Cystitis

Etiology

Acute cystitis is typically caused by a bacterial infection of the urinary bladder. Women are particularly susceptible due to the close proximity of the rectum to the urethral meatus as well as the relatively short urethral length in females. Accounting for approximately 75% to 95% of cases, Escherichia coli is the most common etiologic agent in uncomplicated UTIs in women, followed by Klebsiella.[3] Other common etiologic pathogens include species of the Enterobacteriaceae family, such as Proteus mirabilis, and other bacteria, such as Staphylococcus saprophyticus and enterococcus. Other bacterial species very rarely cause UTIs and usually represent contamination when isolated from the urine culture of an otherwise healthy person. These include bacteria such as Group B streptococci, Lactobacillus, and other coagulase-negative staphylococci other than S. saprophyticus.[4][5][6]

Escherichia coli is also the most common cause of complicated cystitis, but the spectrum of microbial pathogens that may cause a complicated UTI is much broader and includes organisms such as Enterobacter, Citrobacter, Serratia, Pseudomonas, enterococci, staphylococci, and even fungi. The incidence of antimicrobial resistance in complicated infections is also significantly higher. Notable resistant organisms include the extended-spectrum beta-lactamase (ESBL) producing bacteria, as well as carbapenem-resistant and fluoroquinolone-resistant organisms, particularly E. coli.[7][8] 

Epidemiology

Approximately one-third of women will have had a 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 UTIs 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 cystitis episodes for every episode of pyelonephritis.[9]

Depending on the underlying condition, there is wide variation in the incidence of complicated UTIs. The estimated prevalence of asymptomatic bacteriuria in women with diabetes is 26% compared to 6% in non-diabetic females. Patients with diabetes are also at increased risk of developing both acute cystitis and pyelonephritis. UTIs are common in patients who had renal transplantation, with retrospective cohort studies showing an incidence between 47% and 75%.[10]

The risk is highest in the first year post-transplantation. Approximately 2.3% of pregnant women develop a symptomatic UTI. Other risk factors for developing a 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 of the urinary tract, urinary stents, strictures, and obstructive uropathy.[11] 

The incidence of simple cystitis in men is relatively low. It is estimated to be fewer than 10 cases per year per 10,000 men under age 65.[12] Symptoms of a simple UTI in men are the same as in women; dysuria, urinary frequency, urgency, and suprapubic pain. Recurrent symptoms or reinfections after treatment, fever and pelvic or perineal pain suggest prostatitis. Fever, chills, flank pain, or any signs of a systemic illness suggest a complicated urinary tract infection.[11] 

Pathophysiology

Cystitis usually develops due to the colonization of the periurethral mucosa by bacteria from the fecal or vaginal flora and the ascension of such pathogens to the urinary bladder. Uropathogens may have microbial virulence factors that allow them to escape host defenses and invade tissues in the urinary tract. UTIs in males are much less common due to the longer anatomic urethra, the drier periurethral environment, and the antibacterial defenses provided by the prostatic fluid. Traditionally, all UTIs in males were considered complicated. However, uncomplicated UTIs may occasionally occur, especially in males between 15 and 50, especially in those who are sexually active, are uncircumcised, or do anal intercourse, as long as they do not have any risk factors for complicated UTIs such as urologic abnormalities, bladder outlet obstruction, urolithiasis or recent urinary tract instrumentation.[13]

The underlying host factors largely determine the pathogenesis of complicated UTIs. Impairment of the immune system and voiding dysfunction from autonomic neuropathy may predispose patients with diabetes to develop UTIs. In renal insufficiency, accumulation of uremic toxins may reduce host defenses, and decreased renal blood flow may impair antimicrobial clearance. Kidney stones may cause an obstruction and provide a potential nidus of infection. In the setting of urinary catheterization, internal and external biofilms may form on the catheter, and pathogens may persist in retained pools of urine in the urinary bladder.[14]

The overwhelming identifiable bacteria causing most cases of cystitis is Escherichia coli (from 75% to 95% of cases). Other organisms causing cystitis include Klebsiella pneumoniae and Proteus mirabilis. (Klebsiella is the most common cause of UTIs after E. coli.) Patients with recent hospitalizations or prior treatment for a UTI may present with Pseudomonas, enterococci, and staphylococci, such as S. saprophyticus. Many other organisms, such as lactobacilli, Group B streptococci, and coagulase-negative staphylococci, are generally considered contaminants unless there are very high numbers of a single organism where an actual infection is possible.[15]

History and Physical

Acute cystitis often presents urinary symptoms, including dysuria, urinary frequency, urgency, suprapubic pain or tenderness, and occasionally hematuria. Based on a systematic review examining the 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 (90% correlation).[16] Symptoms may be subtle or atypical in the very young and the very old. Urine cloudiness or a "foul odor" in the absence of other signs or symptoms is generally insufficient to justify a diagnosis of cystitis.[17]

Patients with complicated acute cystitis will often present similarly to uncomplicated cystitis. Specific patient populations with complicated cystitis may have atypical symptoms. For example, patients with multiple sclerosis occasionally present with acute neurologic deterioration, while those with a 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 indicate upper UTI or pyelonephritis.

When evaluating a patient with symptoms of UTI, it is important to obtain a history of 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, anatomical or functional urinary tract abnormalities, or pregnancy.

A pelvic examination is important in evaluating women with cystitis, especially if they have recurrent urinary tract infections. Recurrent infections are defined as two documented UTIs within six months or three in one year. Management of recurrent urinary infections is discussed elsewhere, particularly in the American Urological Association Guidelines on Recurrent Urinary Tract Infections.[18] Recurrent infections with the identical organism (called a relapsing infection) suggest a urinary stone. In men, recurrent infections may also indicate chronic bacterial prostatitis. Positive urine cultures are necessary to make a definitive diagnosis of recurrent or relapsing UTIs. 

In frail and debilitated patients, many general symptoms, such as a change of mental or functional status, fevers, chills, and falls, are associated with a presumptive diagnosis of UTI. Recent evidence suggests that only urinary changes (color changes, odor, gross hematuria) and acute dysuria were reliably associated with documented UTIs.[17] Changes in urinary odor and color alone suggest bacteriuria, but the evidence is lacking that antibiotic treatment is warranted until or unless other symptoms, such as fever, develop. Recommended treatment for changes in mental status is hydration (for possible dehydration), observation, and assessment for other causes.[19] Mental status changes may or may not suggest a UTI in these patients, as studies are conflicting.[17][20]

Evaluation

The diagnosis of acute cystitis is usually made clinically in a patient with signs and symptoms consistent with a lower UTI in combination with laboratory evidence of pyuria and/or nitrites. Physical examination findings are often not necessary for the diagnosis of cystitis but may be more important for patients with pyelonephritis or vaginitis. Often in young, non-pregnant women with typical cystitis symptoms, especially in the absence of vaginal discharge or irritation, clinical suspicion may be sufficient in making the diagnosis and initiating treatment without laboratory confirmation.[1][21][22][23] However, it is highly recommended that a urinalysis and a urine culture be obtained prior to starting antibiotic treatment. If the patient does not improve on the initial antibiotic, there will be inadequate clinical information to optimally manage changes in treatment. 

Urinalysis, when indicated, is the most important laboratory test in diagnosing a UTI. A clean catch sample is usually sufficient, but if an uncontaminated specimen with few epithelial cells cannot otherwise be obtained, as in some morbidly obese women, a quick urethral catheterization should be considered. The risk of UTI from a single urethral catheterization in previously uninfected women is only about 1%.[24]

The visual appearance of the urine is notoriously unreliable when diagnosing a UTI. Clear urine may be grossly infected, and cloudy urine may be sterile with the "cloudiness" caused by calcium phosphate debris or protein. One simple test is to add a few drops of glacial acetic acid to a test tube of the cloudy urine specimen. If this causes the "cloudiness" to disappear, the urine is most likely full of calcium phosphate debris.

Pyuria, which is the presence of at least 10 white blood cells (WBCs)/HPF or leukocytes in an unspun midstream urine specimen, is almost always present. The absence of pyuria is suggestive of an alternative diagnosis.

Urinary dipsticks may also be used in the diagnosis of UTI. They detect the presence of leukocyte esterase, an enzyme produced by leukocytes, and nitrites, which indicate the presence of Enterobacteriaceae. (Nitrates are broken down to nitrites only in the presence of bacteria, so a positive nitrite test indicates or is strongly suggestive of bacteriuria).[24] Only Acinetobacter, Pseudomonas, and Enterococcus typically fail to convert nitrates to nitrites.[25] A positive dipstick test for leukocyte esterase or nitrites is helpful and confirmatory in patients with typical symptoms of acute cystitis. A negative dipstick test, however, does not reliably rule out a diagnosis of UTI.[6][26][27] 

It is reasonable to treat patients with UTI symptoms with antibiotics based on positive nitrites, but other diagnoses should be considered if the leukocyte esterase is negative.[28] The positive predictive value of having both a positive leukocyte esterase and nitrites is quite high at 85%, with an equally high negative predictive value of 92%.[28]

A urine culture is beneficial for identifying etiologic pathogens and for determining antimicrobial susceptibility profiles. Greater than or equal to 100,000 CFU (colony forming units)/mL indicates clinically relevant bacteriuria, but the growth of greater than or equal to 1,000 CFU is considered significant in men and from samples obtained through straight catheterization of the bladder. Less than 100,000 CFU/mL does not rule out a urinary tract infection.[15][29] In cases of acute uncomplicated cystitis, however, urine cultures are often considered unnecessary and not routinely done, although they can be very helpful in patients with persistent symptoms and presumed treatment failures, especially in view of the increasing rates of antibiotic resistance.[24]

Urinalyses and urine cultures must be performed prior to antibiotic therapy in all men with acute cystitis symptoms and women with risk factors for complicated UTIs. They are also indicated in patients with atypical symptoms, those who do not respond to treatment, and where symptoms recur within 2 to 4 weeks.[11] A pregnancy test should be done on women of childbearing age.

Men who have recurrent episodes of cystitis should undergo an evaluation for prostatitis. In young men who are sexually active with a single episode of cystitis, urologic evaluation may not be indicated. Risk factors for a complicated UTI should prompt a urologic evaluation and workup. 

Multiple drug-resistant organisms are becoming an increasingly difficult problem. They are defined as bacteria resistant to three or more different categories of antibiotics. Antibiotic drug resistance is a primary reason to obtain urine cultures in any potentially complicated or difficult infection and in all high-risk patients with urinary infections. 

Patients with complicated cystitis 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.[11] This may be in the form of computed tomography (CT) or ultrasonography. CT imaging is usually the test of choice and is more sensitive in detecting abnormal processes that may interfere with treatment response, such as urinary obstruction, stones, diverticula, or abscess formation. Ultrasound of the kidneys, especially when combined with a KUB (short for kidneys, ureters, and bladder: i.e., a flat plate of the abdomen), may be adequate in patients who should minimize radiation exposure or otherwise avoid CT imaging.[11] A cystoscopy may optionally be done as well. 

Treatment / Management

Acute cystitis is treated with antibiotic therapy. The selection of an antimicrobial agent depends on a patient’s risk factors for infection with multiple drug-resistant organisms. Patients who are at low risk for resistant etiologic organisms are treated with one of the first-line or preferred antimicrobial agents, which include:

• Nitrofurantoin 100 mg twice a day for 5 to 7 days
• Sulfamethoxazole-trimethoprim (SMX-TMP) double-strength twice a day for three days (if local antibiotic resistance is <20%)
• Fosfomycin 3 gm as a single oral dose
• Pivmecillinam 400 mg twice a day for 5 to 7 days (not approved in the US)[30]

Nitrofurantoin is generally the first choice antibiotic for simple cystitis. It does not promote resistance or yeast overgrowth, has a high clinical cure rate of 79% to 92%, and can be safely used even in older patients as long as their glomerular filtration rate is >60 ml/min. It has little tissue penetration and therefore is inappropriate for patients with fevers, pyelonephritis, or other evidence of systemic illness.[31][32] Nitrofurantoin is less active against organisms in the Proteeae group (Proteus, Morganella, and Providencia) which produce urease that raises the urinary pH. It has been shown that nitrofurantoin is less effective in UTIs where the urine pH is 8 or higher.[33] Nitrofurantoin is a bacteriostatic rather than a bacteriocidal drug. Therefore, it should not be given for less than five days.[24](A1)

Sulfamethoxazole-Trimethoprim (SMX-TMP) is recommended when local resistance to the antibiotic is <20%. It has good tissue penetration, including into the prostate. The overall clinical cure rate is reported as 79% to 100%.[34][35] Trimethoprim can be used alone with similar efficacy in patients with a sulfa allergy.[36] Unfortunately, resistance to SMX-TMP tends to develop relatively rapidly.[37](A1)

Fosfomycin has a similar overall clinical cure rate as nitrofurantoin.[38] It is often not included in urine culture results and is therefore not used frequently in the US. However, it retains activity against many drug-resistant organisms, including E. coli and Enterococcus; therefore, it is not recommended for routine use initially. It can be used for both Gram-negative and Gram-positive organisms, including vancomycin-resistant strains. It is less effective against Klebsiella and Pseudomonas. Also, it is inappropriate for use in real or suspected pyelonephritis due to insufficient renal tissue levels. It is a bacteriocidal drug that is generally underutilized.(A1)

It works by interfering with bacterial cell wall synthesis but in a manner distinct from beta-lactams. It is a unique antibiotic with relatively little resistance despite being available since 1969. It has been used off-label for prostatitis and has been shown to increase the immune response. It also penetrates biofilms well. While the usual dose is a single 3-gram packet, up to 3 doses can be used 2-3 days apart in complex situations.[39] Fosfomycin can safely be used in pregnancy (FDA category B), where its single-dosing schedule is advantageous.[40] Recent studies have suggested that fosfomycin can also be useful in complicated UTIs and pyelonephritis, but additional studies are needed for confirmation before this can be generally recommended.[40][41][42](A1)

Pivmecillinam is not available in the US but is used elsewhere, particularly in Nordic countries, due to its very low reported bacterial resistance.[43] It is a penicillin with an extended spectrum that is useful only in the urinary tract. Like nitrofurantoin, it does not significantly promote antibiotic resistance but is also not useful in pyelonephritis or systemic infections due to poor tissue penetration.[44] (A1)

Complicated infections are generally treated with 10 to 14 days of antibiotics. People with diabetes will be at increased risk for yeast infections during and immediately following antibiotic treatment, so appropriate steps should be taken. 

Antimicrobial selection should be individualized based on patient factors, including allergies, adverse effects, tolerability, local bacterial resistance patterns, potential drug interactions, cost and insurance coverage, renal function, compliance history, and recent use of a specific antimicrobial agent within the preceding three months. Nitrofurantoin should not be used in patients with creatinine clearance or a glomerular filtration rate (GFR) of less than 60 mL per minute, while SMX-TMP should be avoided in places where regional resistance is greater than 20%, as well as in patients with allergies to sulfa. Risk factors for such resistance include recent prior contact with healthcare, use of SMX-TMP within the previous six months, and travel, especially internationally. The suspicion of pyelonephritis or a complicated UTI also precludes the use of nitrofurantoin, fosfomycin, norfloxacin, pivmecillinam, and possibly fosfomycin because of their poor penetration into renal tissues.[6][45](B3)

Alternative or second-line antimicrobial agents are used in acute cystitis patients with factors or circumstances that prevent using the first-line agents. A 5 to 7-day course of an oral beta-lactam such as amoxicillin-clavulanate 500 mg twice daily, cefpodoxime 100 mg twice daily, cefdinir 300 mg twice daily, cefadroxil 500 mg twice daily, or cephalexin 500 mg twice daily (although this agent is less well-studied) is usually preferred. If beta-lactam agents are contraindicated, doxycycline (a tetracycline) or a fluoroquinolone such as ciprofloxacin, norfloxacin, or levofloxacin for three days (simple UTIs) or 7 to 14 days (complicated UTIs) may be used. Global resistance to SMX-TMP and amoxicillin are approaching or exceeding 20%, making these agents less useful in many geographical areas. 

Another approach is to start patients initially on a single dose of an IV parenteral agent while in the office or ER, such as ceftriaxone 1 gram, ertapenem 1 gram, or gentamycin/tobramycin 5 mg/kg. (Of these, ceftriaxone is preferred, and the aminoglycosides are reserved for those who cannot be safely given either of the other choices.) This is followed by 10 to 14 days of an oral antibiotic depending on the final urine culture results. 

Gentamicin bladder instillations can also be used to help treat UTIs, but this requires catheterization so it is generally not preferred except for selected patients, usually those with neurogenic bladders or on self-catheterization programs.[11][46][47] The suggested dosage is 30 to 60 cc of 480 mg of gentamicin/liter of normal saline or 80 mg of gentamicin in 50 to 60 mL of normal saline.[11] Tobramycin at the same dosage or neomycin/bacitracin/polymixin B (40 mg/mL) may also be used, but gentamicin has been the most studied for this purpose. Chlorhexidine and povidone-iodine bladder instillations have also been effective in reducing bacteriuria and UTIs, but not neomycin/bacitracin/polymixin B.[11][48] Bladder instillation therapy can be a reasonable option for patients already on self-intermittent catheterization with recurrent or intractable UTIs.[48](A1)

Mandelamine can be a useful prophylactic agent, especially for recurrent multi-drug resistant infections.[11][49] Given twice daily (1,000 mg BID), mandelamine is converted to formaldehyde in the bladder if the urine is acidic (5.5 or less).[50] It is usually given together with 500 to 1,000 mg of vitamin C to maintain urinary acidity.[11] Mandelamine should not be used if the glomerular filtration rate (GFR) is <10 mL/min or if the urinary pH cannot be maintained at 5.5 or less. It also is not recommended for use together with sulfonamides due to potential precipitation.[11](A1)

D-mannose has also been used with some success as a non-antibiotic-based UTI prophylactic agent, with some studies and meta-analyses suggesting equivalence with antibiotic prophylaxis.[51][52][53] It is well tolerated with few side effects but is not appropriate for treating an active UTI. The suggested dosage is 2 grams daily. While it seems to be generally helpful as a prophylactic agent, the available data and studies are far from conclusive.[51][52][53][54](A1)

Urine culture and sensitivity testing are required to guide antimicrobial regimens in patients at risk for multiple drug-resistant (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 a high prevalence of MDR organisms, or use of broad-spectrum antimicrobial agents in the previous three months. The appropriate empiric regimen includes nitrofurantoin, SMX-TMP, fosfomycin, and pivmecillinam (if available). An alternative approach would be to defer treatment until culture and susceptibility results are available, especially if the use of any of the above first-line agents is precluded for any reason.

Symptomatic treatment with analgesics may be used in patients with severe dysuria. Phenazopyridine is a urinary analgesic used in the short-term treatment of urinary dysuria or discomfort, but it is not therapeutic and will not affect the clinical course of an infection.

Cystitis in men is relatively uncommon and not very well studied. In a healthy man without any risk factors for a complicated UTI or any symptoms suggestive of infection outside the bladder, the treatment approach should be the same as in women with a complicated UTI. For men with severe symptoms, anatomical or urologic abnormalities, or suspicion of prostate involvement, fluoroquinolones have been recommended for initial use as empiric therapy, pending culture and susceptibility testing results and local quinolone resistance patterns. Quinolones are preferred initial agents, when possible, due to their broad spectrum of activity and high tissue penetration levels. Doxycycline, SMX-TMP, and cephalosporins may also be used initially, which help minimize quinolone resistance. All men with clearly diagnosed UTIs have generally been considered complicated infections and are at risk for developing chronic prostatitis, which may not become clinically apparent for weeks or even months after the initial infection. For this reason, some recommend using prostate-penetrating antibiotics (doxycycline, SMX-TMP, quinolones) in all men with UTIs for at least four to six weeks to allow for the buildup of adequate antibiotic concentrations inside the prostate and reduce the likelihood of developing subsequent chronic prostatitis.[11] 

Patients who do not respond to an appropriate 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 should be obtained, and patients must be treated with a different empiric antimicrobial agent with subsequent tailoring of the regimen based on susceptibility results.[6][11] 

Differential Diagnosis

In female patients with dysuria, differential diagnoses include vaginitis and urethritis. Vaginitis is usually associated with vaginal discharge, dyspareunia, and pruritus. Its 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. Prostatitis must be ruled out in men with lower UTI symptoms, especially when associated with fever, malaise, perineal pain, or obstructive urinary symptoms. Recurrent UTIs in male patients should heighten suspicion of chronic bacterial prostatitis.

• Painful bladder syndrome - No evidence of infection (pyuria, bacteriuria, positive urine cultures) but symptoms of frequency, urgency, and dysuria.; it is usually a diagnosis of exclusion. 
• Pelvic inflammatory disease - This is associated with pelvic and lower abdominal pain, fever, and possible cervical discharge.
• Prostatitis - May present with ejaculatory pain and/or vague pelvic discomfort along with a soft, boggy, tender prostate on rectal exam. Urinalysis is usually negative.
• Vaginitis - Usually associated with vaginal discharge, itching, odor, dyspareunia, and possibly dysuria. Typically no urinary urgency or frequency.
• Vaginitis, atrophic (hormonal) - This condition presents in post-menopausal women and is associated with vaginal dryness, dyspareunia, vaginal discharge (thin, watery), pale labia, and vaginal lining.
• Urethritis - White cells (pyuria) present on urinalysis but no bacteriuria. Sexually active women are at high risk. 

Prognosis

Patients with uncomplicated cystitis typically have an improvement in symptoms within three days after initiation of antibiotic therapy. Recurrent cystitis occurs in 25% of women within six months after their 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 a lower urinary tract infection. It is associated with gas formation in the bladder wall and is potentially fatal if not properly managed. Emphysematous cystitis is more likely to cause abdominal pain (80%) than simple cystitis (50%); pneumaturia will likely be present in about 70% of patients, and half will have bacteremia. The diagnosis is most reliably made with a CT scan. The primary risk factor is diabetes which is present in about 2/3 of affected patients. Other risk factors include female gender, immunocompromised conditions, urinary abnormalities, urinary obstruction or retention, indwelling urinary catheter, age over 60, and chronic UTIs.[55][56] 

Treatment is primarily medical with antibiotics, but catheter drainage should be used in cases of retention, incomplete bladder emptying, or significant hematuria. About 10% of patients will develop a necrotizing infection of the bladder wall and will require surgical intervention involving partial or complete resection.[56]

Complications

• Pyelonephritis
• Renal or perinephric abscess formation
• Renal vein thrombosis
• Sepsis
• Acute renal failure
• Emphysematous pyelonephritis
• Prostatitis