for antibiotic resistant organisms in the hospital setting.

The long-term consequences of asymptomatic bacteriuria have not been fully elucidated, but this condition may have the potential to cause symptomatic UTIs and/or sepsis in a small minority of patients, although such sequelae have not been uniformly substantiated. In addition, the potential for persistent bacteriuria and recurrent UTI to decrease survival continues to be debated, with some investigators finding an association12,13 while others have not.14,15 A recent, well-conducted analysis of patients with asymptomatic bacteriuria failed to show an increase in mortality when comorbid factors were accounted for.95 In summary, most experts currently do not recommend treatment for asymptomatic bacteriuria, except in the high-risk patient populations identified above.83,96

Uncomplicated Lower Urinary Tract Infection. The majority of uncomplicated lower UTIs occur in patients who have no functional or anatomical abnormality of their urinary system. Lower UTIs can be categorized into two distinct categories: cystitis and urethritis. In the emergency department, it may be difficult to distinguish between uncomplicated and complicated cystitis. As a rule, however, the clinician will be able to distinguish between cystitis and urethritis on the basis of history and physical exam. Symptoms of urethritis overlap with cystitis, but urethritis usually has a more gradual onset with milder symptoms and little to no urgency or frequency. Associated vaginal discharge or lesions may make the diagnosis more apparent. It usually is reasonable to assume that a young, non-pregnant female with acute onset of dysuria and frequency has a simple cystitis if she has not had any instrumentation or recent antibiotic therapy.

Certain patient populations are at an increased risk for developing a UTI. One group has determined that recent sexual intercourse, diaphragm use, and a history of previous UTIs are independent risk factors for developing a UTI.11 Although the study population was limited to college age women, other studies that included older women have demonstrated similar risk factors.97 However, these risk factors are not universally agreed upon and many patients with a confirmed diagnosis of UTI will cite no risk factors.

Complicated Lower Urinary Tract Infections and High Risk Patients. Complicated UTIs typically occur in patients who have an underlying urinary tract abnormality causing obstruction. The abnormality may be a physical obstruction (i.e., kidney stone or bladder catheter), or it may be a functional abnormality (i.e., neurogenic bladder or vesicoureteral reflux). Infections in patients with such disease states as diabetes or renal failure, as well as renal transplantation, also fall into the category of so-called complicated UTI. (See Table 3.) Complicated UTIs encompass patients with a wide variety of syndromes and risk factors that increase the likelihood of poor outcomes. Moreover, studies aimed toward evaluating etiological agents in complicated infections demonstrate a broad range of microbial pathogens, of which E. coli is the most common.63

An associated concept is the high-risk patient with UTI, which would include individuals who are pregnant, immunosuppressed, or those who have an indwelling catheter. High-risk patients may or may not have a urogenital abnormality, but the potential sequelae of UTI in these subgroups may overlap with those encountered in patients with complicated infections; as a result, some authors use the terms interchangeably. From a clinical perspective, the important concept is that both patients who have a complicated UTI and those deemed at high risk require more prudent management, which includes a longer duration of therapy and closer follow up.

Upper Urinary Tract Infection. Upper UTI generally refers to pyelonephritis and its potential complications, including perinephric abscess. Many studies have confirmed that pyelonephritis occurs through ascending infection from the bladder.98,99 It is thought that fecal organisms inoculate the urethra, spread into the bladder, and subsequently ascend the ureters to the kidney parenchyma. The incidence of pyelonephritis is much lower then that of cystitis, although the morbidity and mortality are much greater.25 Acute pyelonephritis can progress to chronic pyelonephritis or perinephric abscess depending on host factors such as immune status and obstruction.100

Symptoms of pyelonephritis can vary from dysuria to fulminant urosepsis. Only 20-30% of patients with isolated dysuria actually will have subclinical pyelonephritis.101-103 Patients with subclinical pyelonephritis present with symptoms characteristic of cystitis, but infection is located in the kidney. Subclinical pyelonephritis is impossible to differentiate from cystitis without complicated localization techniques that mostly are used in research studies. Most patients with symptomatic pyelonephritis will present with flank pain, nausea, vomiting, fever, and costovertebral angle tenderness.104

Diagnostic Strategies in Urinary Tract Infection: Urinalysis, Culture, and Imaging Studies

The majority of patients with UTI present with unambiguous symptoms and signs suggestive of this disease process, and therefore, present few diagnostic challenges for the astute clinician. However, a minority of infections, especially those encountered in the elderly or immunocompromised individual, may be more clinically challenging. For example, most clinicians would have little difficulty making the diagnosis of UTI in a young woman presenting with one day of dysuria and frequency, whereas diagnostic challenges are likely to surface when UTI causes obtundation in an elderly male. Because a number of modalities are available for diagnostic evaluation, the practitioner must determine which laboratory tests and/or imaging modalities are appropriate and cost-effective in individuals presenting with symptoms suggestive of UTI.

Diagnostic Approach. Clinical experience suggests that most uncomplicated lower UTIs encountered in the outpatient setting can be diagnosed (and cured) without the use of urine cultures.75 Accordingly, patients who present with symptoms consistent with cystitis or urethritis should undergo a history, physical exam, and urinalysis. The use of dipstick urinalysis and/or microscopic urinalysis provides a diagnostic yield that is sufficiently specific and sensitive to establish the diagnosis of uncomplicated UTI.105 Due to the increased morbidity and mortality associated with pyelonephritis and UTI in high-risk patients, a urine culture still is recommended for the work-up in this patient subgroup.

Urinalysis. A urinalysis continues to be the "workhorse" laboratory evaluation for establishing the diagnosis of UTI in a broad range of patients; therefore, it is the principal modality employed for the work-up of UTI. The primary utility of a urinalysis is to examine for and document the presence of pyuria, hematuria, nitrates, leukocyte esterase, and bacteria. Although semi-quantitative dipstick and microscopic urinalysis are widely used and have been extensively reviewed in the literature, studies are conflicting as to their accuracy.105-110

The presence of red or white cells in the urine can help differentiate the location of the infection. Pyuria is present in almost all patients with urethritis, cystitis, and pyelonephritis. The laboratory/clinical definition of pyuria (number of white cells per high-powered field [hpf]) will affect its sensitivity and specificity for establishing the diagnosis of UTI. One group found that the presence of greater than 5 WBCs per hpf was 85% sensitive for UTI, whereas other authors111 have reported that greater than 10 WBCs/hpf was a more reliable breakpoint for making the diagnosis.107 The presence or absence of pyuria should be interpreted within the context of other findings in the urinalysis. Hematuria can be present with cystitis and pyelonephritis but rarely is seen in urethritis.25 It can be diagnosed semi-quantitatively with a urine dipstick or quantitatively on a microscopic urinalysis. Studies looking at dipstick hematuria have found a sensitivity and specificity of 44% and 88%, respectively.112 Microscopic analysis of the urine also may demonstrate red cell casts that are indicative of upper tract disease.

Several unique esterases produced by neutrophils in the urine form the basis of one of the screening tests for UTI. The leukocyte esterase can be detected rapidly using a urine dipstick, which appears to provide a reliable method for detecting pyuria. Studies have shown that the leukocyte esterase has a sensitivity in the range of 74-96% and a specificity of about 94-98%,108,113,114 although this may not distinguish the presence of pyuria with this degree of accuracy in clinical practice.112,115

The nitrite test on a dipstick urinalysis is a rapid screening test for bacteriuria. It has been found to be 39% sensitive and 93% specific for bacteria in the urine in both prospective and retrospective studies.105,107,112 One investigation combined nitrate results with the presence of microscopic bacteriuria and/or pyuria (> 10 WBCs per hpf) and found a sensitivity and specificity in the range of 71-95% and 54-86%, respectively.107 Other studies have found that the accuracy of this test can be affected by a low level of infection20 or the type of infecting microorganism.116

Urine Culture. Bacteriuria is considered by most clinicians to be the definitive marker of UTI. Studies conducted in the 1950s found that 105 colony forming units (cfu) per milliliter was indicative of a UTI.117,118 However, more recent studies suggest that this level of bacteriuria may miss a large group of UTIs, and support the concept that lower levels (102-104 cfu) should be considered positive.7,119 In one provocative study, patients provided urine samples when a diagnosis of UTI was suspected, but they were not treated for two days after onset of symptoms. A repeat urine culture was obtained two days later at which time empiric treatment was started. Interestingly, urine cultures cleared spontaneously in only 5% of the patients who had a low colony count initially, while 48% now had a colony count of 105 or more.120

It should be emphasized that lower levels of bacteriuria have been shown to predict UTIs in a variety of settings. Levels greater than 102 have shown a sensitivity of 95% and a specificity of 85% for the diagnosis of cystitis in women.121 Male patients with urine samples growing greater than 103 cfu/mL are considered positive for UTI.26 All patients with pyelonephritis have been found to have a higher level of bacteriuria, with cultures almost uniformly growing at levels greater than 104 cfu/mL.117,122 In summary, studies suggest that antibiotic therapy should be considered for any patient with symptoms of a UTI and a culture positive for 103 cfu/mL or greater of a urinary tract pathogen.

Urine Collection. The method by which urine is collected has received little attention in the scientific literature. The most commonly recommended collection technique for women is either a mid-stream clean-catch urine sample, or an in-and-out catheterized specimen. Despite the effort that goes into instruction for a mid-stream clean-catch urine sample, contamination is a frequent problem.123 There is little rigorous scientific research that supports a mid-stream clean-catch urine sample as the standard for urine collection. In one study, urine samples randomly were collected by one of two techniques. One group received instructions on cleaning and technique for obtaining a mid-stream clean-catch urine specimen. The other group did not clean, and no other instructions were given. There was no difference in contamination between the groups. Studies in men revealed similar results.124,125

In-and-out sterile catheterization is the most reliable method to obtain a urine sample from women. This procedure has the lowest chance of contamination from vaginal or perineal flora and has a low risk of complications. There is a risk of inducing infection in 1-3% of patients.126 Catheterizing a male to get a urine sample is not recommended, as any urine sample usually is clean. If the situation demands obtaining a urine sample from a male who cannot cooperate, a catheterized specimen is recommended, but a clean "condom" catheter may as useful as bladder catheterization.127

Imaging Techniques. Radiographic imaging has no role in the initial work up of most UTIs. Some specific imaging modalities may have utility in identifying upper UTIs or their complications. Ultrasound is relatively poor at identifying infectious conditions of the kidney other than perinephric abscess, infected hydronephrosis, or emphysematous pyelonephritis; fortunately, the conditions are rare.128 CAT scan has been found to be better for visualizing all infectious conditions of the kidney and has the advantage of identifying alternative, non-infectious conditions.129,130 The few categories of patients with UTI who should be considered for imaging are patients with recurrent illness or patients who are not improving despite therapy.

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