Cystitis refers to infection of the lower urinary tract, or more specifically the urinary bladder. It may be broadly categorized as either uncomplicated or complicated. Uncomplicated cystitis refers to lower urinary tract infection (UTI) in either men or non-pregnant women who are otherwise healthy. Complicated cystitis, on the other hand, is associated with risk factors that increase the risk of infection or the risk of failing antibiotic therapy.
Bacterial infection typically causes acute cystitis. Escherichia coli is the most common etiologic agent in uncomplicated UTI in women, accounting for approximately 75% to 95% of cases. Other common etiologic pathogens include species of the Enterobacteriaceae family such as Proteus mirabilis and Klebsiella pneumoniae and other bacteria such as Staphylococcus saprophyticus. Other bacterial species very rarely cause UTI and usually represent contamination when isolated from a urine culture of an otherwise healthy person. These include bacteria such as Group B streptococci, enterococci, and Lactobacillus, and other coagulase-negative staphylococci other than S. saprophyticus.
Escherichia coli remains the most common cause of complicated cystitis, but the spectrum of microbial pathogens that may cause UTI is much broader and includes organisms such as Enterobacter, Citrobacter, Serratia, pseudomonads, enterococci, staphylococci, and even fungi. The incidence of antimicrobial resistance in complicated infection is also significantly higher. Notable resistant organisms include the extended-spectrum beta-lactamase (ESBL)-producing organisms, carbapenem-resistant organisms, and fluoroquinolone-resistant organisms.
Approximately one-third of women will have had UTI by age 24 and one half by age 32. The incidence of UTI is 12% in women based on self-reported annual incidence. A university cohort study estimates the annual incidence of UTI at 0.5 to 0.7 UTI per person-year in sexually active women. Factors that increase the risk for uncomplicated cystitis include sexual intercourse, spermicide use, new sex partner within the past year, previous UTI, strong family history of UTI in a first-degree female relative, and post-menopausal state. Acute cystitis is much more common than pyelonephritis with an estimated ratio of 18 to 28 episodes of cystitis for every episode of pyelonephritis.
There is wide variation in the incidence of complicated UTI depending on the underlying condition. The estimated prevalence of asymptomatic bacteriuria in women with diabetes is 26% compared to 6% in women without diabetes. Patients with diabetes are also at increased risk of developing both acute cystitis and pyelonephritis. UTI is common in patients who had renal transplantation with retrospective cohort studies showing an incidence between 47% to 75%. The risk is highest in the first year post-transplantation. Approximately 2.3% of pregnant women develop symptomatic UTI. Other risk factors for developing complicated UTI include nephrolithiasis, immunocompromised status, the presence of foreign bodies such as a urinary catheter, urinary tract instrumentation, renal insufficiency, functional or anatomic abnormality in the urinary tract, and obstructive uropathy.
Cystitis usually develops due to the colonization of the periurethral mucosa by bacteria from the fecal or vaginal flora and ascension of such pathogens to the urinary bladder. Uropathogens may have microbial virulence factors that allow them to escape host defenses and invade host tissues in the urinary tract. UTI in males is much less common due to the longer anatomic urethra and antibacterial defenses provided by the prostatic fluid. Traditionally, all UTIs in males were considered complicated. However, uncomplicated UTIs may occur especially in males between 15 and 50 especially in those who are sexually active and uncircumcised as long as they do not have any risk factors for complicated UTIs such as urologic abnormalities, bladder outlet obstruction, or recent urinary tract instrumentation.
The underlying host factors largely determine the pathogenesis of complicated UTI. Impairment of the immune system and voiding dysfunction from autonomic neuropathy may predispose patients with diabetes to develop UTI. In renal insufficiency, accumulation of uremic toxins may reduce host defenses and decreased renal blood flow may impair antimicrobial clearance. Kidney stones may cause obstruction and may provide a nidus of infection. In the setting of urinary catheterization, internal and external biofilm may form on the catheter and pathogens may persist in retained pools of urine in the urinary bladder.
Acute cystitis often presents with urinary symptoms which include dysuria, urinary frequency urgency, suprapubic pain or tenderness, and occasionally hematuria. Based on a systematic review examining history and examination findings of women with uncomplicated UTI, the combination of dysuria and urinary frequency in the absence of vaginal discharge or irritation is highly predictive of uncomplicated cystitis. Symptoms may be subtle or atypical in the very young and the very old. Elderly patients with UTI may present with confusion or altered mental status.
Patients with complicated acute cystitis will often present in a similar manner to uncomplicated cystitis. Certain patient populations with complicated cystitis may have atypical symptoms. For example, patients with multiple sclerosis occasionally present with acute neurologic deterioration while those with spinal cord injury may present with autonomic dysfunction or increased spasticity.
Cystitis may be differentiated from pyelonephritis by the absence of systemic findings such as fever, chills, or sepsis. Findings such as flank pain, costovertebral angle tenderness, nausea, and vomiting are also more indicative of upper UTI or pyelonephritis.
When evaluating a patient with symptoms of UTI, it is important to obtain history on any previous episode of UTI, any recent antibiotic use, or any other risk factors that may predispose one to complicated infection such as diabetes, immunocompromised status, recent urologic procedures or instrumentation, renal transplantation, history of kidney stones, history of anatomical or functional urinary tract abnormalities, or pregnancy.
The diagnosis of acute cystitis is usually made clinically in a person with signs and symptoms consistent with a lower UTI in combination with laboratory evidence of pyuria. Physical examination findings are often not necessary for the diagnosis of cystitis but may be more important for patients with pyelonephritis. Often in young, nonpregnant women who have typical symptoms of cystitis and especially in the absence of vaginal discharge or irritation, clinical suspicion may be sufficient in making the diagnosis and in initiating treatment without laboratory confirmation.
Urinalysis, when indicated, is the most important laboratory test in the diagnosis of UTI. Pyuria, which is the presence of at least 10 WBCs or leukocytes in an unspun midstream urine specimen, is almost always present. The absence of pyuria is indicative of an alternative diagnosis. Urine dipsticks may also be used in the diagnosis of UTI. They detect the presence of leukocyte esterase, an enzyme produced by leukocytes, and nitrite, which is indicative of the presence of the Enterobacteriaceae. A positive dipstick test for leukocyte esterase or nitrite is most helpful in patients with typical symptoms of acute cystitis. A negative dipstick test, however, does not reliably rule out a diagnosis of UTI.
A urine culture is useful for identifying the etiologic pathogens and for determining antimicrobial susceptibility profiles. Greater than or equal to 100000 CFU/mL indicates clinically relevant bacteriuria, but the growth of greater than or equal to 1000 is considered significant in men and samples obtained through straight catheterization. In cases of acute uncomplicated cystitis, however, urine culture is often unnecessary and not routinely done. Urinalysis and urine culture must be performed prior to therapy in all men who present with symptoms of acute cystitis and all women who have risk factors for complicated UTI. They are also indicated in patients with atypical symptoms, and in those who do not respond to treatment or who have a recurrence of symptoms within 2 to 4 weeks. A pregnancy test must be done in women of childbearing age. Men who have recurrent episodes of cystitis must undergo evaluation for prostatitis. In young men who are sexually active with a single episode of cystitis, urologic evaluation is often not indicated. Any risk factors for complicated UTI should, however, prompt urologic evaluation and workup.
Patients who have complicated cystitis and who do not respond after 48 to 72 hours of appropriate antimicrobial treatment will require further evaluation through radiographic imaging of the upper urinary tract. This may be in the form of computed tomography or ultrasonography. CT imaging is usually the test of choice and is more sensitive in the detection of processes that may interfere with treatment response such as obstruction, stone formation, or abscess formation. Ultrasound of the kidneys may be adequate in patients who should not be exposed to radiation.
Acute cystitis is treated with antibiotic therapy. The selection of an antimicrobial agent depends on a patient’s risk factors for infection with a multidrug-resistant (MDR) organism. Patients who are at low risk for resistant etiologic organisms are treated with 1 of the first-line or preferred antimicrobial agents which include:
Antimicrobial selection should be individualized based on patient factors which include allergy, adverse effects, tolerability, local resistance patterns, cost, or recent use of a specific antimicrobial agent within the preceding three months. Nitrofurantoin should not be used in patients with creatinine clearance of less than 30 mL per minute and TMP-SMX must be avoided in places with regional resistance greater than 20%. The suspicion for pyelonephritis or complicated UTI also precludes the use of nitrofurantoin, fosfomycin, and pivmecillinam because of poor penetration into the renal tissue.
Alternative or second-line antimicrobial agents are used in acute cystitis in patients with factors or circumstances that prevent the use of the first-line agents. A 5 to 7-day course of oral beta-lactams such as amoxicillin-clavulanate 500 mg twice daily, cefpodoxime 100 mg twice daily, cefdinir 300 mg twice daily, cefadroxil 500 mg twice daily, and cephalexin 500 mg twice daily (although this agent is less well-studied) is usually preferred. If beta-lactam agents are contraindicated, a fluoroquinolone such as ciprofloxacin or levofloxacin for 3 days may be used.
Urine culture and sensitivity testing are required to guide antimicrobial regimen in patients who are at risk for MDR organisms. Risk factors include a previous MDR isolate (resistant to three or more antimicrobial classes), recent stay in a healthcare facility, recent travel to areas with high prevalence of MDR organisms, or recent use of broad-spectrum antimicrobial agents in the past three months. The appropriate empiric regimen includes nitrofurantoin, fosfomycin, and pivmecillinam (if available). An alternative approach would be to defer treatment until culture and susceptibility results are available especially if factors preclude the use of any of the above said first-line agents.
Symptomatic treatment with analgesics may be used in patients who present with severe dysuria. Phenazopyridine is a urinary analgesic used in short-term treatment of urinary dysuria or discomfort.
Cystitis in men is uncommon and not very well studied. In a healthy man without any risk factors for complicated UTI or without any symptoms suggestive of infection outside the bladder, the treatment approach should be the same as that in women with uncomplicated UTI. For men who have severe symptoms, anatomical or urologic abnormalities, or suspicion of prostate involvement, a fluoroquinolone should be used for empiric therapy pending culture and susceptibility testing results.
Patients who do not respond to antimicrobial regimen after 48 to 72 hours or who have a recurrence of symptoms within a few weeks will require further evaluation including consideration of other potential causes or infection with resistant organisms. Urine culture and susceptibility testing must be obtained, and patients must be treated with a different empiric antimicrobial agent with the subsequent tailoring of the regimen based on susceptibility results.
In female patients who present with dysuria, differential diagnoses include vaginitis and urethritis. Vaginitis is usually associated with vaginal discharge, dyspareunia, and pruritus and causes include bacterial vaginosis, trichomoniasis, or yeast infection. Painful bladder syndrome may be considered in patients with persistent symptoms of bladder discomfort but with no evidence of infectious etiology. This is, however, a diagnosis of exclusion. In men with lower UTI symptoms, prostatitis must be ruled out especially when associated with fever, malaise, perineal pain, and obstructive urinary symptoms. Recurrent UTIs in male patients should heighten suspicion for chronic bacterial prostatitis.
Patients with uncomplicated cystitis typically have improvement of symptoms within 3 days after initiation of antibiotic therapy. Recurrent cystitis occurs in 25% of women within 6 months after the first UTI and the rate increases in women with more than one prior UTI. Complications are rare especially in patients who are appropriately treated. Bacteremia and sepsis from uncomplicated cystitis are uncommon. Emphysematous cystitis is a rare but serious complication of lower UTI. It is associated with the gas formation in the bladder wall and may be potentially fatal if not adequately managed. Risk factors include diabetes, immunocompromised conditions, urinary abnormalities, urinary obstruction, indwelling urinary catheter, and chronic UTIs. In cases of necrotizing infection, surgical intervention may be required.