Urinary tract infection (UTI) is a common and painful human illness that, fortunately, is rapidly responsive to modern antibiotic therapy. In the preantibiotic era, UTI caused significant morbidity. Hippocrates, writing about a disease that appears to have been acute cystitis, said that the illness could last for a year before either resolving or worsening to involve the kidneys. When chemotherapeutic agents used to treat UTI were introduced in the early twentieth century, they were relatively ineffective, and persistence of infection after 3 weeks of therapy was common. Nitrofurantoin, which became available in the 1950s, was the first tolerable and effective agent for the treatment of UTI.
Since the most common manifestation of UTI is acute cystitis and since acute cystitis is far more prevalent among women than among men, most clinical research on UTI has involved women. Many studies have enrolled women from college campuses or large health maintenance organizations in the United States. Therefore, when reviewing the literature and recommendations concerning UTI, clinicians must consider whether the findings are applicable to their patient populations.
UTI may be asymptomatic (subclinical infection) or symptomatic (disease). Thus, the term UTI encompasses a variety of clinical entities, including asymptomatic bacteriuria (ABU), cystitis, prostatitis, and pyelonephritis. The distinction between symptomatic UTI and ABU has major clinical implications. Both UTI and ABU connote the presence of bacteria in the urinary tract, usually accompanied by white blood cells and inflammatory cytokines in the urine. However, ABU occurs in the absence of symptoms attributable to the bacteria in the urinary tract and does not usually require treatment, while UTI has more typically been assumed to imply symptomatic disease that warrants antimicrobial therapy. Much of the literature concerning UTI, particularly catheter-associated infection, does not differentiate between UTI and ABU. In this chapter, the term UTI denotes symptomatic disease; cystitis, symptomatic infection of the bladder; and pyelonephritis, symptomatic infection of the kidneys. Uncomplicated UTI refers to acute cystitis or pyelonephritis in nonpregnant outpatient women without anatomic abnormalities or instrumentation of the urinary tract; complicated UTI is a catch-all term that encompasses all other types of UTI. Recurrent UTI is not necessarily complicated; individual episodes can be uncomplicated and treated as such. Catheter-associated bacteriuria can be either symptomatic (CAUTI) or asymptomatic.
Epidemiology and Risk Factors
Except among infants and the elderly, UTI occurs far more commonly in females than in males. During the neonatal period, the incidence of UTI is slightly higher among males than among females because male infants more commonly have congenital urinary tract anomalies. After 50 years of age, obstruction from prostatic hypertrophy becomes common in men, and the incidence of UTI is almost as high among men as among women. Between 1 year and ~50 years of age, UTI and recurrent UTI are predominantly diseases of females. The prevalence of ABU is ~5% among women between ages 20 and 40 and may be as high as 40–50% among elderly women and men.
As many as 50–80% of women in the general population acquire at least one UTI during their lifetime—uncomplicated cystitis in most cases. Recent use of a diaphragm with spermicide, frequent sexual intercourse, and a history of UTI are independent risk factors for acute cystitis. Cystitis is temporally related to recent sexual intercourse, with a sixtyfold increase in the relative odds of acute cystitis in the 48 h after intercourse. In healthy postmenopausal women, sexual activity, diabetes mellitus, and incontinence are risk factors for UTI.
Many factors predisposing women to cystitis also increase the risk of pyelonephritis. Factors independently associated with pyelonephritis in young healthy women include frequent sexual intercourse, a new sexual partner, a UTI in the previous 12 months, a maternal history of UTI, diabetes, and incontinence. The common risk factors for cystitis and pyelonephritis are not surprising given that pyelonephritis typically arises through the ascent of bacteria from the bladder to the upper urinary tract. However, pyelonephritis can occur without clear antecedent cystitis.
About 20–30% of women who have had one episode of UTI will have recurrent episodes. Early recurrence (within 2 weeks) is usually regarded as relapse rather than reinfection and may indicate the need to evaluate the patient for a sequestered focus. Intracellular pods of infecting organisms within the bladder epithelium have been demonstrated in animal models of UTI, but the importance of this phenomenon in humans is not yet clear. The rate of recurrence ranges from 0.3 to 7.6 infections per patient per year, with an average of 2.6 infections per year. It is not uncommon for multiple recurrences to follow an initial infection, resulting in clustering of episodes. Clustering may be related temporally to the presence of a new risk factor or to the sloughing of the protective outer bladder epithelial layer in response to bacterial attachment during acute cystitis. The likelihood of a recurrence decreases with increasing time since the last infection. A case-control study of predominantly white premenopausal women with recurrent UTI identified frequent sexual intercourse, use of spermicide, a new sexual partner, a first UTI before 15 years of age, and a maternal history of UTI as independent risk factors for recurrent UTI.
The only consistently documented behavioral risk factors for recurrent UTI include frequent sexual intercourse and spermicide use. In postmenopausal women, anatomic factors affecting bladder emptying, such as cystoceles, urinary incontinence, and residual urine, are most strongly associated with recurrent UTI.
In pregnant women, ABU has clinical consequences, and both screening for and treatment of this condition are indicated. Specifically, ABU during pregnancy is associated with preterm birth and perinatal mortality for the fetus and with pyelonephritis for the mother. A Cochrane meta-analysis found that treatment of ABU in pregnant women decreased the risk of pyelonephritis by 75%.
The majority of men with UTI have a functional or anatomic abnormality of the urinary tract, most commonly urinary obstruction secondary to prostatic hypertrophy. That said, not all men with UTI have detectable urinary abnormalities; this point is particularly relevant for men ≤45 years of age. Lack of circumcision is also associated with an increased risk of UTI, because Escherichia coli is more likely to colonize the glans and prepuce and subsequently migrate into the urinary tract.
Women—but not men—with diabetes have a two- to threefold higher rate of ABU and UTI than women without diabetes. Increased duration of diabetes and the use of insulin rather than oral medication are also associated with a higher risk of UTI among women with diabetes. Poor bladder function, obstruction in urinary flow, and incomplete voiding are additional factors commonly found in patients with diabetes that increase the risk of UTI. Impaired cytokine secretion may contribute to ABU in diabetic women.
The uropathogens causing UTI vary by clinical syndrome but are usually enteric gram-negative rods that have migrated to the urinary tract. The susceptibility patterns of these organisms vary by clinical syndrome and by geography. In acute uncomplicated cystitis in the United States, the etiologic agents are highly predictable: E. coli accounts for 75–90% of isolates; Staphylococcus saprophyticus for 5–15% (with particularly frequent isolation from younger women); and Klebsiella species, Proteus species, Enterococcus species, Citrobacter species, and other organisms for 5–10%. Similar etiologic agents are found in Europe and Brazil. The spectrum of agents causing uncomplicated pyelonephritis is similar, with E. coli predominating. In complicated UTI (e.g., CAUTI), E. coli remains the predominant organism, but other aerobic gram-negative rods, such as Klebsiella species, Proteus species, Citrobacter species, Acinetobacter species, Morganella species, and Pseudomonas aeruginosa, also are frequently isolated. Gram-positive bacteria (e.g., enterococci and Staphylococcus aureus), and yeasts are also important pathogens in complicated UTI. Data on etiology and resistance are generally obtained from laboratory surveys and should be understood in the context that organism identification is performed only in cases in which urine is sent for culture—i.e., typically when complicated UTI or pyelonephritis is suspected. The available data demonstrate a worldwide increase in the resistance of E. coli to antibiotics commonly used to treat UTI. North American and European surveys of E. coli isolates from women with acute cystitis have documented rates of resistance to trimethoprim-sulfamethoxazole (TMP-SMX) greater than 20% and rates of resistance to ciprofloxacin between 5% and 10% in some regions. Since resistance rates vary by local geographic region, with individual patient characteristics, and over time, it is important to use current and local data when choosing a treatment regimen.
The urinary tract can be viewed as an anatomic unit united by a continuous column of urine extending from the urethra to the kidneys. In the majority of UTIs, bacteria establish infection by ascending from the urethra to the bladder. Continuing ascent up the ureter to the kidney is the pathway for most renal parenchymal infections. However, introduction of bacteria into the bladder does not inevitably lead to sustained and symptomatic infection. The interplay of host, pathogen, and environmental factors determines whether tissue invasion and symptomatic infection will ensue (Fig. 288-1). For example, bacteria often enter the bladder after sexual intercourse, but normal voiding and innate host defense mechanisms in the bladder eliminate these organisms. Any foreign body in the urinary tract, such as a urinary catheter or stone, provides an inert surface for bacterial colonization. Abnormal micturition and/or significant residual urine volume promotes true infection. In the simplest of terms, anything that increases the likelihood of bacteria entering the bladder and staying there increases the risk of UTI.
Pathogenesis of urinary tract infection. The relationship between specific host, pathogen, and environmental factors determines the clinical outcome.
Bacteria can also gain access to the urinary tract through the bloodstream. However, hematogenous spread accounts for <2% of documented UTIs and usually results from bacteremia caused by relatively virulent organisms, such as Salmonella and S. aureus. Indeed, the isolation of either of these pathogens from a patient without a catheter or other instrumentation warrants a search for a bloodstream source. Hematogenous infections may produce focal abscesses or areas of pyelonephritis within a kidney and result in positive urine cultures. The pathogenesis of candiduria is distinct in that the hematogenous route is common. The presence of Candida in the urine of a noninstrumented immunocompetent patient implies either genital contamination or potentially widespread visceral dissemination.
In women, vaginal ecology is an important environmental factor affecting the risk of UTI. Colonization of the vaginal introitus and perirurethral area with organisms from the intestinal flora (usually E. coli) is the critical initial step in the pathogenesis of UTI. Sexual intercourse is associated with an increased risk of vaginal colonization with E. coli and thereby increases the risk of UTI. Nonoxynol-9 in spermicide is toxic to the normal vaginal microflora and thus is likewise associated with an increased risk of E. coli vaginal colonization and bacteriuria. In postmenopausal women, the previously predominant vaginal lactobacilli are replaced with gram-negative colonization. The use of topical estrogens to prevent UTI in postmenopausal women is controversial; given the side effects of systemic hormone replacement, oral estrogens should not be used to prevent UTI.
Anatomic and Functional Abnormalities
Any condition that permits urinary stasis or obstruction predisposes the individual to UTI. Foreign bodies such as stones or urinary catheters provide an inert surface for bacterial colonization and formation of a persistent biofilm. Thus, vesicoureteral reflux, ureteral obstruction secondary to prostatic hypertrophy, neurogenic bladder, and urinary diversion surgery create an environment favorable to UTI. In persons with such conditions, E. coli strains lacking typical urinary virulence factors are often the cause of infection. Inhibition of ureteral peristalsis and decreased ureteral tone leading to vesicoureteral reflux are important in the pathogenesis of pyelonephritis in pregnant women. Anatomic factors—specifically, the distance of the urethra from the anus—are considered to be the primary reason why UTI is predominantly an illness of young women rather than of young men.
The genetic background of the host influences the individual's susceptibility to recurrent UTI, at least among women. A familial disposition to UTI and to pyelonephritis is well documented. Women with recurrent UTI are more likely to have had their first UTI before age 15 years and to have a maternal history of UTI. A component of the underlying pathogenesis of this familial predisposition to recurrent UTI may be persistent vaginal colonization with E. coli, even during asymptomatic periods. Vaginal and periurethral mucosal cells from women with recurrent UTI bind threefold more uropathogenic bacteria than do mucosal cells from women without recurrent infection. Epithelial cells from susceptible women may possess specific types or greater numbers of receptors to which E. coli can bind, thereby facilitating colonization and invasion. Mutations in host response genes (e.g., those coding for Toll-like receptors and the interleukin 8 receptor) have also been linked to recurrent UTI and pyelonephritis. Polymorphisms in the interleukin 8–specific receptor gene CXCR1 are associated with increased susceptibility to pyelonephritis. Lower-level expression of CXCR1 on the surface of neutrophils impairs neutrophil-dependent host defense against bacterial invasion of the renal parenchyma.
An anatomically normal urinary tract presents a stronger barrier to infection than a compromised urinary tract. Thus, strains of E. coli that cause invasive symptomatic infection of the urinary tract in otherwise normal hosts often possess and express genetic virulence factors, including surface adhesins that mediate binding to specific receptors on the surface of uroepithelial cells. The best-studied adhesins are the P fimbriae, hairlike protein structures that interact with a specific receptor on renal epithelial cells. (The letter P denotes the ability of these fimbriae to bind to blood group antigen P, which contains a d-galactose-d-galactose residue.) P fimbriae are important in the pathogenesis of pyelonephritis and subsequent bloodstream invasion from the kidney.
Another adhesin is the type 1 pilus (fimbria), which all E. coli strains possess but not all E. coli strains express. Type 1 pili are thought to play a key role in initiating E. coli bladder infection; they mediate binding to uroplakins on the luminal surface of bladder uroepithelial cells. The binding of type 1 fimbriae of E. coli to receptors on uroepithelial cells initiates a complex series of signaling events that leads to apoptosis and exfoliation of uroepithelial cells, with the attached E. coli organisms carried away in the urine.
Approach to the Patient: Clinical Manifestations
The most important issue to be addressed when a UTI is suspected is the characterization of the clinical syndrome as ABU, uncomplicated cystitis, pyelonephritis, prostatitis, or complicated UTI. This information will shape the diagnostic and therapeutic approach.
A diagnosis of ABU can be considered only when the patient does not have local or systemic symptoms referable to the urinary tract. The clinical presentation is usually that of a patient who undergoes a screening urine culture for a reason unrelated to the genitourinary tract and is incidentally found to have bacteriuria. The presence of systemic signs or symptoms such as fever, altered mental status, and leukocytosis in the setting of a positive urine culture does not merit a diagnosis of symptomatic UTI unless other potential etiologies have been considered.
The typical symptoms of cystitis are dysuria, urinary frequency, and urgency. Nocturia, hesitancy, suprapubic discomfort, and gross hematuria are often noted as well. Unilateral back or flank pain is generally an indication that the upper urinary tract is involved. Fever is also an indication of invasive infection of either the kidney or the prostate.
Mild pyelonephritis can present as low-grade fever with or without lower-back or costovertebral-angle pain, whereas severe pyelonephritis can manifest as high fever, rigors, nausea, vomiting, and flank and/or loin pain. Symptoms are generally acute in onset, and symptoms of cystitis may not be present. Fever is the main feature distinguishing cystitis and pyelonephritis. The fever of pyelonephritis typically exhibits a high, spiking "picket-fence" pattern and resolves over 72 h of therapy. Bacteremia develops in 20–30% of cases of pyelonephritis. Patients with diabetes may present with obstructive uropathy associated with acute papillary necrosis when the sloughed papillae obstruct the ureter. Papillary necrosis may also be evident in some cases of pyelonephritis complicated by obstruction, sickle cell disease, analgesic nephropathy, or combinations of these conditions. In the rare cases of bilateral papillary necrosis, a rapid rise in the serum creatinine level may be the first indication of the condition. Emphysematous pyelonephritis is a particularly severe form of the disease that is associated with the production of gas in renal and perinephric tissues and occurs almost exclusively in diabetic patients (Fig. 288-2). Xanthogranulomatous pyelonephritis occurs when chronic urinary obstruction (often by staghorn calculi), together with chronic infection, leads to suppurative destruction of renal tissue (Fig. 288-3). On pathologic examination, the residual renal tissue frequently has a yellow coloration with infiltration by lipid-laden macrophages. Pyelonephritis can also be complicated by intraparenchymal abscess formation; this situation should be suspected when a patient has continued fever and/or bacteremia despite antibacterial therapy.
Emphysematous pyelonephritis. Infection of the right kidney of a diabetic man by Escherichia coli, a gas-forming, facultative anaerobic uropathogen, has led to destruction of the renal parenchyma (arrow) and tracking of gas through the retroperitoneal space (arrowhead).
Xanthogranulomatous pyelonephritis. A. This photograph shows extensive destruction of renal parenchyma due to long-standing suppurative inflammation. The precipitating factor was obstruction by a staghorn calculus, which has been removed, leaving a depression (arrow). The mass effect of xanthogranulomatous pyelonephritis can mimic renal malignancy. B. A large staghorn calculus (arrow) is seen obstructing the renal pelvis and calyceal system. The lower pole of the kidney shows areas of hemorrhage and necrosis with collapse of cortical areas. (Both images: Courtesy of Dharam M. Ramnani, MD, Virginia Urology Pathology Laboratory, Richmond, VA.)
Prostatitis includes both infectious and noninfectious abnormalities of the prostate gland. Infections can be acute or chronic, are almost always bacterial in nature, and are far less common than the noninfectious entity of chronic pelvic pain syndrome (formerly known as chronic prostatitis). Acute bacterial prostatitis presents as dysuria, frequency, and pain in the prostatic, pelvic, or perineal area. Fever and chills are usually present, and symptoms of bladder outlet obstruction are common. Chronic bacterial prostatitis presents more insidiously as recurrent episodes of cystitis, sometimes with associated pelvic and perineal pain. Men who present with recurrent cystitis should be evaluated for a prostatic focus.
Complicated UTI presents as a symptomatic episode of cystitis or pyelonephritis in a man or woman with an anatomic predisposition to infection, with a foreign body in the urinary tract, or with factors predisposing to a delayed response to therapy.
The diagnosis of any the UTI syndromes or ABU begins with a detailed history (Fig. 288-4). The history given by the patient has a high predictive value in uncomplicated cystitis. A meta-analysis evaluating the probability of acute UTI on the basis of history and physical findings concluded that, in women presenting with at least one symptom of UTI (dysuria, frequency, hematuria, or back pain) and without complicating factors, the probability of acute cystitis or pyelonephritis is 50%. The even higher rates of accuracy of self-diagnosis among women with recurrent UTI probably account for the success of patient-initiated treatment of recurrent cystitis. If vaginal discharge and complicating factors are absent and risk factors for UTI are present, then the probability of UTI is close to 90%, and no laboratory evaluation is needed. Similarly, a combination of dysuria and urinary frequency in the absence of vaginal discharge increases the probability of UTI to 96%. Further laboratory evaluation with dipstick testing or urine culture is not necessary in such patients before the initiation of definitive therapy.
Diagnostic approach to urinary tract infection. STD, sexually transmitted disease; CAUTI, catheter-associated UTI; ABU, asymptomatic bacteriuria; CA-ABU, catheter-associated ABU.
When the patient's history is applied as a diagnostic tool, it is important to recall that the studies included in the meta-analysis cited above did not enroll children, adolescents, pregnant women, men, or patients with complicated UTI. One significant concern is that sexually transmitted disease—that caused by Chlamydia trachomatis in particular—may be inappropriately treated as UTI. This concern is particularly relevant for female patients under the age of 25. The differential diagnosis to be considered when women present with dysuria includes cervicitis (C. trachomatis, Neisseria gonorrhoeae), vaginitis (Candida albicans, Trichomonas vaginalis), herpetic urethritis, interstitial cystitis, and noninfectious vaginal or vulvar irritation. Women with more than one sexual partner and inconsistent use of condoms are at high risk for both UTI and sexually transmitted disease, and symptoms alone do not always distinguish between these conditions.
The Urine Dipstick Test, Urinalysis, and Urine Culture
Useful diagnostic tools include the urine dipstick test and urinalysis, both of which provide point-of-care information, and the urine culture, which can retrospectively confirm a prior diagnosis. Understanding the parameters of the dipstick test is important in interpreting its results. Only members of the family Enterobacteriaceae convert nitrate to nitrite, and enough nitrite must accumulate in the urine to reach the threshold of detection. If a woman with acute cystitis is forcing fluids and voiding frequently, the dipstick test for nitrite is less likely to be positive, even when E. coli is present. The leukocyte esterase test detects this enzyme in the host's polymorphonuclear leukocytes in the urine, whether the cells are intact or lysed. Many reviews have attempted to describe the diagnostic accuracy of dipstick testing. The bottom line for clinicians is that a urine dipstick test can confirm the diagnosis of uncomplicated cystitis in a patient with a reasonably high pretest probability of this disease. Either nitrite or leukocyte esterase positivity can be interpreted as a positive result. Blood in the urine may also suggest a diagnosis of UTI. A dipstick test negative for both nitrite and leukocyte esterase in the same type of patient should prompt consideration of other explanations for the patient's symptoms and collection of urine for culture. A negative dipstick test is not sufficiently sensitive to rule out bacteriuria in pregnant women, in whom it is important to detect all episodes of bacteriuria. Performance characteristics of the dipstick test differ in men (highly specific) and in noncatheterized nursing home residents (highly sensitive).
Urine microscopy reveals pyuria in nearly all cases of cystitis and hematuria in ~30% of cases. In current practice, most hospital laboratories use an automated system rather than manual examination for urine microscopy. A machine aspirates a sample of the urine and then classifies the particles in the urine by size, shape, contrast, light scatter, volume, and other properties. These automated systems can be overwhelmed by high numbers of dysmorphic red blood cells, white blood cells, or crystals; in general, counts of bacteria are less accurate than are counts of red and white blood cells. Our clinical recommendation is that the patient's symptoms and presentation should outweigh an incongruent result on automated urinalysis.
The detection of bacteria in a urine culture is the diagnostic "gold standard" for UTI; unfortunately, however, culture results do not become available until 24 h after the patient's presentation. Identifying specific organism(s) can require an additional 24 h. Studies of women with symptoms of cystitis have found that a colony count threshold of >102 bacteria/mL is more sensitive (95%) and specific (85%) than a threshold of 105/mL for the diagnosis of acute cystitis in women. In men, the minimal level indicating infection appears to be 103/mL. Urine specimens frequently become contaminated with the normal microbial flora of the distal urethra, vagina, or skin. These contaminants can grow to high numbers if the collected urine is allowed to stand at room temperature. In most instances, a culture that yields mixed bacterial species is contaminated except in settings of long-term catheterization, chronic urinary retention, or the presence of a fistula between the urinary tract and the gastrointestinal or genital tract.
The approach to diagnosis is influenced by which of the clinical UTI syndromes is suspected (Fig. 288-4).
Uncomplicated Cystitis in Women
Uncomplicated cystitis in women can be treated on the basis of history alone. However, if the symptoms are not specific or if a reliable history cannot be obtained, then a urine dipstick test should be performed. A positive nitrite or leukocyte esterase result in a woman with one symptom of UTI increases the probability of UTI from 50% to ~80%, and empirical treatment can be considered without further testing. In this setting, a negative dipstick result does not rule out UTI, and a urine culture, close clinical follow-up, and possibly a pelvic examination are recommended. These recommendations are made with the caveat that factors associated with complicated UTI, such as pregnancy, are not present.
The signs and symptoms of cystitis in men are similar to those in women, but this disease differs in several important ways in the male population. Collection of urine for culture is strongly recommended when a man has symptoms of UTI, as the documentation of bacteriuria can differentiate the less common syndromes of acute and chronic bacterial prostatitis from the very common entity of chronic pelvic pain syndrome, which is not associated with bacteriuria and thus is not usually responsive to antibacterial therapy. If the diagnosis is unclear, localization cultures using the two- or four-glass Meares-Stamey test (urine collection after prostate massage) should be undertaken to differentiate between bacterial and nonbacterial prostatic syndromes, and the patient should be referred to a urologist. Men with febrile UTI often have an elevated serum level of prostate-specific antigen as well as an enlarged prostate and enlarged seminal vesicles on ultrasound—findings indicative of prostate involvement. In 85 men with febrile UTI, symptoms of urinary retention, early recurrence of UTI, hematuria at follow-up, and voiding difficulties were predictive of surgically correctable disorders. Men with none of these symptoms had normal upper and lower urinary tracts on urologic workup.
The diagnosis of ABU involves both microbiologic and clinical criteria. The microbiologic criterion is usually ≥105 bacterial cfu/mL except in catheter-associated disease, in which case ≥102 cfu/mL is the cutoff. The clinical criterion is that the person has no signs or symptoms referable to UTI.
Treatment: Urinary Tract Infections
Antimicrobial therapy is warranted for any symptomatic UTI. The choice of antimicrobial agent and the dose and duration of therapy depend on the site of infection and the presence or absence of complicating conditions. Each category of UTI warrants a different approach based on the particular clinical syndrome.
Uncomplicated Cystitis in Women
Since the species and antimicrobial susceptibilities of the bacteria that cause acute uncomplicated cystitis are highly predictable, many episodes of uncomplicated cystitis can be managed over the telephone (Fig. 288-4). Most patients with other UTI syndromes require further diagnostic evaluation. Although the risk of serious complications with telephone management appears to be low, studies of telephone management algorithms generally have involved otherwise healthy white women who are at low risk for complications of UTI.
In 1999, TMP-SMX was recommended as the first-line agent for treatment of uncomplicated UTI in the published guidelines of the Infectious Diseases Society of America. Antibiotic resistance among uropathogens causing uncomplicated cystitis has since increased, appreciation of the importance of collateral damage (as defined below) has increased, and newer agents have been studied. Unfortunately, there is no longer a single best agent for acute uncomplicated cystitis.
Collateral damage refers to the adverse ecologic effects of antimicrobial therapy, including killing of the normal flora and selection of drug-resistant organisms. Outbreaks of Clostridium difficile infection offer an example of collateral damage in the hospital environment. The implication of collateral damage in this context is that a drug that is highly efficacious for the treatment of UTI is not necessarily the optimal first-line agent if it also has pronounced secondary effects on the normal flora or is likely to change resistance patterns. Drugs used for UTI that have a minimal effect on fecal flora include pivmecillinam, fosfomycin, and nitrofurantoin. In contrast, trimethoprim, TMP-SMX, quinolones, and ampicillin affect the fecal flora more significantly; these drugs are notably the agents for which rising resistance levels have been documented.
Several effective therapeutic regimens are available for acute uncomplicated cystitis in women (Table 288-1). Well-studied first-line agents include TMP-SMX and nitrofurantoin. Second-line agents include fluoroquinolone and β-lactam compounds. Single-dose fosfomycin treatment for acute cystitis is widely used in Europe but has produced mixed results in randomized trials. Pivmecillinam is not currently available in the United States or Canada but is a popular agent in some European countries. The pros and cons of other therapies are discussed briefly below.
Table 288-1 Treatment Strategies for Acute Uncomplicated Cystitis |Favorite Table|Download (.pdf)
Table 288-1 Treatment Strategies for Acute Uncomplicated Cystitis
|Drug and Dose||Estimated Clinical Efficacy (%)||Estimated Bacterial Efficacy (%)||Common Side Effects|
|Nitrofurantoin, 100 mg bid × 5–7 d||84–95||86–92||Nausea, headache|
|TMP-SMX, 1 DS tablet bid × 3 d||90–100||91–100||Rash, urticaria, nausea, vomiting, hematologic abnormalities|
|Fosfomycin, 3-g single-dose sachet||70–91||78–83||Diarrhea, nausea, headache|
|Pivmecillinam, 400 mg bid × 3–7 d||55–82||74–84||Nausea, vomiting, diarrhea|
|Fluoroquinolones, dose varies by agent; 3-d regimen||85–95||81–98||Nausea, vomiting, diarrhea, headache, drowsiness, insomnia|
|β-Lactams, dose varies by agent; 5- to 7-d regimen||79–98||74–98||Diarrhea, nausea, vomiting, rash, urticaria|
Traditionally, TMP-SMX has been recommended as first-line treatment for acute cystitis, and it remains appropriate to consider the use of this drug in regions with resistance rates not exceeding 20%. TMP-SMX resistance has clinical significance: in TMP-SMX-treated patients with resistant isolates, the time to symptom resolution is longer and rates of both clinical and microbiologic failure are higher. Individual host factors associated with an elevated risk of UTI caused by a strain of E. coli resistant to TMP-SMX include recent use of TMP-SMX or another antimicrobial agent and recent travel to an area with high rates of TMP-SMX resistance. The optimal setting for empirical use of TMP-SMX is uncomplicated UTI in a female patient who has an established relationship with the practitioner and who can thus seek further care if her symptoms do not respond promptly.
Resistance to nitrofurantoin remains low despite >60 years of use. Since this drug affects bacterial metabolism in multiple pathways, several mutational steps are required for the development of resistance. Nitrofurantoin remains highly active against E. coli and most non–E. coli isolates. Proteus, Pseudomonas, Serratia, Enterobacter, and yeasts are all intrinsically resistant to this drug. Although nitrofurantoin has traditionally been prescribed as a 7-day regimen, similar microbiologic and clinical efficacies are noted with a 5-day course of nitrofurantoin or a 3-day course of TMP-SMX for treatment of women with acute cystitis; 3-day courses of nitrofurantoin are not recommended for acute cystitis. Nitrofurantoin does not reach significant levels in tissue and cannot be used to treat pyelonephritis.
Most fluoroquinolones are highly effective for short-course therapy for cystitis; the exception is moxifloxacin, which does not achieve adequate urinary levels. The fluoroquinolones commonly used for UTI include ofloxacin, ciprofloxacin, and levofloxacin. The main concern about fluoroquinolone use for acute cystitis is the propagation of fluoroquinolone resistance, not only among uropathogens but also among other organisms causing more serious and difficult-to-treat infections at other sites. Fluoroquinolone use is also a factor driving the emergence of C. difficile outbreaks in hospital settings. Most experts now call for restricting fluoroquinolones to specific instances of uncomplicated cystitis in which other antimicrobial agents are not suitable. Quinolone use in the elderly has been associated with an increased risk of Achilles tendon rupture.
Except for pivmecillinam, β-lactam agents generally have not performed as well as TMP-SMX or fluoroquinolones in acute cystitis. Rates of pathogen eradication are lower and relapse rates are higher with β-lactam drugs. The generally accepted explanation is that β-lactams fail to eradicate uropathogens from the vaginal reservoir. A proposed role for intracellular biofilm communities is intriguing. Many strains of E. coli that are resistant to TMP-SMX are also resistant to amoxicillin and cephalexin; thus, these drugs should be used only for patients infected with susceptible strains.
Urinary analgesics are appropriate in certain situations to speed resolution of bladder discomfort. The urinary tract analgesic phenazopyridine is widely used but can cause significant nausea. Combination analgesics containing urinary antiseptics (methenamine, methylene blue), a urine-acidifying agent (sodium phosphate), and an antispasmodic agent (hyoscyamine) are also available.
Since patients with pyelonephritis have tissue-invasive disease, the treatment regimen chosen should have a very high likelihood of eradicating the causative organism and should reach therapeutic blood levels quickly. High rates of TMP-SMX-resistant E. coli in patients with pyelonephritis have made fluoroquinolones the first-line therapy for acute uncomplicated pyelonephritis. Whether the fluoroquinolones are given orally or parenterally depends on the patient's tolerance for oral intake. A randomized clinical trial demonstrated that a 7-day course of therapy with oral ciprofloxacin (500 mg twice daily, with or without an initial IV 400-mg dose) was highly effective for the initial management of pyelonephritis in the outpatient setting. Oral TMP-SMX (one double-strength tablet twice daily for 14 days) is also effective for treatment of acute uncomplicated pyelonephritis if the uropathogen is known to be susceptible. If the pathogen's susceptibility is not known and TMP-SMX is used, an initial IV 1-g dose of ceftriaxone is recommended. Oral β-lactam agents are less effective than the fluoroquinolones and should be used with caution and close follow-up. Options for parenteral therapy for uncomplicated pyelonephritis include fluoroquinolones, an aminoglycoside with or without ampicillin, an extended-spectrum cephalosporin with or without an aminoglycoside, or a carbapenem. Combinations of a β-lactam and a β-lactamase inhibitor (e.g., ampicillin-sulbactam, ticarcillin-clavulanate, and piperacillin-tazobactam) or imipenem-cilastatin can be used in patients with more complicated histories, previous episodes of pyelonephritis, or recent urinary tract manipulations; in general, the treatment of such patients should be guided by urine culture results. Once the patient has responded clinically, oral therapy should be substituted for parenteral therapy.
Nitrofurantoin, ampicillin, and the cephalosporins are considered relatively safe in early pregnancy. One retrospective case-control study suggesting an association between nitrofurantoin and birth defects awaits confirmation. Sulfonamides should clearly be avoided both in the first trimester (because of possible teratogenic effects) and near term (because of a possible role in the development of kernicterus). Fluoroquinolones are avoided because of possible adverse effects on fetal cartilage development. Ampicillin and the cephalosporins have been used extensively in pregnancy and are the drugs of choice for the treatment of asymptomatic or symptomatic UTI in this group of patients. For pregnant women with overt pyelonephritis, parenteral β-lactam therapy with or without aminoglycosides is the standard of care.
Since the prostate is involved in the majority of cases of febrile UTI in men, the goal in these patients is to eradicate the prostatic infection as well as the bladder infection. In men with apparently uncomplicated UTI, a 7- to 14-day course of a fluoroquinolone or TMP-SMX is recommended. If acute bacterial prostatitis is suspected, antimicrobial therapy should be initiated after urine and blood are obtained for cultures. Therapy can be tailored to urine culture results and should be continued for 2–4 weeks. For documented chronic bacterial prostatitis, a 4- to 6-week course of antibiotics is often necessary. Recurrences, which are not uncommon in chronic prostatitis, often warrant a 12-week course of treatment.
Complicated UTI (other than that discussed above) occurs in a heterogeneous group of patients with a wide variety of structural and functional abnormalities of the urinary tract and kidneys. The range of species and their susceptibility to antimicrobial agents are likewise heterogeneous. As a consequence, therapy for complicated UTI must be individualized and guided by urine culture results. Frequently, a patient with complicated UTI will have prior urine culture data that can be used to guide empirical therapy while current culture results are awaited. Xanthogranulomatous pyelonephritis is treated with nephrectomy. Percutaneous drainage can be used as the initial therapy in emphysematous pyelonephritis and can be followed by elective nephrectomy as needed. Papillary necrosis with obstruction requires intervention to relieve the obstruction and to preserve renal function.
Treatment of ABU does not decrease the frequency of symptomatic infections or complications except in pregnant women, persons undergoing urologic surgery, and perhaps neutropenic patients and renal transplant recipients. Treatment of ABU in pregnant women and patients undergoing urologic procedures should be directed by urine culture results. In all other populations, screening for and treatment of ABU are discouraged. The majority of cases of catheter-associated bacteriuria are asymptomatic and do not warrant antimicrobial therapy.
Multiple institutions have released guidelines for the treatment of CAUTI, which is defined by bacteriuria and symptoms in a catheterized patient. The signs and symptoms either are localized to the urinary tract or can include otherwise unexplained systemic manifestations, such as fever. The accepted threshold for bacteriuria varies from ≥103 cfu/mL to ≥105 cfu/mL.
The formation of biofilm—a living layer of uropathogens—on the urinary catheter is central to the pathogenesis of CAUTI and affects both therapeutic and preventive strategies. Organisms in a biofilm are relatively resistant to killing by antibiotics, and eradication of a catheter-associated biofilm is difficult without removal of the device itself. Furthermore, because catheters provide a conduit for bacteria to enter the bladder, bacteriuria is inevitable with long-term catheter use.
The typical signs and symptoms of UTI, including pain, urgency, dysuria, fever, peripheral leukocytosis, and pyuria, have less predictive value for the diagnosis of infection in catheterized patients. Furthermore, the presence of bacteria in the urine of a patient who is febrile and catheterized does not necessarily predict CAUTI, and other explanations for the fever should be considered.
The etiology of CAUTI is diverse, and urine culture results are essential to guide treatment. Fairly good evidence supports the practice of catheter change during treatment for CAUTI. The goal is to remove biofilm-associated organisms that could serve as a nidus for reinfection. Pathology studies reveal that many patients with long-term catheters have occult pyelonephritis. A randomized trial in persons with spinal cord injury who were practicing intermittent catheterization found that relapse was more common after 3 days of therapy than after 14 days. In general, a 7- to 14-day course of antibiotics is recommended, but further studies on the optimal duration of therapy are needed.
In the setting of long-term catheter use, systemic antibiotics, bladder-acidifying agents, antimicrobial bladder washes, topical disinfectants, and antimicrobial drainage-bag solutions have all been ineffective at preventing the onset of bacteriuria and have been associated with the emergence of resistant organisms. The best strategy for prevention of CAUTI is to avoid insertion of unnecessary catheters and to remove catheters once they are no longer necessary. Evidence is insufficient to recommend suprapubic catheters and condom catheters as alternatives to indwelling urinary catheters as a means to prevent CAUTI. However, intermittent catheterization may be preferable to long-term indwelling urethral catheterization in certain populations (e.g., spinal cord–injured persons) to prevent both infectious and anatomic complications. Antimicrobial catheters impregnated with silver or nitrofurazone have not been shown to provide significant clinical benefit in terms of reducing rates of symptomatic UTI.
The appearance of Candida in the urine is an increasingly common complication of indwelling catheterization, particularly for patients in the intensive care unit, those taking broad-spectrum antimicrobial drugs, and those with underlying diabetes mellitus. C. albicans is still the most common isolate, although C. glabrata and other non-albicans species are also isolated frequently. The clinical presentation varies from an asymptomatic laboratory finding to pyelonephritis and even sepsis. In asymptomatic patients, removal of the urethral catheter results in resolution of candiduria in more than one-third of cases. Treatment is recommended for patients who have symptomatic cystitis or pyelonephritis and for those who are at high risk for disseminated disease. High-risk patients include those with neutropenia, those who are undergoing urologic manipulation, and low-birth-weight infants. Fluconazole (200–400 mg/d for 14 days) achieves high levels in urine and is the first-line regimen for Candida infections of the urinary tract. The newer azoles and echinocandins are characterized by only low-level urinary excretion and thus are not recommended, although cases of successful eradication of candiduria with some of these agents have been reported. For Candida isolates with high levels of resistance to fluconazole, oral flucytosine and/or parenteral amphotericin B are options. Bladder irrigation with amphotericin B generally is not recommended.
Prevention of Recurrent UTI in Women
Recurrence of uncomplicated cystitis in reproductive-age women is common, and a preventive strategy is indicated if recurrent UTIs are interfering with a patient's lifestyle. The threshold of two or more symptomatic episodes per year is not absolute; decisions about interventions should take the patient's preferences into account.
Three prophylactic strategies are available: continuous, postcoital, or patient-initiated therapy. Continuous prophylaxis and postcoital prophylaxis usually entail low doses of TMP-SMX, a fluoroquinolone, or nitrofurantoin. These regimens are all highly effective during the period of active antibiotic intake. Typically, a prophylactic regimen is prescribed for 6 months and then discontinued, at which point the rate of recurrent UTI often returns to baseline. If bothersome infections recur, the prophylactic program can be reinstituted for a longer period.
Patient-initiated therapy involves supplying the patient with materials for urine culture and self-medication with a course of antibiotics at the first symptoms of infection. The urine culture is refrigerated and delivered to the physician's office for confirmation of the diagnosis. When an established and reliable patient-provider relationship exists, the urine culture can be omitted as long as the symptomatic episodes respond completely to short-course therapy and are not followed by relapse.
Cystitis is a risk factor for recurrent cystitis and pyelonephritis. ABU is common among elderly and catheterized patients but does not in itself increase the risk of death. The relationships among recurrent UTI, chronic pyelonephritis, and renal insufficiency have been widely studied. In the absence of anatomic abnormalities, recurrent infection in children and adults does not lead to chronic pyelonephritis or to renal failure. Moreover, infection does not play a primary role in chronic interstitial nephritis; the primary etiologic factors in this condition are analgesic abuse, obstruction, reflux, and toxin exposure. In the presence of underlying renal abnormalities (particularly obstructing stones), infection as a secondary factor can accelerate renal parenchymal damage. In spinal cord–injured patients, use of a long-term indwelling bladder catheter is a well-documented risk factor for bladder cancer. Chronic bacteriuria resulting in chronic inflammation is one possible explanation for this observation.