Introduction
Urinary tract infections (UTIs) are one of the most common bacterial infections, affecting 150 million people each year worldwide. Annually, UTIs result in 10.5 million office visits (constituting 0.9% of all ambulatory visits) and 2 to 3 million emergency department visits in the United States alone. Within the United States, societal costs, including health care costs and time missed from work, are approximately $3.5 billion per year. It is estimated that up to one out of every three women has had at least one episode of UTI requiring antimicrobial therapy by 24 years of age, with the lifetime risk being greater than 50%. The prevalence of UTIs among women is thought to increase even further with age, with 10% of women over 65 years and 30% of women older than 85 years reporting UTI within the prior 12 months. Clinicians managing urogynecologic patients need to be well-versed not only in management of acute UTIs, but also of recurrent UTIs (rUTIs) and asymptomatic bacteriuria (ASB) because of high incidence in this population (i.e., postmenopausal women and patients undergoing procedures that require instrumentation of the genitourinary tract).
By definition, UTIs include cystitis (infection of the bladder/lower urinary tract) and pyelonephritis (infection of the kidney/upper urinary tract) ( Table 36.1 ). UTI is diagnosed based on the presence of a pathogen in the urinary tract and associated symptoms. Uncomplicated UTIs typically affect individuals who are otherwise healthy and have no structural or neurological urinary tract abnormalities; these infections are differentiated into lower tract UTIs (cystitis) and upper tract UTIs (pyelonephritis). In contrast, a complicated UTI refers to cystitis or pyelonephritis in a patient with a variety of factors including urologic abnormalities (such as nephrolithiasis, strictures, stents, or urinary diversions), immunocompromising conditions (such as neutropenia or advanced human immunodeficiency virus infection), or poorly controlled diabetes mellitus. Certain populations, such as pregnant women and renal transplant recipients, also have unique management considerations. There are multiple definitions for rUTI, but the most common is at least two episodes of culture-positive, symptomatic UTIs within 6 months, or at least three in 1 year. Finally, ASB is the presence of one or more species of bacteria growing in the urine at specified quantitative counts (≥10 5 colony-forming units [CFU]/mL), irrespective of the presence of pyuria, in the absence of signs or symptoms attributable to UTI.
| Diagnosis | Definition |
|---|---|
| Acute uncomplicated urinary tract infection | Infection of the lower and/or upper genitourinary tract that is diagnosed based on the presence of a urinary tract pathogen and its associated symptoms in an otherwise healthy individual without structural or neurological urinary tract abnormalities |
| Cystitis | Infection of the bladder/lower urinary tract |
| Pyelonephritis | Infection of the kidney/upper urinary tract |
| Complicated urinary tract infection | Cystitis or pyelonephritis in a patient with urologic abnormalities, immunocompromising conditions, or poorly controlled diabetes mellitus |
| Recurrent urinary tract infection | At least two episodes of culture-positive, symptomatic UTI in 6 months, or three or more in 1 year |
| Asymptomatic bacteriuria | The presence of bacterial growth on urine culture at ≥10 5 colony-forming units/mL in the absence of signs or symptoms attributable to UTI |
| Urosepsis | Systemic response to uropathogen leading to organ dysfunction |
Acute, symptomatic, uncomplicated lower urinary tract infection
Definitions
Uncomplicated UTIs are differentiated into lower UTIs (cystitis) and upper UTIs (pyelonephritis) ( Table 36.1 ). In this chapter we will discuss the diagnosis and management of lower UTIs (i.e., cystitis). Management guidelines for acute, symptomatic, uncomplicated UTI have been developed for nonpregnant premenopausal women without underlying structural urologic abnormalities, but they likely can be extrapolated to postmenopausal women without urological sequelae and/or recurrent infections.
Pathophysiology
UTIs can be caused by both gram-negative and gram-positive bacteria, but the most common causative agent for uncomplicated UTIs is uropathogenic Escherichia coli . UTI typically starts with periurethral contamination by a uropathogen residing in the gut, followed by colonization of the urethra and migration of the pathogen to the bladder. This process requires microbial virulence factors including flagellae, pili, and other adhesins that facilitate mucosal adherence and stimulation of the host immune response.
There are multiple factors that typically aid in UTI deterrence. These include: the acidic vaginal environment, the glycosaminoglycan (GAG) layer of the bladder, and immunoglobulins in the urine. The acidic pH of the vagina in premenopausal women inhibits the growth of enterobacteria such as E. coli and promotes the growth of Lactobacilli , a genus of microbes associated with health. The GAGs in the bladder lining and immunoglobulins in the urine restrict bacterial adherence. Tamm–Horsfall proteins secreted by the loop of Henle may also inhibit bacterial adherence to the urothelial cells, and antimicrobial peptides may serve to modulate the immune response during bacterial presence.
Diagnosis
There is currently no “gold standard” definition for an acute UTI, which poses a challenge not only for clinical care but also for epidemiologic research. Historically, establishing a diagnosis of symptomatic UTI requires a patient to have symptoms and signs of UTI with laboratory tests confirming the diagnosis (bacteriuria ≥10 5 CFU/mL). Some experts advocate for relaxing these diagnostic criteria to include symptomatic patients with urine culture of 100 CFU/mL or more. Lower colony counts on culture may represent a partially treated infection, an earlier stage of infection, the effects of diluting the bacterial concentration with urination, or the mode of specimen collection (i.e., voided vs. catheterized sampling).
Cystitis in women usually causes dysuria, although it may also cause frequency, urgency, and suprapubic discomfort. Occasionally, mild incontinence and hematuria may occur. Gross hematuria is rare. Upper tract infections commonly present with fever, chills, malaise, flank pain, costovertebral angle tenderness, and occasionally nausea and vomiting. In young women, patients with dysuria and frequency without vaginal discharge or irritation have a 90% probability of a UTI. Dysuria remains the most discriminating symptom in older women seen in urogynecologic offices. However, in older women symptoms of frequency and urgency are less specific because of the high prevalence of other bladder symptom conditions like overactive bladder in aging populations.
Diagnostic testing
Urine dipstick.
For many women with dysuria, lack of vaginal discharge, and classic acute simple cystitis (not in the setting of rUTI), no additional testing is warranted to make the diagnosis. For those with suggestive, but not clearly diagnostic, features, a urinary dipstick can be helpful to rule out an infection but may have less of a role in confirming an infection. In these settings, the absence of nitrites and leukocyte esterase lowers the probability of UTI. Nitrites are seen in the setting of gram-negative bacteria because these types of bacteria convert nitrates to nitrites. Leukocyte esterase on urinary dipstick corresponds to pyuria, or white blood cells in the urine. False-negative nitrite results could occur in the setting of gram-positive bacteria, but cystitis is uncommon in patients without pyuria. More commonly, false-positive urine dipstick results are seen, especially when voided specimens are used. In women, poor collection techniques and vaginal contamination with voided samples contribute to false-positive findings ( ). Therefore, although urine dipsticks can provide clinical information, ultimately the provider should incorporate clinical judgment and/or additional diagnostic testing when making final decisions regarding treatment.
Microscopic urinalysis.
Microscopic examination of urine can detect the presence of bacteria, leukocytes, and red blood cells. Pyuria is defined as 10 or more leukocytes/mL or 3 or more leukocytes/high-powered field of unspun urine. As earlier, in the absence of pyuria, the diagnosis of UTI should be questioned. Pyuria has been proposed as a way to differentiate between acute UTI and ASB, but recent guidelines recommend that the diagnosis of ASB can be made even in the setting of pyuria. Patients could exhibit pyuria with negative urine culture (i.e., sterile pyuria) if urinalysis is performed after initiating antimicrobial therapy. Neither microscopic hematuria nor bacteriuria on urinalysis is a particularly sensitive finding for UTI. However, microscopic urinalysis is the gold standard for evaluation of hematuria outside of infection (see Chapter 40 ). Beyond this standard indication for testing, it is likely an unnecessary cost.
Urine culture.
Urine culture may not be necessary for acute cystitis, but the primary disadvantage of symptom-based diagnosis is that it may result in overtreatment and inappropriate antibiotic use. This is especially possible in older women, where symptoms of UTI overlap with other noninfectious bladder symptom conditions. Urine culture is considered the reference standard for diagnosis of UTI. Cultures should be submitted for scenarios such as negative urine dipstick test in a symptomatic patient, poor response to initial therapy, and recurrent symptoms less than 1 month after treatment for a previous UTI. As mentioned previously, although a culture result of 10 5 CFU/mL or more in a voided urine sample has historically been considered diagnostic for UTI, some feel that 100 CFU/mL or more should suffice in a patient who has symptoms consistent with UTI, as well as pyuria. If there is a suspicion for pyelonephritis (i.e., fever, costovertebral tenderness/flank pain), then a urine culture and antibiotic susceptibilities should always be obtained.
Clinical management
Antibiotics for simple cystitis.
The Infectious Diseases Society of America (IDSA) published an updated clinical practice guideline on the treatment of women with acute uncomplicated cystitis and pyelonephritis in 2010. They note that the focus of these guidelines is treatment of nonpregnant, premenopausal women with no known urological abnormalities. Postmenopausal women, those without rUTI, and/or those with well-controlled diabetes without urological sequelae can usually be treated with the same recommendations.
The three first-line antibiotics for UTI treatment are nitrofurantoin, trimethoprim-sulfamethoxazole (TMP-SMX), and fosfomycin ( Table 36.2 ). Fluoroquinolones should only be used if there is any suspicion for early pyelonephritis.
| Dose | Side Effects and Contraindications | Estimated Clinical Efficacy | |
|---|---|---|---|
| First-Line Antibiotics | |||
| Nitrofurantoin monohydrate/macrocrystals | 100 mg BID × 5 days |
| 79%–92% |
| Trimethoprim/sulfamethoxazole | 160/800 mg BID × 3 days |
| 79%–100% |
| Fosfomycin trometamol | 3 g single dose |
| 63%–91% |
| Second-Line Antibiotics | |||
| β-lactams | Dose varies; typically 3- to 5-d regimen |
| |
| Fluoroquinolones | Dose varies; typically for 3–5 days |
|
Nitrofurantoin is bacteriostatic and therapeutically active only in the lower urinary tract. It is effective against E. coli and many gram-negative species with low levels of resistance. However, it can be ineffective against other uropathogens. TMP-SMX is a broad-spectrum antibiotic that covers gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, and most gram-negative bacteria. In regions where there is greater than 20% local E. coli resistance to TMP-SMX, an alternative treatment should be given. Reported duration of TMP-SMX treatment has ranged from 3 to 14 days, with the 3-day course having similar efficacy to 5- to 10-day regimens. Finally, fosfomycin tromethamine, the stable salt form of fosfomycin, is taken in a single dose that becomes highly concentrated in the urine, resulting in urine levels that persist for 30 to 40 hours. Fosfomycin has activity against both gram-positive and gram-negative bacteria, including S. aureus , Enterococcus , Pseudomonas aeruginosa , and Klebsiella pneumoniae . There are relatively low levels of resistance to fosfomycin, making it a drug of choice in infections with multidrug-resistant organisms, but there is some suggestion that single-dose regimen may have less efficacy than other therapies. When first-line medications are not available or cannot be prescribed because of patient allergies, intolerances, or bacterial resistance, second-line antimicrobials, β-lactams, and fluoroquinolones can be used. Although 3-day fluoroquinolone regimens (i.e., ciprofloxacin and levofloxacin) are efficacious, they are not first-line agents because of increasing resistance, higher expense, and serious adverse events, as described in a 2016 Food and Drug Administration warning.
Antimicrobial-sparing strategies.
Given that acute simple cystitis has a low risk of progression in patients without risk factors for serious infection ( ), antimicrobial-sparing strategies are attractive to consider. Delaying antimicrobial therapy while awaiting urine culture results appears to be a reasonable approach in women without comorbidities, especially if empiric therapy is complicated by resistance or drug intolerance. In a randomized trial of nonpregnant women younger than 75 years of age with acute simple cystitis, symptom duration and severity were similar with immediate antimicrobial therapy compared with four other strategies, including delayed antimicrobial therapy and antimicrobial therapy based on a symptom score, urinalysis findings, or urine culture results ( ). One large, retrospective database analysis of patients 65 years of age or older with lower UTI suggested an association between delaying antimicrobial therapy and subsequent bloodstream infection within 60 days, but this study had significant limitations, including potential misdiagnosis of cystitis ( ).
Substituting antiinflammatory agents for antimicrobial therapy has also been evaluated, but currently is not recommended as the initial approach to management of symptomatic acute simple cystitis. Two trials comparing nonsteroidal antiinflammatory drugs (ibuprofen and diclofenac) to antibiotics (fosfomycin and norfloxacin) showed that between 50% and 75% of women achieved symptom improvement, but there were higher incidences of pyelonephritis or additional therapy in the nonsteroidal antiinflammatory arms ( ; ).
Complicated urinary tract infections
Definition
UTIs are considered to be “complicated” when there are host factors (e.g., poorly controlled diabetes or immunosuppression), anatomical abnormalities (e.g., outlet obstruction), or functional abnormalities (e.g., incomplete voiding because of detrusor muscle dysfunction) that lead to an infection that could be more difficult to eradicate than uncomplicated infections ( ).
Pathophysiology and clinical management
Because the underlying comorbidities that may predispose to complicated UTI are heterogenous, there is not one unifying pathophysiologic mechanism. Important guiding principles include the continued necessity of assessing relevant clinical symptoms (e.g., dysuria, urgency, frequency, flank pain, costovertebral angle tenderness, suprapubic pain, and fever) to diagnose UTI. In some clinical situations, the symptoms may be atypical (i.e., neurogenic bladder disturbances, catheter-associated UTI), but it is important to maintain discretion regarding antibiotic usage and to remember that many lower urinary tract symptoms and systemic symptoms are not always attributed to UTI. Pretreatment urine cultures are an important component of management for patients with suspected complicated UTI, as bacteria are more likely to be resistant to antibiotics in this population.
Best practices include hospitalization for patients with suspected complicated UTI and associated systemic symptoms. The initial antimicrobial regimen should be chosen based on local resistance data and previous urine culture results from the patient, if available. Efforts should be made to improve contributing host factors and/or to mitigate or remove any structural or anatomic factors whenever possible. The antibiotic regimen should then be tailored on the basis of susceptibility results. Finally, longer courses of antibiotics (i.e., 7–14 days) are recommended for most cases.
Recurrent symptomatic urinary tract infection
Definition
There are multiple definitions for rUTI. We support the culture-based definition of at least two culture-proven episodes in 6 months, or at least three in 1 year ( Table 36.1 ). It is assumed that these episodes are separate events; however, there is no consensus recommendation to document resolution of any episode with posttreatment culture. Generally, a recurrence is thought to be return of symptoms at least 2 weeks after prior treatment, or documentation of clearance. In the absence of documentation of clearance, a patient may also have a persistent infection that was not adequately cleared with initial therapy.
Diagnosis
When first seeing a patient with possible rUTI it is imperative to obtain clarification surrounding the details of UTI events, including UTI testing and culture results when available, as well as current prevention practices. The symptoms that the patient attributes to the UTI should be documented, including duration and response to therapy, because these may vary between patients. Symptoms are typically acute in onset and include dysuria, urinary frequency and urgency, suprapubic or flank pain, hematuria, and/or documented fever. Patients often attribute many nonspecific symptoms (i.e., foul-smelling urine, cloudy urine, general malaise, confusion) to UTI, although these are signs more consistent with ASB (see later).
Pathophysiology
Classically, major risk factors for UTI include sexual activity and a history of UTI, but the factors predisposing postmenopausal women to rUTI have been significantly less investigated than those for premenopausal women. Some women have a genetic predisposition to UTI owing to differences in mucosal bacterial binding properties, which could be related to certain red blood cell antigens.
Premenopausal.
For premenopausal women, the pathogenesis of recurrent cystitis is assumed to be the similar to that of sporadic infection. Most uropathogens originate in the rectal flora, colonize the periurethral area and urethra, and ascend to the bladder. In studies of young women, frequency of sexual intercourse, spermicide exposure (with or without diaphragm use), a new sexual partner within the past year, a history of first UTI before the age of 15 years, and a maternal history of UTI have been demonstrated to increase risk of rUTI. Increasing evidence suggests that alteration of the normal vaginal flora, especially loss of hydrogen peroxide–producing lactobacilli, may predispose women to introital colonization with E. coli and ensuing cystitis ( ).
Postmenopausal.
The urogenital microbiome undergoes changes as women age, often reducing a woman’s natural defense mechanisms against UTI. The healthy premenopausal vagina is known to be largely colonized by Lactobacilli . After menopause, decreased systemic and local estrogen levels result in an elevated vaginal pH, which in turn results in fewer Lactobacilli in the vagina. Together, these factors increase the chance of microbes with uropathogenic capability establishing residence in the vagina and distal urethra. Recently, the discovery of the female urobiome has raised the possibility of alternatives to antibiotic treatment that modulate or boost the innate healthy commensal urinary microbiome. Despite sharing many bacterial species, the urinary microbiome is a unique niche that is related to, but not the same as, the vaginal microbiome. Ongoing studies will help clarify how components of the female urinary microbiome relate to the pathophysiology of UTIs in postmenopausal women.
In rUTI, similar to acute UTI, E. coli is the most common uropathogen. Preclinical data show that E. coli has the capacity to form intracellular bacterial communities (IBCs) that allow bacteria to survive in the urinary bladder after antibiotic treatment. These IBCs also shield bacteria from the host immune response. The detection of exfoliated urothelial cells with IBCs in the urine of women with UTI supports the hypothesis that intracellular bacterial niches persist, which may have important implications for UTI recurrence and treatment. Although E. coli remains the most common uropathogen, among postmenopausal women there is a higher proportion of non– E. coli bacteria, with up to 35% of rUTIs occurring in the setting of other microbes. K. pneumoniae and Enterococcus faecalis are other common uropathogens in postmenopausal UTIs, which raises questions as to whether rUTIs occur because of changes in the host immune response. Overall, risk factors for non– E. coli UTI include history of rUTI, recent pelvic surgery, and older age. Prolapse and urinary incontinence do not seem to be related to presence of non– E. coli uropathogens.
Evaluation
Initial physical examination should include abdominal and focused neurologic examinations, as well as pelvic examination, to detect manageable conditions, including genitourinary atrophy in postmenopausal women or urethral diverticulum. An assessment of bladder emptying should be considered by urethral catheterization or bladder scan (ultrasonography), especially in patients with neurologic disease, diabetes, or significant prolapse.
Radiographic imaging studies of the upper and lower urinary tract should only be considered in occasional scenarios, such as in patients with poor response to appropriate antimicrobial therapy, infections caused by unusual organisms such as Proteus, a history of calculi, potential ureteral obstruction, recurrent pyelonephritis, suspected urethral diverticula, or a history of many UTIs during childhood. The indications for cystourethroscopy in women with UTI are controversial, because findings often do not often alter management. However, it is reasonable to consider cystoscopy in patients with inadequate response to appropriate antimicrobial therapy, gross hematuria, suspected urethral diverticulum, and suspected mesh or nonabsorbable suture material in the bladder or urethra. It should also be considered in older patients for whom bladder cancer may be of concern for other reasons.
Acute infections
Compared with uncomplicated UTI, the most important difference in management for those with rUTIs is that clinicians should obtain urine culture and sensitivity with each symptomatic acute cystitis episode before initiating treatment. This is because of the lower prevalence of E. coli and the higher chance of antibiotic resistance in this patient population, as well as the need for confirmation of UTI diagnoses in more complex clinical scenarios. Similar to patients without a history of rUTI, clinicians should offer hydration and urinary analgesics for patient comfort while awaiting urine culture results. Patients who have classic symptoms (i.e., dysuria, new-onset urinary urgency and/or frequency) and prefer prompt antibiotic therapy can provide urine samples for testing and initiate empirical therapy based on microbial history, allergy profile, and medical status. Two heterogeneous trials have evaluated this management strategy with different approaches. studied single-dose versus short-course antibiotics after UTI-predisposing conditions, and compared intermittent TMP-SMX versus daily prophylactic TMP-SMX. Both trials were very small, and, with recent concerns for antimicrobial resistance, existing guidelines suggest that empiric or self-start therapy should at least be preceded by a urine culture collection to guide antibiotic management. Treatment refinements can follow final urine culture results. Management of symptomatic UTIs should be informed by microbial identification and susceptibility, as well as the local antibiogram, which provides clinicians with information regarding microbial resistance patterns in the local community. Most patients with rUTI can be prescribed 3 to 5 days of an appropriate antibiotic for each cystitis episode, but for those with refractory infections, short interval between infection, or multiple recent recurrent episodes, a longer course of antibiotics can be initiated. It is usually unnecessary to use antibiotics for longer than a 7-day period.
Prevention strategies
The goal of rUTI prevention is to avoid or suppress subsequent infections. Although the most robust evidence is found with vaginal estrogen and antibiotics, alternative nonantibiotic options exist as well. In an era of antimicrobial stewardship, we generally consider starting with estrogen prophylaxis for appropriate candidates and adding antibiotics if needed for persistent rUTIs.
Vaginal estrogen prophylaxis.
The pathogenesis of rUTIs in peri- and postmenopausal women may, in part, be related to the vaginal microbial changes associated with menopause. Lower systemic and local estrogen levels raise the vaginal pH and decrease the lactobacillus-dominant vaginal flora typical for premenopausal women. Together, these factors increase the chance that microbes with uropathogenic capability establish residence in the vagina.
In peri- or postmenopausal women, there is high-quality evidence that vaginal estrogen therapy can reduce the risk of rUTI, but there is little evidence recommending one formulation over another. Vaginal estrogen cream (17β-estradiol or conjugate equine estrogen), vaginal ring (17β-estradiol), or vaginal tablet (estradiol hemihydrate) could likely be used to prevent UTI recurrence, although one study suggests lower efficacy of the ring. The vaginal tablet has not technically been evaluated specifically for UTI prevention. In contrast to vaginal estrogen, oral estrogen has not been shown to decrease rUTI and has a much different risk and benefit profile.
Antibiotic prophylaxis.
There is a large body of evidence-based literature supporting antibiotic prophylaxis for treatment of rUTIs. The most recent systematic review identified 28 trials with sample sizes ranging from 26 to 308 ( n = 2758) ( ). Of the trials that compared prophylactic antibiotics to placebo, antibiotics were associated with a decreased likelihood of experiencing at least one UTI recurrence (relative risk [RR] 0.26, 95% confidence interval [CI] 0.18–0.37), and there was no difference when comparing nitrofurantoin to other antibiotics (RR 0.81, 95% CI 0.63–1.03). Unfortunately, the majority of trials were completed before 1995, and therefore do not necessarily consider growing antibiotic resistance.
The most common adverse events associated with antibiotic prophylaxis include gastrointestinal side effects, vaginal and/or oral candidiasis, and skin rash. Nitrofurantoin specifically has rare but potentially serious pulmonary and hepatic toxicity in the range of 0.001% to 0.7% of cases of long-term nitrofurantoin use. Current recommendations are to avoid nitrofurantoin use when creatinine clearance is below 30 mL/min, and the potential serious risks of long-term use should be discussed with patients.
There are scant data on the long-term impacts of antibiotic prophylaxis on antibiotic resistance. One study evaluating lactobacilli compared with antibiotics for UTI prevention showed that E. coli resistance in fecal and urine isolates increased to approximately 80% to 95% after only 1 month of trimethoprim-sulfamethoxazole prophylaxis ( ). The most common prophylactic options are presented in Table 36.3 .
