URINARY TRACT INFECTIONS

PATHOPHYSIOLOGY

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 overcome 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 nonlocalizing 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 nonbacterial 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 cyc lophosphamide 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 10 ⁵ colony forming units (CFUs) per milliliter (mL) of a voided sample, or 10 ⁴ 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 suspected of having complicated disease or anatomic abnormalities.

TREATMENT

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 con sidered 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 ).

PROGNOSIS

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.

PATHOPHYSIOLOGY

Ascension of pathogens from the lower tract is the most common mechanism of infection, and in many cases cystitis precedes pyelonephritis. The responsible pathogens, and their relative frequencies, are the same as in cystitis (see Plate 5-1 ). Many of the risk factors are also similar.

In rarer cases, the kidney may be hematogenously seeded in the setting of bacteremia, usually with gram-positive organisms (i.e., Staphylococcus aureus ).

As with cystitis, the risk of pyelonephritis depends on both host and bacterial factors. In young women, frequency of sexual activity has been associated with a higher incidence of pyelonephritis, presumably because of increased contamination of the lower urinary tract with enteric flora. Diabetics are three times more likely than non-diabetics to develop pyelonephritis during a lower tract infection because of numerous factors. Pregnant women are also at increased risk because of relaxation of smooth muscle around the ureters, which facilitates ascension of infected urine from the lower tract as well as deficiencies in certain aspects of the normal immune response. Patients with nephrolithiasis may have stones that become seeded with bacteria, which make the bacteria very difficult to clear.

Individuals with vesicoureteral reflux (VUR) have multiple factors that render them susceptible to pyelonephritis. First, the retrograde flow of urine from the bladder into the ureters facilitates bacterial ascension. Second, high-grade reflux into the ureters during voiding can cause incomplete bladder emptying and urinary stasis. Third, chronic reflux may cause upper tract scarring, which alters local antiadherence mechanisms. Fourth, those with reflux are more likely to undergo catheterization and instrumentation, which promote colonization of the urinary tract. Finally, lower tract infections may themselves increase the degree of reflux because of the increased intracystic pressure associated with inflammation. Thus individuals with vesicoureteral reflux (VUR) often experience chronic pyelonephritis during childhood, which can lead to renal scarring if severe and untreated.

Several factors determine whether a given pathogen is likely to establish upper tract infection. E. coli with type 1 and P fimbriae, for example, are more capable of adhering to the urothelium, which facilitates ascension to the renal parenchyma. These mechanisms are particularly important for pathogens causing pyelonephritis in anatomically normal urinary tracts.

As bacteria infect the upper tract, an inflammatory response occurs in the renal interstitium, where large numbers of leukocytes (predominantly neutrophils in the acute phase) may be seen. Tubular injury, suppurative necrosis, and abscess formation may occur. Even with extensive inflammation, however, the glomeruli and local vasculature generally remain intact. Neutrophils and proteinaceous material are flushed out in the urine as casts. Grossly, the kidney appears enlarged, with multiple, discrete, small surface abscesses.

PRESENTATION AND DIAGNOSIS

In addition to the symptoms associated with cystitis (see Plate 5-2 ), which may or may not be present, acute pyelonephritis features high fever, anorexia, nausea/vomiting, costovertebral angle tenderness, and flank, abdominal, or pelvic pain. Patients with severe disease may have concurrent septic shock and multiorgan failure. Older patients may have altered mental status. Acute kidney injury does not usually occur in pyelonephritis unless there is concomitant obstruction or shock.

As in cystitis, urinalysis should be positive for leukocyte esterase, indicating the presence of white blood cells, and nitrites, indicating the presence of bacteria. Proteinuria (of up to 2 g/day) may also be noted. On urine microscopy, white blood cell casts may be seen in addition to white blood cells and bacteria.

A complete blood count with differential may reveal leukocytosis with neutrophilia. In some cases, serum chemistries may reveal azotemia or electrolyte abnormalities secondary to dehydration.

Urine culture and at least two sets of blood cultures should be obtained before initiation of antibiotic therapy to determine if there is concurrent bacteremia.

In the absence of acute kidney injury or urinary tract obstruction, radiologic studies do not need to be pursued at the outset. In patients who fail to defervesce after 48 to 72 hours of treatment with appropriate antibiotics, however, a renal ultrasound or computed tomography (CT) scan of the abdomen and pelvis may be performed. In uncomplicated pyelonephritis, ultrasonography is usually normal, whereas a CT scan may reveal perinephric stranding and patchy areas of diminished, inhomogeneous enhancement. The presence of an abscess, gas collection, or obstruction indicates complicated pyelonephritis.

TREATMENT

Patients with pyelonephritis should be admitted for intravenous antibiotics if their symptoms are severe or they are unable to comply with oral treatment. For example, a toxic-appearing patient with high fevers, shaking chills, and rigors should be admitted. Patients who are pregnant or immunocompromised should also be admitted. Otherwise, patients can often be managed in an outpatient setting.

For patients being treated on an outpatient basis, fluoroquinolones are appropriate empiric treatment. In patients with drug allergies or a high likelihood of infection with resistant agents, oral third-generation cephalosporins, such as cefpodoxime, may also be considered. Patients should be advised to maintain adequate fluid intake and follow up closely until symptoms resolve.

For patients who require hospitalization and intravenous antibiotics, appropriate empiric therapies include ceftriaxone (a third-generation cephalosporin) or, in areas of low resistance, fluoroquinolones. Fluid resuscitation is also critical. The antibiotic regimen can be refined once culture results clarify the organism's sensitivities.

Empiric treatment should be more aggressive for patients with urosepsis or a high risk of being colonized with drug-resistant organisms, such as residents of long-term care facilities or those with a history of frequent hospitalizations. In such cases, initial treatment should employ a broad-spectrum antibiotic, such as piperacillin-tazobactam, ampicillin-sulbactam, or cefepime. Pending culture results, clinicians may wish to add a second agent with additional gram-negative coverage, such as an aminoglycoside or fluoroquinolone. The double coverage strategy provides the highest chances of providing an agent that is active against the causative organism; however, patients should be carefully monitored for renal toxicity and other adverse effects, especially if they are elderly.

In hospitalized patients, pyelonephritis should be treated for 7 to 14 days, depending on severity. It is advisable to obtain a repeat urine culture 5 to 9 days after the completion of treatment, since a subset of patients will experience relapse, possibly without symptoms. Patients with positive repeat cultures should undergo an additional 2 to 4 weeks of treatment and may require evaluation for the presence of an infectious focus, such as an abscess or an infected stone.

PROGNOSIS

The prognosis of uncomplicated pyelonephritis is excellent unless urosepsis occurs, in which case mortality rates are substantially higher. Moreover, in patients with chronic renal disease or renal scars from childhood pyelonephritis, acute pyelonephritis may lead to further deterioration of renal function. Poor prognosis is also associated with older age, underlying comorbidities, and infection with resistant gram-negative pathogens.