Cystitis

OVERVIEW: What every practitioner needs to know

Are you sure your patient has cystitis? What should you expect to find?

The discussion that follows is limited to infectious causes of cystitis.

Urinary tract infection (UTI) is the most common bacterial illness occurring in adults. Fungal UTIs are common in catheterized, but not in noncatheterized, patients. Viral UTIs are uncommon.

UTI is defined as the presence of urinary symptoms in the presence of significant levels of bacteria in the urine. Patients with significant bacteriuria in the absence of symptoms referable to the urinary tract are considered to have asymptomatic bacteriuria. Although asymptomatic bacteriuria is common, it is of clinical significance only in pregnant women and individuals who undergo invasive genitourinary procedures. There are no quantitative levels established for diagnosing fungal or viral UTI.

UTI in women with no functional or structural abnormality of the urinary tract is considered to be uncomplicated, whereas UTI in patients with abnormalities of the urinary tract or comorbidities that increase the risk of treatment failure or serious complications are considered complicated.

Complicating factors include obstruction (e.g., from strictures, tumors, urolithiasis, prostatic hypertrophy), instrumentation (e.g., indwelling urethral catheter, ureteral stent), impaired voiding (e.g., neurogenic bladder, vesicoureteral reflux, ileal conduit), metabolic abnormalities (e.g., poorly controlled diabetes mellitus, renal failure, immunosuppression (e.g., renal transplant), pregnancy, and male sex (prostatitis may be present). In general, children with UTIs are relatively more likely than adults to have a complicating factor, thus, UTIs in children are considered complicated.

Cystitis (bladder infection) in the noncatheterized person is manifested by dysuria, urinary frequency, urinary urgency, and/or suprapubic pain and may be accompanied by hematuria. Pyelonephritis (upper tract infection) or other more invasive disease should be considered if the patient has fever, back pain, nausea/vomiting, hemodynamic instability, or other manifestations of severe disease.

Symptoms of complicated cystitis may be absent or difficult to elicit if the patient is very young, has altered mental status, has decreased sensation (neurogenic bladder), or is catheterized. Catheterized patients do not manifest the usual symptoms of dysuria, frequency or urgency. Moreover, catheterized patients often have pyuria and bacteriuria, thus, it is difficult to determine whether cystitis versus asymptomatic bacteriuria is present.

UTI in catheterized patients is usually considered present if fever accompanies significant bacteriuria, but fever is generally thought to represent significant tissue involvement as seen with upper tract infection. Since reliable noninvasive localization tests to distinguish between lower and upper tract infection in patients with bacteriuria do not exist, it is not clear if bladder infection alone, in catheterized or noncatheterized patients, causes fever. However, bacteria invade the bladder epithelium in the mouse model, and it is possible that at least low grade fever is compatible with infection localized to the bladder in humans. Clinically, however, the presence of fever suggests the extension of infection beyond the bladder.

UTI in patients with neurogenic bladder may be associated with symptoms of increased spasticity or autonomic dysreflexia. As noted, it is not possible to know whether these symptoms can be caused by cystitis only or whether they represent a response to more invasive infection.

Key physical findings with cystitis are the presence in some patients of mild to moderate suprapubic tenderness and, in women, the absence of vaginal discharge and irritation. Fever and costovertebral angle tenderness suggest pyelonephritis. Patients with cystitis are generally not ill-appearing, but severe dysuria can lead to marked discomfort. In patients with altered mental status, the diagnosis of cystitis is difficult. UTI is suspected in the setting of fever and bacteriuria with no other obvious cause for the fever, but, again, it is not clear whether fever can be associated with isolated cystitis.

Cloudy or odorous urine alone are not diagnostic of symptomatic infection and do not warrant antimicrobial treatment. However, some patients with recurrent UTI are adamant that such symptoms and signs are reliable indicators of subsequent symptomatic infection and want to be treated.

If the diagnosis of UTI is not clear cut in a woman, a pelvic examination should be considered to rule out urethritis or cervicitis. Pregnancy testing may also be appropriate in women of childbearing age.

A urine culture is of limited use in uncomplicated cystitis, since empiric treatment is usually successful and results usually become available after the patient’s symptoms have resolved. Culture is more useful for diagnosis and treatment in those with early or multiple recurrences. Urine culture should always be performed in patients with complicated UTI, because complicated UTIs are more likely to be caused by multiple-antimicrobial resistant organisms and culture and susceptibility results can assist with antimicrobial selection.

Absence of bacteriuria suggests that UTI is not the cause of the patient’s symptoms. However, most laboratories do not quantify urine cultures below 10⁴CFU/mL, thus, a negative culture report may be misleading (since cystitis is often associated with lower colony counts). Conversely, a positive urine culture only indicates the patient has bacteriuria. It does not distinguish between asymptomatic bacteriuria and symptomatic UTI or whether antimicrobial treatment is indicated.

Likewise, absence of pyuria suggests an alternative diagnosis, but the presence of pyuria does not necessarily mean the patient warrants antimicrobial treatment for UTI.

E. colicauses up to 95% of episodes of uncomplicated cystitis. Although E. coliis also the most commonly isolated organism in complicated cystitis, there is a broader spectrum of uropathogens in complicated UTI and a much higher prevalence of antimicrobial-resistant uropathogens.

The recommended duration of treatment for women with uncomplicated cystitis is 1 to 5 days, depending on the regimen used (Table I), and for complicated cystitis is at least 7 days (Table II).

Table I:

Table II:

How did the patient develop cystitis? What was the primary source from which the infection spread?

Cystitis in women develops when bacteria, usually E. colior other Enterobacteriaceae, or yeast from ingested products reach the patient’s fecal flora and, from there, move to the vagina and periurethra, the urethra, and ultimately the bladder. This process is facilitated by the proximity of the urethra to the rectum, allowing frequent colonization of the periurethral area and then ascension to the bladder via the short urethra. Movement of bacteria from the vagina to the bladder is facilitated by intercourse. In men, the same process is thought to occur, but urinary tract infections are much less common, probably because of the distance between the urethral meatus and the rectum, the long urethra, and antibacterial properties of prostatic fluid.

The events that determine whether bacteriuria is transient or persists in an asymptomatic state (asymptomatic bacteriuria) or cystitis (symptomatic bladder infection), are not known. Further, it is not known what factors in a healthy person result in bacteria ascending the ureters to the kidney to cause pyelonephritis.

Bacteremia as a source of cystitis is rare but might be the case in some patients with Staphylococcus aureusbacteremia that seeds the kidneys and then the bladder.

In catheterized men and women, bacteria from the patient’s endogenous flora or from an exogenous source, such as the hands of a healthcare worker or a contaminated urine collection device, can ascend to the bladder via the extraluminal or intraluminal route.

In some cases, uropathogenic bacteria appear inoculated directly into a woman’s vagina during intercourse with a man who is colonized. Likewise, there are reports of men who develop a UTI following intercourse with a woman who carries the same uropathogen. Such sexual transmission of uropathogens is hard to prove but is highly suggested by studies in which uropathogenic strains of sexual partners have been typed and compared.

Uropathogenic E. coli, the predominant pathogen causing uncomplicated cystitis and pyelonephritis, are a specific subset of extraintestinal pathogenic E. coliwith enhanced virulence potential. Virulence and fitness factors include pili, fimbriae, flagella, adhesions, siderophores, toxins, polysaccharide coatings, and other properties that enable the bacteria to avoid or subvert host defenses, injure or invade host tissues, and stimulate an inflammatory response.

E. colithat cause complicated UTI, conversely, have a lower prevalence of genetic or phenotypic virulence characteristics and are less likely to originate from a uropathogenic clone than strains causing acute uncomplicated UTI. Thus, host factors are relatively more important in the pathogenesis of complicated UTI than in uncomplicated UTI.

Recurrent cystitis, most episodes of which are caused by the genetically identical strain of bacteria as the previous episode (in healthy women), is thought to have the same pathogenesis. Uropathogenic strains can persist in the fecal flora for years after elimination from the urinary tract with antimicrobials and cause subsequent recurrent uncomplicated cystitis. Moreover, recent studies in mice have shown that E. coliinoculated into the bladder rapidly invade the bladder epithelium, form intracellular colonies of bacteria that resist clearance by host defenses or with antimicrobials, and develop reservoirs of bacteria in the epithelial lining of the bladder that then can recur in bacteriuric episodes. It is not known whether this phenomenon occurs in the human, but intracellular populations of bacteria, similar to those observed in the mouse model, have been identified in exfoliated cells in the urine of some women with cystitis. Thus, it is possible that some same-strain recurrences of cystitis are, in fact, due to a persistent nidus of infection in the bladder following “successful” treatment.

In men, the prostate may become chronically infected and intermittently cause recurrent cystitis. Same-strain recurrent cystitis in men is suggestive of chronic bacterial prostatitis, and this diagnosis should be considered in men with recurrent cystitis.

In other patients with complicated UTI, recurrent infections may be related to reinfection with the same or different species in the same way described above for uncomplicated infection or to relapse secondary to a persistent nidus of infection related to a complicating factor, such as nephrolithiasis or a chronic urologic device.

Which individuals are at greater risk of developing cystitis?

Women are much more likely than men to develop uncomplicated cystitis. Whereas cystitis in the normal healthy male is rare, the self-reported annual incidence of UTI in women is approximately 12% and, by 32 years of age, one-half of all women report having had at least one UTI. The incidence of cystitis in young healthy women starting a new contraceptive method was 0.5 to 0.7 episodes per person-year. In a population-based study of postmenopausal women, the incidence of cystitis was 0.07 episodes per patient-year. Among young women who present with their first UTI, the recurrence rate within 6 months is approximately 24%, if the UTI was caused by E. coli, but only 8% if caused by another uropathogen. In other studies, among women who present with acute cystitis, the recurrence rate at 3 months has been shown to be approximately 33%. In one study, the recurrence rate during 1 year was 44%.

Risk factors

Risk factors for cystitis in healthy women include recent sexual intercourse, recent spermicide use (including spermicide-coated spermicides), having a history of a previous UTI, and having a new sexual partner in the past year. Case-control studies have shown no associations between recurrent cystitis and pre- and postcoital voiding patterns, frequency of urination, delayed voiding habits, wiping patterns (front to back/back to front), douching, use of hot tubs, or occlusive underwear.

A genetic predisposition to recurrent cystitis in otherwise healthy women is suggested by the strong associations between women with recurrent cystitis and UTI history in their first degree female relatives. For example, there is evidence that polymorphisms affecting the innate immune response may be associated with an increased risk of cystitis in women. In addition, women who are nonsecretors of blood group antigens are more likely to have recurrent cystitis because of the increased number of receptors for E. coli on the surface of uroepithelium.

Risk factors for acute cystitis in postmenopausal women include insulin-treated diabetes and a previous history of multiple UTIs. Some studies have shown that sexual activity, urinary incontinence, parity, postcoital urination, vaginal dryness, and postvoid residual bladder volume are not independently associated with acute cystitis in this population. On the other hand, other studies in this population have shown an association with sexual intercourse, increased residual urine volume, cystocele, and prior genitourinary surgery. Cystoscopy occasionally identifies a bladder diverticulum, which may or may not be a predisposing factor to recurrent UTI, in such women.

Some women note onset or increased frequency of cystitis following bladder surgery, such as bladder suspension for incontinence. Such women may be found to have partial bladder outlet obstruction by urodynamic studies.

In otherwise healthy men, risk factors for cystitis include lack of circumcision (probably due to colonization of the prepuce) and homosexuality (association is with insertive anal intercourse).

Urinary catheterization is a strong risk factor for UTI in both men and women. Although female sex is a risk factor for catheter-associated UTI, the female:male UTI risk is not nearly as great as with uncomplicated UTI. Catheterization facilitates access to the bladder by both endogenous and exogenous bacteria.

Beware: there are other diseases that can mimic cystitis:

Dysuria may be seen with other conditions, including urethritis or vaginitis or urethral trauma. Perhaps most important, it is often difficult to determine whether symptoms in a patient with bacteriuria are due to cystitis or to some other cause. It is a special challenge to distinguish symptomatic infection versus asymptomatic bacteriuria in a patient who has altered mental status, decreased sensation, or urethral catheterization.

Vaginitis may be associated with dysuria but is usually manifested by vaginal discharge or odor, pruritus, dyspareunia, and absence of frequency or urgency. The most common causes are yeast, trichomonas, or bacterial vaginosis. Studies have shown that women with symptoms of cystitis have a much higher likelihood of having UTI if vaginal irritation or discharge is absent.

Urethritis caused by chlamydia, gonorrhea, trichomonas, yeast, herpes simplex virus, or noninfectious irritants may cause dysuria, but usually are not associated with urinary frequency or urgency.

Cystitis is also more likely than these other conditions if hematuria is present, if the symptoms are of acute onset, or if the patient has a known history of documented UTI manifested by similar symptoms.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

A quantitative urine culture is the most important test for confirming the diagnosis of cystitis, but, as noted previously, a positive culture does not by itself signify clinical importance (i.e., whether the patient’s symptoms are related to the bacteriuria, thus, whether the patient warrants treatment for a UTI). The absence of bacteriuria in a urine culture is helpful in that it suggests (if collected in an appropriate manner before the patient is treated) a UTI is not the cause of the patient’s symptoms.

Pyuria is present in almost all persons with cystitis (and in many with asymptomatic bacteriuria), but the presence of pyuria does not distinguish symptomatic from asymptomatic UTI. In this regard, the vast majority of patients with catheter-associated bacteriuria have pyuria, even when they have no symptoms or fever. In addition, pyuria may be present with conditions other than UTI. The absence of pyuria is most useful in diagnosis of UTI, since it suggests another condition is causing the symptoms.

Pyuria is usually assessed with a commercially available dipstick that detects the presence of leukocyte esterase or by direct microscopy. A small proportion of patients with symptoms of cystitis with true bladder bacteriuria have a negative test for pyuria, perhaps related to specimen transport or storage.

The presence of nitrite reflects the presence of Enterobacteriaceae, which convert urinary nitrate to nitrite. The nitrite test is usually combined with the leukocyte esterase test on the urine dipstick. The test is sensitive and specific for detection of high levels of Enterobacteriaceae, but the sensitivity is lower for detection of some other organisms, such as S. saprophyticusand Enterococcus, and with low colony counts that can occur in a high proportion of patients with uncomplicated cystitis. Moreover, false-positive tests can occur in patients who have ingested substances that can discolor the urine, such as phenazopyridine and beets.

Gross or microscopic hematuria is commonly seen in patients with cystitis and is a useful clue, as this finding is not usually seen in other causes of dysuria, such as urethritis or vaginitis.

Other findings on urinalysis, including urine Gram stain results, are neither sensitive nor specific for the diagnosis of cystitis.

Blood tests are generally not warranted if symptoms suggest cystitis.

Results that confirm the diagnosis

Pyuria is present in almost all patients with cystitis. The sensitivity and specificity of pyuria in young healthy women for detection of significant levels of bacteriuria is approximately 75 to 96% and 94 to 98%, respectively. In catheterized individuals, the sensitivity and specificity are much lower. In either setting, the absence of pyuria is of greater significance, as it should lead one to consider an alternative diagnosis. As noted, the presence of pyuria does not allow one to distinguish between asymptomatic bacteriuria or cystitis and, thus, whether treatment is indicated.

A urine culture can confirm the presence of significant bacteriuria and, thus, cystitis in a patient with typical symptoms. Although the traditional definition of significant bacteriuria in voided urine (i.e., that level of bacteriuria suggesting true bladder bacteriuria) is at least 10⁵CFU/mL, studies of paired voided and bladder aspirate or catheter urine specimens have shown that lower colony counts in voided urine are meaningful. Thus, counts as low as 10²CFU/mL of an uropathogen in voided urine in a symptomatic patient are considered significant. One recent study in women comparing voided urine specimens with catheter urine specimens showed that low colony counts of E. coli in voided urine was highly predictive of bladder urine colony counts, but that low colony counts of enterococci and Group B streptococcus in voided urine were not predictive of growth in the bladder, suggesting that these latter organisms were more likely to represent urethral contaminants. Low counts of any organism are likely to be significant in catheter urine specimens.

Given that commercial laboratories often do not quantify to levels below 10⁴CFU/mL in voided urine, guidelines suggest that at least 10³CFU/mL of uropathogens in voided or catheter urine should be the threshold for significant bacteriuria in men and women with symptoms of UTI. Importantly, laboratory reports of no or insignificant bacterial growth from a urine culture should be ignored in a patient with urinary symptoms if the laboratory does not quantify to low colony counts.

If the laboratory does quantify to low levels of bacteriuria and if the colony count is less than 10²CFU/mL (note, however, that such low quantities are likely to be reported only in UTI research laboratories), then cystitis is an unlikely diagnosis and other conditions should be considered. Of note, even in research laboratories, a small percentage of young healthy women with typical symptoms of acute uncomplicated cystitis and pyuria have no detectable growth on urine cultures. It is possible that symptoms in such women are caused by fastidious organisms or perhaps from noninfectious conditions.

The diagnosis of cystitis is made in the setting of typical symptoms, absence of vaginal discharge and irritation in a woman, and absence of upper tract infection symptoms (pyelonephritis). The presence of pyuria and significant bacteriuria provide supportive evidence for UTI, but their absence suggests an alternative diagnosis.

Pyelonephritis and severe prostatitis, but not cystitis, may be associated with positive blood cultures.

What imaging studies will be helpful in making or excluding the diagnosis of cystitis?

Imaging studies are generally not indicated in women with recurrent uncomplicated cystitis. Thus, studies have shown that anatomic abnormalities are occasionally found in such women but are not necessarily associated with risk of UTI and/or often not correctable.

Host factors are of greater importance in complicated UTI, and recurrent infections may be prevented if a urologic abnormality that predisposes to infection can be corrected. Thus, imaging studies are often performed in men or women with recurrent complicated cystitis to look for a predisposing cause, but the role of such studies has not been clearly defined. The diagnostic approach should be determined by patient history and clinical presentation. Bladder ultrasound or cystoscopy is indicated in the presence of hematuria or atypical urinary symptoms to rule out bladder stones or cancer. Renal and pelvic ultrasound, computed tomography (CT) urogram, magnetic resonance imaging (MRI), intravenous or retrograde pyelography, or urodynamic studies may be indicated in the workup of causes for recurrent UTI.

Ultrasound or CT may also be warranted in acutely infected patients to rule out a serious problem, such as obstruction, but more invasive studies are usually performed after the infection is under control.

As noted, recurrent cystitis is a hallmark of chronic prostatitis in men. Imaging studies are generally not helpful in establishing the diagnosis of chronic prostatitis in men.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has cystitis, what therapies should you initiate immediately?

Consult services are generally not indicated for patients with cystitis. However, it may be appropriate to consult Urology or Infectious Diseases for patients with recurrent cystitis to determine whether imaging studies or cystoscopy is indicated. In healthy ambulatory women with recurrent uncomplicated cystitis with typical symptoms, the yield of urological evaluation is very low. Children, men, and older women with recurrent cystitis should have urological evaluation to rule out an obvious predisposing factor that may be correctable. Infectious Diseases should be consulted for help with management of a patient infected with a highly resistant uropathogen, such as an extended spectrum beta lactamase (ESBL)-producing organism. Urology or Infectious Diseases consultation is also useful to counsel women on causes for recurrent cystitis and behavioral approaches to try to reduce the UTI risk, and especially for help with antimicrobial prophylaxis or self-diagnosis/self-treatment approaches (Table III).

Table III:

Cystitis tends to be a mild infection, although some patients have severe dysuria. Studies of college women with UTI have demonstrated that, on average, symptoms last several days and may be severe for a day, causing patients to miss school or work. Placebo controlled trials of women with acute uncomplicated cystitis have shown that 25-42% of women who receive placebo will have resolution of their symptoms within a few days, and it is uncommon that such patients progress to more serious infection, such as pyelonephritis. Thus, the primary goal of treatment in such women is to ameliorate symptoms rather than to prevent complications. Cystitis in a pregnant woman is an exception in that UTI in pregnancy has been associated with progression to pyelonephritis and adverse outcomes of the pregnancy.

Similar placebo studies of men with cystitis, or catheterized men or women with cystitis, have not been performed. However, asymptomatic bacteriuria in the catheterized patient rarely progresses to symptomatic infection, including pyelonephritis, and does not warrant antimicrobial treatment.

Several factors should be considered in picking an anti-infective for cystitis. These include the likely efficacy of the drug, the patient’s allergy history, the potential risk for adverse events, whether the prevalence of resistance in the community is known for the type of infection being treated, drug cost to the patient, and drug availability. Use of an antimicrobial, such as trimethoprim-sulfamethoxazole (or a fluoroquinolone), in the past 3 to 6 months is a risk factor for resistance to that agent, so an agent in another class should be considered for treatment.

In addition, it is important to consider whether the agent has a propensity to cause ecological adverse effects (“collateral damage”)—the selection of drug-resistant organisms and colonization or infection with multidrug-resistant organisms. Such considerations of collateral damage led to recent recommendations that fluoroquinolones, a highly effective class of drugs for the treatment of UTI, not be considered first-line in women with uncomplicated cystitis.

None of the antimicrobials currently available for uncomplicated cystitis are clearly better than the others in terms of optimizing clinical outcomes, and the optimal empiric antimicrobial in one region of the world may be different from that in another. Generally, a culture and drug susceptibilities do not need to be performed in women with uncomplicated cystitis. If the woman does not respond to treatment or has an early recurrence, a urine culture should then be considered, and she should be empirically treated with a broader spectrum antimicrobial, such as a fluoroquinolone, pending culture results.

Trimethoprim-sulfamethoxazole (TMP-SMX) is highly effective, well tolerated, inexpensive, and remains a first-line antimicrobial for uncomplicated cystitis (Table I). However, resistance is high in some areas of the United States and the world, and it is not appropriate for empiric use in such areas. Recent guidelines for management of uncomplicated cystitis suggest that TMP-SMX should be avoided if the likelihood of resistance of uropathogens in the community is greater than 20%. Of course, clinicians almost never have access to reliable resistance data in their community.

Nitrofurantoin and fosfomycin, in contrast to other first- and second-line antimicrobials for uncomplicated cystitis (Table I), cause minimal collateral damage and do not exhibit cross-resistance with other agents.

Nitrofurantoin has excellent activity against E. coli, including ESBL-producing strains, and enterococci, including vancomycin-resistant strains. Nitrofurantoin should be avoided in patients with pyelonephritis, prostatitis, renal insufficiency (creatinine clearance <40), and in patients infected with Klebsiella pneumoniae, Proteus mirabilis, or Pseudomonas aeruginosa.

Fosfomycin, even though it appears less clinically active than TMP-SMX or fluoroquinolones, is considered a first-line antimicrobial for cystitis in recent guidelines, because it exhibits minimal collateral damage. As with any agent, resistance can develop with increased use of fosfomycin. Fosfomycin should be avoided if pyelonephritis is suspected.

In contrast to the many comparative studies of antimicrobials in women with uncomplicated cystitis, complicated UTI is a much more heterogeneous condition and fewer studies are available to inform treatment guidelines. Thus, most studies of complicated UTI include patients who have febrile UTIs, and it is often not possible to ascertain the drug’s effectiveness in cystitis patients. Furthermore, men and women with complicated cystitis are infected with a wide variety of potential causative uropathogens, and multidrug resistance is common. The optimal duration of treatment has also not been determined, but most experts recommend 7 days for complicated cystitis (vs shorter regimens for cystitis).

Fluoroquinolones are generally considered the empiric drugs of choice for complicated cystitis, unless the patient is known to have been recently infected with fluoroquinolone-resistant uropathogens, as they are often the only oral agents active against the causative uropathogen. However, the prevalence of resistance among uropathogens is increasing for both uncomplicated and complicated cystitis, and fluoroquinolone resistance is not uncommon in complicated UTI. Thus, a urine culture should be performed in all patients with complicated cystitis, and it is reasonable to delay treatment in most cases until the susceptibility data are available. If treatment cannot be delayed due to patient discomfort or anxiety, it is reasonable to start empiric treatment with a fluoroquinolone.

Use of TMP-SMX or fluoroquinolones in the past 3 to 6 months is associated with an increased likelihood of resistance to these agents, and one should consider using an alternative for empiric treatment.

Parenteral antimicrobials may be necessary to treat patients with cystitis. Choice of such regimens must be based on antimicrobial susceptibility of the infecting uropathogen(s). Recommended regimens are shown in Treatment Table I and Table II. Of note, although carbapenems are highly effective for UTI, doripenem and ertapenem have little activity against Pseudomonas aeruginosa. Tigecycline has little renal excretion and is not indicated for the treatment of UTI.

Further complicating the management of acute cystitis, even uncomplicated cystitis, is the emergence of ESBL-producing strains of E. coliand K. pneumoniae. If ESBL-producing strains are known or suspected to be present, one should consider using either nitrofurantoin or fosfomycin, since both have demonstrated activity both in vitro and clinically against such strains, although published data are sparse. ESBL strains are usually resistant to TMP-SMX and fluoroquinolones.

Risk factors for ESBL UTIs include healthcare-associated infections, advancing age, and comorbidities. In community acquired UTIs, risk factors include those older than 60 years of age, female sex, diabetes mellitus, recurrent UTI, healthcare-associated UTI, and previous antimicrobial use.

Even more highly resistant strains have been reported to cause UTIs. These include highly resistant Acinetobacterspecies and New Delhi metalloprotease (NDM-1) producing E. coliand K. pneumoniae. Optimal treatment for these organisms is yet to be determined, although fosfomycin appears effective against most NDM-1 producing E. colistrains.

Candiduria

Asymptomatic candiduria does not warrant treatment, unless the patient is at high risk of dissemination, as with a patient who is neutropenic, an infant with low birth weight, or a patient about to undergo a urologic procedure. Elimination of predisposing factors, such as the urinary catheter, often results in resolution of candiduria. Neutropenic patients and neonates should be treated as though they have invasive candidiasis. Patients about to undergo a urologic procedure should be given fluconazole 200 to 400mg daily or amphotericin B deoxycholate 0.3 to 0.6mg/kg daily for several days before and after the procedure. Imaging of the kidneys to rule out abscess, fungus ball, or urologic abnormality is recommended in those patients who are treated.

Patients with symptomatic cystitis should be treated with oral fluconazole if the strain is fluconazole-susceptible (no other currently available azole is useful because of minimal excretion of active drug into the urine). Echinocandins are also not excreted into the urine and are not recommended for the treatment of UTI. For patients who are allergic to fluconazole, who clearly experience treatment failure with oral fluconazole, or who are infected with a fluconazole-resistant strain, intravenous amphotericin B or oral flucytosine can be used. Bladder irrigation is generally not recommended but may be useful for treatment of patients with fluconazole-resistant Candidaspecies, especially C. glabrataand C. krusei.

Treatment with flucytosine is limited by toxicity and the development of resistance when used alone. Bladder irrigation with amphotericin B deoxycholate is associated with a high relapse rate.

Response to treatment and follow-up

Patients with cystitis should respond rapidly if the infecting uropathogen is susceptible to the antimicrobial used. If there is not substantial clinical improvement within 24 hours, patients should be reassessed with a renal ultrasound or computed tomography to exclude urinary obstruction or upper tract infection or an alternative diagnosis.

Imaging studies or cystoscopy may also be warranted in patients with persistent hematuria or in patients with frequent recurrences.

In patients with a complicating factor predisposing to infection or its severity, efforts should be made (as appropriate and feasible) to correct the defect to achieve cure and to reduce the risk of subsequent UTIs.

Follow-up urine cultures in patients whose symptoms have resolved are not generally indicated, as there is no reason to treat asymptomatic bacteriuria, including those with complicated cystitis. Pregnant women are exceptions to this recommendation, as eradication of asymptomatic bacteriuria has been shown to have beneficial effects on pregnancy outcomes.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection what anti-infective should I order?

Almost any bacteria can cause urinary tract infection. Empiric regimens, as listed in Table I and Table II, are recommended for treatment ofcystitis, with tailoring of the regimen, as appropriate, based on theresults of the urine culture and antimicrobial susceptibilities(recommended for all patients with complicated cystitis).

2. Next list other key therapeutic modalities.

Cystitis in healthy ambulatory women rarely progresses to pyelonephritis or other serious conditions, even when untreated (as evidenced by placebo studies of uncomplicated cystitis). There is no modality recommended to reduce complications other than antimicrobials. Urinary analgesics are recommended in patients with severe dysuria, although they are usually not needed for more than 1 or 2 days, since symptoms tend to start to improve within a few hours with appropriate antimicrobial treatment. There is increasing interest in delayed or nonantimicrobial management of uncomplicated cystitis. Thus, a recent pilot study in uncomplicated cystitis showed that clinical resolution was similar with ibuprofen and ciprofloxacin. However, a larger follow-up study comparing ibuprofen and fosfomycin for treatment of women with cystitis demonstrated a reduced number of antimicrobial treatment courses in women in the ibuprofen group, but there was a higher burden of symptoms and more cases of pyelonephritis in the ibuprofen group.

Nevertheless, progression to pyelonephritis is uncommon in uncomplicated cystitis, and it is reasonable to delay treatment of mildly symptomatic cystitis to see if symptoms resolve on their own (which they do in a sizeable proportion of women given placebo for cystitis). It is not clear whether the same can be said for complicated cystitis. Although pregnant women with untreated bacteriuria are at risk for adverse pregnancy outcomes, long-term bacteriuria in asymptomatic hosts, such as chronically catheterized patients with neurogenic bladder, rarely progresses to pyelonephritis or other serious adverse outcomes. Nevertheless, in symptomatic complicated cystitis, antimicrobial treatment with a drug to which the infecting uropathogen is susceptible will likely prevent any such progression. Given the high prevalence of drug resistance in complicated UTI, delay in treatment until the antimicrobial susceptibilities are available is reasonable in those with mild to moderate cystitis, based on clinical judgment.

Removal of the complicating factor, when feasible, is warranted to reduce the risk of further progression of cystitis to more serious infection.

What complications could arise as a consequence of cystitis?

What should you tell the family about the patient's prognosis?

Cystitis is generally not associated with serious outcomes. In healthy women, the spontaneous symptom resolution rate in the placebo arms of studies is approximately 25 to 42%, and such patients infrequently progress to pyelonephritis. However, uncomplicated cystitis is often associated with significant morbidity that can last for days, even when treated appropriately.

Although long-term asymptomatic bacteriuria in hosts with complicating conditions rarely progresses to pyelonephritis or other serious adverse outcomes, the natural history of complicated cystitis has not been described. It is often difficult to distinguish cystitis from asymptomatic bacteriuria in patients who are catheterized, have altered sensorium, or have neurogenic bladder, and it is possible that more serious outcomes, including upper tract infection, might occasionally be the result of delayed diagnosis. Thus, fever, back pain, worsening mental status, and hemodynamic instability in the setting of bacteriuria (and no other obvious cause) suggest urinary tract infection is not confined to the bladder and appropriate imaging and treatment for presumptive pyelonephritis should be considered.

Adverse outcomes are more likely to occur in patients with diabetes, chronic urologic devices, or obstruction, so a lower threshold for considering more serious infection might be present is reasonable in patients with these conditions.

Basically, the prognosis of uncomplicated and complicated cystitis, per se, is good once the diagnosis is made and antimicrobial treatment is started (in complicated cystitis, should be based on results of the urine culture).

In pregnant women, untreated bacteriuria can lead to serious complications, including premature delivery and adverse fetal outcomes. In pregnant women, both asymptomatic bacteriuria and symptomatic UTI should be treated and followed closely to ensure eradication of bacteriuria.

What pathogens are responsible for this disease?

Essentially, any organism can cause UTI. This is especially true in complicated cystitis, and a urine culture should be performed to distinguish the different uropathogens as symptoms are nonspecific. E. colicauses the vast majority of episodes of uncomplicated cystitis, whereas there is a much broader spectrum of uropathogens causing complicated UTI. Chronically catheterized patients often have polymicrobial infection. The proportion of UTIs caused by different uropathogens as reported in different studies is shown below.

Organisms isolated from patients with complicated cystitis tend to be more resistant to antimicrobials compared with those isolated from uncomplicated cystitis. This is because patients with complicated cystitis have more frequent exposure to antimicrobials and to healthcare settings where exposure to multidrug-resistant pathogens is more likely. UTIs in elderly patients and patients with chronic indwelling catheters are often polymicrobial.

Estimated proportion of episodes of cystitis caused by different uropathogens include:

Uncomplicated cystitis

Gram-negative bacteria

E. coli75 to 95%

P. mirabilis1 to 2%

Klebsiella spp. 1 to 2%

Citrobacterspp. <1%

Enterobacterspp. <1%

P. aeruginosa<1%

Other <1%

Gram-positive bacteria

S. saprophyticus5 to >20%

Enterococci 1 to 2%

Group B streptococci <1%

S. aureus<1%

Other <1%

Complicated urinary tract infections

Gram-negative bacteria

E. coli 10 to 60%

P. mirabilis5 to 55%

K. pneumoniae 8 to 26%

Providencia spp. 0 to 58%

P. aeruginosa2 to 32%

Other* 4 to 39%

*Includes Citrobacter spp., Enterobacter spp., Morganella morganii, and Serratiia marcescens

P. mirabilis, Providencia stuartii,and M. morganiiare urease-producing organisms and are especially common in patient with indwelling urological devices.

Gram-positive bacteria

Enterococcus spp. 1 to 10%

Coagulase negative staphylococcus 1 to 24%

Group B streptococci 1 to 2%

Other gram-positive organisms 1 to 39%

Other causes of complicated cystitis include:

Fungi

Candida albicansand other Candidaspecies are common in catheterized patients.

Viruses

Adenovirus and BK polyomavirus occasionally cause hemorrhagic cystitis in severely immunocompromised patients. It is not clear whether viruses cause cystitis in immunocompetent persons, but they possibly account for some episodes that are culture negative for bacteria or fungi.

Mycobacteria

Cystitis caused by mycobacteria is rare in developed countries, but not in underdeveloped countries. Bacillus Calmette-Guerin (BCG), which is instilled into the bladder to treat some bladder tumors, may cause cystitis.

Parasites

Schistosoma haematobium infection is common in Africa and the Middle East and can cause cystitis due to an inflammatory reaction to Schistosomaeggs embedded in the host’s bladder. It is rare in the United States but can be found in immigrants. Schistosomainfection is a common cause of hematuria in endemic areas.

What other clinical manifestations may help me to diagnose and manage cystitis?

The physical examination is of limited usefulness in the setting of uncomplicated cystitis. Suprapubic tenderness may be present in some patients, but it is an insensitive and nonspecific finding. Fever and costovertebral angle tenderness are useful clues to the presence of pyelonephritis.

A physical examination is more important for patients in whom complicated UTI is suspected. For example, a urinary catheter or nephrostomy tube or physical findings suggestive of a nongenitourinary condition may be found in a patient who cannot provide a coherent history.

What other additional laboratory findings may be ordered?

If vaginal symptoms occur, such as complaints of discharge, irritation, or odor, a vaginal examination should be performed with a wet mount to look for evidence of bacterial vaginosis, yeast, or trichomoniasis. A voided urine or swab specimen may be indicated for testing for Chlamydia trachomatisor Neisseria gonorrhoeae.

Likewise, in men with dysuria who have urethral discharge, a voided urine or swab specimen should be sent for testing for C. trachomatisor N. gonorrhoeae.

Herpes can also cause dysuria and mimic cystitis. The diagnosis is usually made clinically, but culture or serology may be helpful in some patients with equivocal signs or symptoms.

How can cystitis be prevented?

Recurrent uncomplicated cystitis

Table III shows strategies recommended to prevent recurrent uncomplicated cystitis. Women with recurrent UTI should be counseled about the strong association between sexual intercourse and UTI. Thus, a reduction in sexual frequency should be effective in reducing UTI risk, but this approach is not likely to be feasible in many women. Spermicide use, including spermicide-coated condoms, is also a strong risk factor, and use of an alternative contraceptive or infection-prevention method in which spermicide is not used is likely to be effective.

Many behavioral approaches have been recommended, but none have been shown effective in case-control studies. However, none have been evaluated in prospective studies. Such approaches include urinating soon after intercourse, liberalizing fluid intake, not routinely delaying voiding, wiping front to back after defecation, avoiding tight fitting underwear, avoiding douching. Since these approaches are low risk and all have biological rationale, it is reasonable to recommend some or all to the patient as activities that might be helpful but that there are no published data to support their usefulness.

Cranberry juice or tablets have long been touted as a preventive modality, and a beneficial effect has been reported by several underpowered studies. Many women have tried cranberry, and many report a beneficial effect. Recent studies, however, suggest that cranberry is not effective. Because it is considered a safe approach, if the patient believes that cranberry is effective, there is no reason to talk her out of it.

Topical estrogen has been shown in some studies of older women to normalize vaginal flora and reduce vaginal colonization with uropathogens and, thus, reduce the risk of UTI. Systemic estrogens have not been shown effective.

Antimicrobial prophylaxis, although highly effective in reducing the risk of UTI, should be considered only as a last resort given the potential side effects of the drugs themselves and the increasing concern about selection for antimicrobial resistance. If a woman has three or more UTIs in the past 12 months or two or more in the past 6 months and has not benefited from the approaches described, then antimicrobial prophylaxis should be considered. However, this approach should be discussed carefully with the woman to make sure she understands the potential risks. The choice of antimicrobial depends on the susceptibility patterns of uropathogens causing recent infections and the patient’s allergy history.

There are two approaches to antimicrobial prophylaxis. First, if the UTI episodes appear to be related to intercourse, administration of an antimicrobial soon after intercourse is highly effective and results in less antimicrobial use than does continuous antimicrobial prophylaxis. Several drugs have been shown effective for postcoital prophylaxis as shown in Table III. Fluoroquinolones, such as ciprofloxacin 125mg, are highly effective but should not be used unless other approaches are not effective because of the concern about selecting for resistance.

Continuous antimicrobial prophylaxis consists of a nighttime dose of an antimicrobial. Table III shows effective regimens. It is recommended that the urine be sterile before starting a long-term continuous antimicrobial regimen. Again, fluoroquinolones are highly effective but not recommended because of the concern about selecting for resistance.

Antimicrobial prophylaxis should be continued for 3-6 months if tolerated by the patient, and then discontinued to determine whether the pattern of recurrences remains the same. Longer courses can be used if the patient benefited from the regimen and if she starts having recurrences again after it has been stopped.

Breakthrough episodes of cystitis may occur, and they may or may not be caused by uropathogens resistant to the prophylactic agent. Such breakthrough infections should be cultured to determine whether the patient is, in fact, having UTIs and whether the antimicrobial regimen remains appropriate.

Another antimicrobial management strategy for use in women with recurrent cystitis is self-diagnosis and self-treatment. This is a management strategy rather than a prevention strategy. Thus, several studies have shown that women who have previously documented UTIs can accurately diagnose subsequent UTIs with a high degree of accuracy and successfully treat such UTIs with recommended antimicrobial regimens they have been provided. This strategy should be limited to women with previously documented UTIs who are compliant with taking medications. They should be counseled to call the provider if their symptoms do not improve on the antimicrobial in which case a urine culture should be performed and consideration given to changing the antimicrobial.

Recurrent complicated cystitis

Men and women with underlying anatomical or functional risk factors for cystitis and who have recurrent cystitis present more of a management challenge. Known anatomic or functional factors that increase the risk of UTI should be corrected if possible. Not infrequently, patients are treated repeatedly for positive urine cultures even though they are asymptomatic. There is no reason to culture the urine after treatment if the patient has had resolution of symptoms, except in the case of pregnant women.

The optimal method of preventing recurrent complicated cystitis in the noncatheterized patient is not known. Often times, these patients are treated with antimicrobials frequently over many years for symptomatic events and subsequently develop highly resistant organisms, in some cases necessitating use of parenteral antimicrobials for treatment of cystitis. Long-term antimicrobial prophylaxis, such as that described, for recurrent uncomplicated cystitis is occasionally used but is not as effective as for recurrent uncomplicated cystitis, and emergence of resistant organisms ultimately limits efficacy.

Cranberry has not been demonstrated to reduce the risk of recurrent complicated cystitis.

Risk of recurrent cystitis in patients with urethral catheterization can be reduced by removing the catheter as soon as appropriate. The collecting system should be kept closed to avoid contamination. Condom catheterization appears associated with lower UTI risk in men without cognitive impairment and should be used rather than indwelling catheterization when appropriate and feasible. Likewise, intermittent catheterization and suprapubic catheterization appear associated with less risk for UTI than indwelling catheterization. Antimicrobial coated urinary catheters have not been demonstrated to reduce the risk of symptomatic UTI. Antibiotics instilled into the bladder or drainage bag are not effective.

Bacteriuria in pregnant women has been shown associated with premature delivery and other adverse outcomes, and screening and treatment of bacteriuria are recommended in all pregnant women.

Antimicrobial prophylaxis is common practice after renal transplant, and it has been shown to decrease the occurrence of symptomatic infection to low levels. However, the optimal approach to screening and treatment of asymptomatic bacteriuria in renal transplant patients has not yet been determined.

Screening and treatment of asymptomatic bacteriuria are not recommended in any population specifically to reduce the risk of cystitis.

Suppressive therapy

Long-term suppressive therapy may be indicated in some patients with recurrent complicated cystitis as a last resort if the underlying predisposing factor cannot be corrected and if the patients have frequent recurrences of symptomatic UTI requiring antimicrobial treatment. The decision to use suppressive therapy must be individualized and periodically reassessed as drug resistance or drug effects, such as Clostridium difficilecolitis, are potential downsides to such an approach. Of course, such complications may also occur with serial treatment of recurrent UTIs.

What's the evidence?

What's the evidence?

Foxman, B. “The epidemiology of urinary tract infection”. Nat Rev Urol. vol. 7. 2010. pp. 653-60. (A nice contemporary review of the epidemiology of UTI.)

Hooton, TM. “Clinical practice. Uncomplicated urinary tract infection”. N Engl J Med. vol. 366. 2012 Mar 15. pp. 1028-37. (A thorough review of uncomplicated UTI, their diagnosis, management and preventive strategies.)

Nicolle, LE. “Complicated urinary tract infection in adults”. Can J Infect Dis Med Microbiol. vol. 16. 2005. pp. 349-60. (A thorough and excellent discussion of complicated UTIs, their management, and preventive strategies.)

Foxman, B, Brown, P. “Epidemiology of urinary tract infections: transmission and risk factors, incidence, and costs”. Infect Dis Clin North Am. vol. 17. 2003. pp. 227-41. (A thorough review of UTI epidemiology that covers risk factors, incidence and costs.)

Hooton, TM, Scholes, D, Hughes, JP. “A prospective study of risk factors for symptomatic urinary tract infection in young women”. N Engl J Med. vol. 335. 1996. pp. 468-74. (A large study evaluating risk factors for uncomplicated UTI in college women.)

Jackson, SL, Boyko, EJ, Scholes, D, Abraham, L, Gupta, K, Fihn, SD. “Predictors of urinary tract infection after menopause: a prospective study”. Am J Med. vol. 117. 2004. pp. 903-11. (A prospective study of risk factors for UTI in older women.)

Johansen, TEB, Botto, H, Cek, M. “Critical review of current definitions of urinary tract infections and proposal of an EAU/ESIU classification system”. Internat J Antimicrob Agents. vol. 38S. 2011. pp. 64-70. (An attempt to more accurately classify UTI into uncomplicated and complicated UTI.)

Johnson, JR. “Microbial virulence determinants and the pathogenesis of urinary tract infection”. Infect Dis Clin North Am. vol. 17. 2003. pp. 261-78. (A detailed review of virulence determinants of uropathogens.)

Hooton, TM. “Recurrent urinary tract infection in women”. Int J Antimicrob Agents. vol. 17. 2001. pp. 259-68. (Frequency, pathogenesis and management of recurrent UTI in women.)

Nicolle, LE. “Managing recurrent urinary tract infections in women”. Women’s Health. vol. 1. 2005. pp. 39-50. (A review of recurrent UTI, risk factors and management/prevention.)

Mulvey, MA, Schilling, JD, Martinez, JJ, Hultgren, SJ. “Bad bugs and beleaguered bladders: interplay between uropathogenic Escherichia coli and innate host defenses”. Proc Natl Acad Sci USA. vol. 97. 2000. pp. 8829-35. (A description of the pathogenesis of bladder infection in a mouse model that forms the basis of an intriguing theory as to how some recurrent UTI occur in women.)

Scholes, D, Hooton, TM, Roberts, PL, Stapleton, AE, Gupta, K, Stamm, WE. “Risk factors for recurrent urinary tract infection in young women”. J Infect Dis. vol. 182. 2000. pp. 1177-82. (A case control study of women with and without recurrent UTI that evaluates factors associated with recurrences in young healthy women.)

Bent, S, Nallamothu, BK, Simel, DL, Fihn, SD, Saint, S. “Does this woman have an acute uncomplicated urinary tract infection”. JAMA. vol. 287. 2002. pp. 2701-10. (An analysis of literature on the diagnosis of UTI in women suggesting that urinalysis and culture have a limited role in the diagnosis of UTI.)

Stamm, WE, Counts, GW, Running, KR, Fihn, S, Turck, M, Holmes, KK. “Diagnosis of coliform infection in acutely dysuric women”. N Engl J Med. vol. 307. 1982. pp. 463-8. (A seminal study showing that acute uncomplicated cystitis is often associated with low bacterial colony counts.)

Hooton, TM, Roberts, PL, Cox, ME. “Stapleton AE. Voided midstream urine culture and acute cystitis in premenopausal women”. N Engl J Med. vol. 369. 2013 Nov 14. pp. 1883-91. (A study showing that low midstream urine colony counts of E.coli, but not enterococcus or Group B streptococci, are predictive of bladder infection.)

Ferry, SA, Holm, SE, Stenlund, H, Lundholm, R, Monsen, TJ. “Clinical and bacteriological outcome of different doses and duration of pivmecillinam compared with placebo therapy of uncomplicated lower urinary tract infection in women: the LUTIW project”. Scand J Prim Health Care. vol. 25. 2007. pp. 49-57. (A placebo study showing that many women with cystitis who are not treated with antimicrobials have clinical resolution of their symptoms.)

Gupta, K, Hooton, TM, Naber, KG. “International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases”. Clin Infect Dis. vol. 52. 2011. pp. e103-20. (New treatment guidelines for cystitis and pyelonephritis, uncomplicated.)

Warren, JW, Abrutyn, E, Hebel, JR, Johnson, JR, Schaeffer, AJ, Stamm, WE. “Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in women. Infectious Diseases Society of America (IDSA)”. Clin Infect Dis. vol. 29. 1999. pp. 745-58. (Previous UTI guidelines on uncomplicated cystitis and pyelonephritis.)

Katchman, EA, Milo, G, Paul, M, Christiaens, T, Baerheim, A, Leibovici, L. Am J Med. vol. 118. 2005. pp. 1196-207. (A review showing that short- course treatment is effective for cystitis.)

Grigoryan, L, Trautner, BW, Gupta, K. “Diagnosis and management of urinary tract infections in the outpatient setting”. a review. JAMA. vol. 312. 2014 Oct 22-29. pp. 1677-84.

Gágyor, I, Bleidorn, J, Kochen, MM, Schmiemann, G, Wegscheider, K, Hummers-Pradier, E. “Ibuprofen versus fosfomycin for uncomplicated urinary tract infection in women: randomised controlled trial”. BMJ. vol. 351. 2015 Dec 23. pp. h6544

Foxman, B. “The epidemiology of urinary tract infection”. Nat Rev Urol. vol. 7. 2010. pp. 653-60.

DRG CODES and expected length of stay

Cystitis is not a diagnosis that warrants hospitalization in and of itself. Thus, a patient with a diagnosis of cystitis who develops fever, altered mental status, hemodynamic changes, or other such physiologic changes should be assumed to have more invasive infection and be managed accordingly, including hospitalization.

Rarely, a patient with cystitis might be admitted for parenteral antimicrobials, because he or she is infected with a highly resistant strain and/or the patient does not tolerate any of the possible oral treatment options. However, even in these cases, therapy is usually provided in the outpatient setting via use of an intravenous catheter.

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