Urinary tract infections (UTIs) can involve the bladder alone (lower UTI, also known as acute cystitis) or extend to the renal pelvis and parenchyma (upper UTI, also known as acute pyelonephritis). If untreated, such infections can progress in vulnerable hosts to systemic bacterial disease, known as urosepsis.
Although “cystitis” refers, in the strictest sense, to inﬂammation of the bladder, by far the most common cause is bacterial infection, which occurs when bacteria ascend to the bladder from the urethra. Thus use of the term “cystitis” without additional qualiﬁcation usually implies bacterial infection of the bladder. In contrast, “nonbacterial cystitis” is often used to specify bladder inﬂammation associated with viruses, parasites, radiation, chemical irritants, and other agents.
Cystitis is considered “uncomplicated” when it occurs in women with anatomically and neurologically normal urinary tracts. In contrast, cystitis is considered “complicated” when it occurs in the setting of structural or functional abnormalities of the urinary tract; in association with an indwelling urinary catheter; in conjunction with an upper urinary tract infection; or in men, pregnant women, or hospitalized patients.
Acute uncomplicated cystitis occurs in women when enteric ﬂora from the perianal region colonize the adjacent vaginal introitus and then ascend the urethra to reach the bladder. Escherichia coli (E. coli) is the most common pathogen, accounting for nearly 80% of all infections. Other common pathogens include Staphylococcus saprophyticus, Klebsiella pneumoniae, and Proteus mirabilis, in order of descending frequency. Less commonly, Citrobacter and Enterococcus may be responsible. Complicated cystitis, in contrast, often involves additional pathogenetic mechanisms, such as the presence of a urinary catheter or bladder outlet obstruction, and in these cases the responsible pathogens differ. E. coli, for example, accounts for only 35% of such infections. Instead, there is a higher prevalence of other gram-negative species, such as Pseudomonas aeruginosa, and gram-positive organisms, such as Enterococcus and coagulase negative staphylococci.
In any patient, the likelihood of urinary tract infection depends on the balance between host defenses and pathogen virulence factors. In the host, several mechanisms defend the urinary tract from infection. For example, the low pH and high urea concentration in urine inhibit bacterial proliferation. In addition, the presence of certain molecules on the epithelial surface of the urinary tract such as human defensins, Tamm Horsfall proteins, and glycosaminoglycans confer protection against bacterial adhesion. Lastly, the ﬂow of urine itself plays an important mechanical role in the clearance of bacteria.
These protective mechanisms, however, may be over come or impaired in certain circumstances. For example, when women engage in sexual intercourse, there is often substantial displacement of both fecal and vaginal ﬂora toward the urethra. This risk further increases with the use of diaphragms or spermicides, which may render the vaginal environment more hospitable to the proliferation of uropathogens. In older women, a decline in estrogen can lead to a loss of the protective lactobacilli that are part of the normal vaginal ﬂora, enabling increased colonization with uropathogens. Pregnancy alters the pH and osmolality of urine, making it more favorable to bacterial growth.
Several pathologic conditions can also interfere with normal host defenses and increase the likelihood of infection. Diabetes mellitus, for example, has several pathologic effects that predispose affected individuals to infection. Urinary stasis, which can result from anatomic or functional obstruction, makes it more difﬁcult to clear bacteria from the bladder. Indwelling urinary catheters also increase the infection risk by facilitating migration of uropathogens into the bladder. Bacteria adhere to the catheter surface and contribute to the creation of a bioﬁlm, which contains bacteria, bacterial glycocalyces, host proteins, and urinary salts such as apatite and struvite. The bacteria can then travel along the catheter beneath this bioﬁlm until they reach the bladder. Indeed, long-term use of urinary catheters will always result in colonization and infection. In contrast, urinary catheters that are used for fewer than 7 days are less likely to cause clinically signiﬁcant infections as long as the catheter connections are left undisturbed and a closed drainage system is scrupulously maintained.
Uropathogenic organisms also have several factors that determine their invasiveness, persistence, and site of infection. Genetic differences both within and across species can modulate adhesion to host cells and resistance to the defenses described above. For example, some serogroups of E. coli have surface ﬁmbriae that offer improved adhesion and facilitate extension to the upper urinary tract. Similarly, bacteria that express K capsular antigens, such as Klebsiella species, are resistant to neutrophil phagocytosis. Finally, motility mechanisms, such as ﬂagellation, permit certain bacteria to navigate the urinary tract against the ﬂow of micturition.
PRESENTATION AND DIAGNOSIS
The major symptoms of cystitis include painful and frequent urination, urgency, hesitancy, and pelvic pressure. These symptoms reﬂect irritation of urethral and vesicular mucosa. Foul smelling, discolored, or blood tinged urine may also be noted. The presence of fever or abdominal pain should prompt suspicion for upper tract disease (see Plate 5-5).
In certain populations, such as the elderly, symptoms may be less speciﬁc and include depressed mental status and failure to thrive, or there may be no symptoms at all. Children less than 2-years-old may also have non-localizing symptoms. These differences likely reﬂect an inability to mount an efﬁcient immune response.
Because urethritis can sometimes mimic the symptoms of cystitis, patients should be evaluated for possible gonorrhea or Chlamydia urethritis, as well as for bacterial vaginitis or genital herpes. In addition, the differential must include the numerous causes of non bacterial cystitis. For example, trauma may cause bladder inﬂammation and is often seen in women after forceful sexual intercourse. Interstitial cystitis (also known as bladder pain syndrome) may also be associated with cystitis-like symptoms. Hemorrhagic cystitis is most commonly seen in patients undergoing cyclophosphamide treatment but can also result from adenovirus infection, especially in children. Finally, radiation therapy can cause cystitis secondary to scarring.
After a careful history is taken to assess for the above diagnoses, a midstream urine sample should be collected in a sterile fashion and sent for urinalysis with microscopic evaluation. On urine dipstick, a positive leukocyte esterase indicates the presence of white blood cells, whereas positive urine nitrites reﬂect the presence of bacteria, which reduce urinary nitrates. In the setting of suggestive symptoms, these dipstick results may be enough to warrant empiric antibiotic treatment for cystitis in otherwise healthy young women.
On microscopy, the presence of clinically signiﬁcant pyuria, deﬁned as more than 10 leukocytes per cubic millimeter, suggests active infection and should prompt empiric therapy in a patient with suggestive symptoms. Microscopic evaluation can detect bacteria in the urine but is not diagnostic, as false positives can occur due to unsterile collection technique.
A urine culture should be performed to conﬁrm the diagnosis, identify the pathogen, and determine its antibiotic susceptibilities. Infection is probable if culture yields more than 105 colony forming units (CFUs) per milliliter (mL) of a voided sample, or 104 CFUs/mL of a collected sample (i.e., with a catheter). Some women may have symptoms of cystitis and pyuria, but with either low bacterial titers or no growth on cultures. Urethritis from other causes should be considered in these cases, such as infection with Chlamydia trachomatis or Neisseria gonorrhoeae.
Imaging is generally not required in patients with acute uncomplicated cystitis, but ultrasonography or computed tomography may be pursued in those sus pected of having complicated disease or anatomic abnormalities.
In cases of uncomplicated cystitis, the Infectious Diseases Society of America recommends empiric treatment with trimethoprim-sulfamethoxazole (TMP-SMX). A 3-day course is often adequate. A 5-day course of nitrofurantoin is another acceptable ﬁrst-line treatment. In certain areas of the United States, where there is concern for resistant E. coli, a ﬂuoroquinolone may be considered as the initial agent of choice. Among ﬂuoroquinolones, ciproﬂoxacin has been shown to have the highest efﬁcacy in short courses. Other drugs that may be used include cephalosporins, amoxicillin with clavulanic acid, and tetracyclines. If the patient has a history of prior infections, susceptibilities on prior cultures should be examined before choosing the initial treatment.
When initiating treatment, rapid hydration of the patient can increase urine production and facilitate clearance of some bacteria through voiding. As discussed earlier, urinary pH plays an integral role in the innate antibacterial activity of urine. Ingestion of cranberry juice (in large quantities) can acidify the urine because cranberries contain precursors of hippuric acid, a weak organic acid. Hence, urine becomes a less hospitable medium for bacterial overgrowth, helping prevent both extension of current infection and future bacterial overgrowth.
In complicated infections, the duration and choice of therapy depend on the population in question.
For pregnant women, nitrofurantoin, sulfonamides, cephalexin, and amoxicillin with clavulanic acid should be considered, although sulfonamides should not be used near term. Fluoroquinolones and tetracyclines are classiﬁed as class C drugs for pregnant women because of their teratogenic effects. The duration of treatment for a lower UTI in a pregnant woman ranges from 3 to 7 days, with shorter courses favored to minimize antibiotic exposure.
In young ambulatory men, the presence of UTI should raise suspicion for anatomic anomalies and may prompt further evaluation with imaging studies. In older men, UTIs may occur in the setting of prostatic disease or catheterization. The choice of antibiotics for men is similar to women, but the duration of therapy should be extended to 7 to 10 days.
For chronically catheterized patients or residents of long-term facilities, the choice of an initial antibiotic agent should be based on local patterns of resistance, including susceptibility data from prior infections. Initial agents may include β-lactams or later generation cephalosporins, such as ceftriaxone or cefepime. If a UTI occurs in the presence of a urinary catheter, the catheter must be removed or changed.
Antibiotic therapy should be adjusted after cultures reveal sensitivities. In high-risk populations, including pregnant women and children, a repeat urinalysis and urine culture should be performed 2 weeks after the completion of the antibiotic course to document clearance of the infection. Low-grade bacteriuria may persist after treatment and may represent colonization in a patient who has otherwise shown clinical improvement (see Plate 5-7).
The prognosis of cystitis is usually excellent, but recurrent UTIs are common. Women who experience a UTI have at least a 20% probability of developing another one within 6 months.
UTI recurrence may be attributable to either relapse or reinfection. A relapse occurs 1 to 2 weeks after completion of treatment and involves the same pathogen responsible for the initial disease. Relapse indicates inadequate treatment, undiagnosed upper tract infection, or obstructive disease such as renal calculi or, in men, prostatic enlargement. Patients may need up to 2 weeks of antibiotics. Those with a second symptomatic relapse warrant a repeat course of antibiotics for 2 to 6 weeks, depending on the pathogen and its susceptibilities. Patients with relapsing disease should be evaluated for possible predisposing factors.
A reinfection can also occur shortly after initial therapy. Unlike in relapse, however, the causative organism may be different in the second episode.
Reinfection is especially common in cases where there are ongoing niduses of infection, such as urinary catheters with established bioﬁlms. The management strategies are the same as those outlined above for ﬁrst-time episodes. The source of infection should be identiﬁed and eliminated if possible.
Some patients will require prophylactic treatment to prevent recurrent infection. Some young women, for example, experience frequent UTIs associated with sexual intercourse. These patients should be advised to void after sexual activity and can be prescribed antibiotics for single-dose postcoital chemoprophylaxis. Trimethoprim-sulfamethoxazole, nitrofurantoin, or ciproﬂoxacin can be used in this setting. In postmenopausal women, use of intravaginal estriol cream has been shown to decrease the recurrence of UTIs. Other nonspeciﬁc therapies, such as hydration and maintenance of an acidic urine pH, are also reasonable options.