Urinary Tract Infection (UTI) and Cystitis (Bladder Infection) in Females

UTI is defined as significant bacteriuria in the setting of symptoms of cystitis or pyelonephritis. These infections account for a significant number of emergency department (ED) visits,[4] and 20% of women develop at least one UTI. (See Epidemiology.)

Escherichia coli causes the majority of uncomplicated cystitis cases. Among the pathogens responsible for the remainder are Staphylococcus saprophyticus, Proteus mirabilis, Klebsiella pneumoniae, or Enterococcus faecalis. (See Etiology.)

A presumptive diagnosis of uncomplicated cystitis can be made on the basis of findings of the history and physical examination, along with urinalysis.[5, 6] Proper specimen collection is necessary. In addition, clinicians need to appreciate the epidemiologic and host factors that may identify patients with complicated cystitis or clinically inapparent upper UTI, in whom more comprehensive assessment is indicated. (See Workup.)

Successful emergent management includes selection of appropriate antimicrobial therapy with recommendations for follow-up care. Oral therapy with an antibiotic effective against gram-negative aerobic coliform bacteria is the principal therapeutic intervention in patients with cystitis. (See Treatment, as well as Medication.)

The following terms are defined for uniformity in this article:

• Asymptomatic bacteriuria (ASB) refers to 2 consecutive urine cultures growing more than 100,000 colony-forming units (CFU)/mL of a bacterial species in a patient lacking symptoms of a UTI
• Uropathogens are bacteria with specific virulence factors that facilitate their invasion of the urinary tract
• Complicated UTIs are defined as UTIs that are associated with metabolic disorders, that are secondary to anatomic or functional abnormalities that impair urinary tract drainage, or that involve unusual pathogens (eg, yeast), which increase the risk for therapeutic failure

The urinary tract normally is sterile. Uncomplicated UTI involves the urinary bladder in a host without underlying renal, metabolic, or neurologic diseases. Cystitis represents bladder mucosal invasion, most often by enteric coliform bacteria (eg, Escherichia coli) that inhabit the periurethral vaginal introitus and ascend into the bladder via the urethra.

In recurrent E coli UTIs, peak colonization rates of the periurethral area 2-3 days prior to the development of the symptoms of acute cystitis range from 46% to 90%. During this same period, asymptomatic bacteriuria rates increase from 7% to 70%.[7]

Because sexual intercourse may promote this migration, cystitis is common in otherwise healthy young women. Generally, urine is a good culture medium. Factors unfavorable to bacterial growth include a low pH (5.5 or less), a high concentration of urea, and the presence of organic acids derived from a diet that includes fruits and protein. Organic acids enhance acidification of the urine.

Frequent and complete voiding has been associated with a reduction in the incidence of UTI. Normally, a thin film of urine remains in the bladder after emptying, and any bacteria present are removed by the mucosal cell production of organic acids.

If the defense mechanisms of the lower urinary tract fail, upper tract or kidney involvement occurs and is termed pyelonephritis. Host defenses at this level include local leukocyte phagocytosis and renal production of antibodies that kill bacteria in the presence of complement. For more information on this topic, see the Medscape Reference articles Acute Pyelonephritis and Pathophysiology of Complicated Urinary Tract Infections.

In general, there are 3 main mechanisms responsible for UTIs:

• Colonization with ascending spread
• Hematogenous spread
• Periurogenital spread

Bacterial virulence

Uropathogenic bacteria, derived from a subset of fecal flora, have traits that enable adherence, growth, and resistance of host defenses. These traits facilitate colonization and infection of the urinary tract.

Adhesins are bacterial surface structures that enable attachment to host membranes. In E coli infection, these include both pili (ie, fimbriae) and outer-membrane proteins (eg, Dr hemagglutinin that binds to Dr blood group antigen). P fimbriae, which attach to globoseries-type glycolipids found in the colon and urinary epithelium, are associated with pyelonephritis and cystitis and are found in many E coli strains that cause urosepsis.

Type 1 fimbriae bind to mannose-containing structures found in many different cell types, including Tamm-Horsfall protein (the major protein found in human urine). Whether this facilitates or inhibits uroepithelial colonization is the subject of some debate.

Other factors that may be important for E coli virulence in the urinary tract include capsular polysaccharides, hemolysins, cytotoxic necrotizing factor (CNF) protein, and aerobactins. Several Kauffman serogroups of E coli that contain these virulence factors may be more likely to cause UTIs, including O1, O2, O4, O6, O16, and O18.

Another example of bacterial virulence is the swarming capability of Proteus mirabilis. Swarming involves the expression of specific genes when these bacteria are exposed to surfaces such as catheters. This results in the coordinated movement of large numbers of bacteria, enabling P mirabilis to move across solid surfaces. This likely explains the association of P mirabilis UTIs with instrumentation of the urinary tract.

Host resistance

Most uropathogens gain access to the urinary tract via an ascending route. The shorter length of the female urethra allows uropathogens easier access to the bladder. The continuous unidirectional flow of urine helps to minimize UTIs, and anything that interferes with this increases the host's susceptibility to UTI. Examples of interference include volume depletion, sexual intercourse, urinary tract obstruction, instrumentation, use of catheters not drained to gravity, and vesicoureteral reflux.

Secretory defenses help promote bacterial clearance and prevent adherence. Secretory immunoglobulin A (IgA) reduces attachment and invasion of bacteria in the urinary tract. Women who are nonsecretors of the ABH blood antigens appear to be at higher risk for recurrent UTIs; this may occur because of a lack of specific glycosyltransferases that modify epithelial surface glycolipids, allowing E coli to bind to them better.

In premenopausal women, lactobacilli are the predominant vaginal flora and serve to suppress vaginal colonization by the uropathogens. Most antibiotics, except sulfamethoxazole and the quinolones, can eradicate these protective bacteria.

Urine itself has several antibacterial features that suppress UTIs. Specifically, the pH, urea concentration, osmolarity, and various organic acids prevent most bacteria from surviving in the urinary tract.

E coli causes 70% to 95% of both upper and lower UTIs. Various organisms are responsible for the remainder of infections, including S saprophyticus, Proteus species, Klebsiella species, Enterococcus faecalis, other Enterobacteriaceae, and yeast. Some species are more common in certain subgroups, such as Staphylococcus saprophyticus in young women. However, S saprophyticus can produce acute cystitis in older women and in young men and should not be automatically regarded as a contaminant in the urine cultures of these individuals.[8]

Most complicated UTIs are nosocomial in origin. Increasingly, UTIs in patients in healthcare institutions and in those with frequent antibiotic exposure are caused by multidrug-resistant gram-negative pathogens, such as extended-spectrum beta-lactamase (ESBL) and carbapenemase producers. However, the prevalence of multidrug-resistant pathogens varies by locale.[9]

The most important risk factor for bacteriuria is the presence of a catheter.[10] Eighty percent of nosocomial UTIs are related to urethral catheterization, whereas 5% to 10% are related to genitourinary manipulation. Catheters inoculate organisms into the bladder and promote colonization by providing a surface for bacterial adhesion and causing mucosal irritation. For more information on this topic, see the Medscape Reference article Catheter-Related Urinary Tract Infection.

Sexual intercourse contributes to increased risk, as does use of a diaphragm and/or spermicide. Routine pelvic examinations also are associated with an increased risk for UTI for 7 weeks post procedure.[11] Women who are elderly, are pregnant, or have preexisting urinary tract structural abnormalities or obstruction carry a higher risk for UTI.

UTIs are the most common type of infection after renal transplantation. Susceptibility is especially high in the first 2 months following transplantation. Triggering factors include vesicoureteral reflux and immunosuppression. Corynebacterium urealyticum (ie, CDC group D2) has been reported to cause encrusted pyelitis and cystitis in these patients.

Calculi related to UTIs most commonly occur in women who experience recurrent UTIs with Proteus, Pseudomonas, and Providencia species. Perinephric abscesses most commonly are associated with E coli, Proteus species, and S aureus but also may be secondary to Enterobacter, Citrobacter, Serratia, Pseudomonas, and Klebsiella species. More unusual causes include enterococci, Candida species, anaerobes, Actinomyces species, and Mycobacterium tuberculosis. Twenty-five percent of infections are polymicrobial.

Candiduria is defined as more than 1000 CFU/mL of yeast from 2 cultures. Candida albicans, which is germ tube positive, is the usual culprit. Germ tube–negative Candida species (tropicalis, parapsilosis, glabrata, lusitaniae, krusei) are less common.

Risk factors for candiduria include diabetes mellitus, indwelling urinary catheters, and antibiotic use. Candiduria may clear spontaneously or may result in (or from) deep fungal infections.

United States statistics

UTIs in women are very common; approximately 25% to 40% of women in the United States aged 20-40 years have had a UTI. UTIs account for over 6 million patient visits to physicians per year in the United States; approximately 20% of those visits are to EDs.

Cystitis occurs in 0.3% to 1.3% of pregnancies but does not appear to be related to asymptomatic bacteriuria. Acute pyelonephritis occurs in 1% to 2% of pregnancies. UTIs occur in 3% to 50% of renal transplant patients and frequently are silent.

In 2007, approximately 3.9% of office visits were related to symptoms involving the genitourinary tract.[12] Estimates based on office and ED visits suggest per annum about 7 million episodes of acute cystitis. Some studies estimate that UTIs (cystitis plus pyelonephritis) cost at least $1 billion per year.

International statistics

UTIs have been well studied in Sweden and other parts of Europe.[13] These studies have shown that 1 in 5 adult women experience a UTI at some point, confirming that it is an exceedingly common worldwide problem.

The epidemiology of UTI in the tropics is less well documented. UTIs appear to be common and associated with structural abnormalities. Chronic infection from Schistosoma haematobium disrupts bladder mucosal integrity and causes urinary tract obstruction and stasis. Salmonella bacteriuria, with or without bacteremia, is very common in patients with schistosomiasis. Treatment requires both antischistosomal and anti-Salmonella agents.

Age- and sex-related demographics

Uncomplicated UTIs are much more common in women than men when matched for age. A study of Norwegian men aged 21-50 years showed an approximate incidence of 0.0006-0.0008 infections per person-year, compared with approximately 0.5-0.7 per person-year in similarly aged women in the United States.

The largest group of patients with UTI is adult women. The incidence of UTI in women tends to rise with increasing age. Several peaks above baseline correspond with specific events, including an increase in women aged 18-30 years (associated with coitus—so-called honeymoon cystitis—and pregnancy).

Rates of infection are high in postmenopausal women because of bladder or uterine prolapse causing incomplete bladder emptying; loss of estrogen with attendant changes in vaginal flora (notably, loss of lactobacilli), which allows periurethral colonization with gram-negative aerobes, such as E coli; and higher likelihood of concomitant medical illness, such as diabetes.

Of neonates, boys are slightly more likely than girls to present with UTI as part of a gram-negative sepsis syndrome. The incidence in preschool-aged children is approximately 2% and is 10 times more common in girls. UTI occurs in 5% of school-aged girls, but it is rare in school-aged boys.

Even with effective antibiotic treatment, the average duration of severe symptoms in women with cystitis is somewhat longer than 3 days. Features that have been associated with a more prolonged course than average include a history of somatization, previous cystitis, urinary frequency, and more severe symptoms at baseline.[14]

Although simple lower UTI (cystitis) may resolve spontaneously, effective treatment lessens the duration of symptoms and reduces the incidence of progression to upper UTI. Even with effective treatment, however, about 25% of women with cystitis will experience a recurrence.

Younger patients have the lowest rates of morbidity and mortality. Factors associated with an unfavorable prognosis include the following:

• Old age

• General debility

• Renal calculi or obstruction

• Recent hospitalization

• Urinary tract instrumentation or antibiotic therapy

• Diabetes mellitus

• Chronic nephropathy

• Sickle cell anemia

• Underlying cancer

• Intercurrent chemotherapy

The mortality associated with acute uncomplicated cystitis in women aged 20-60 years appears to be negligible. A longitudinal cohort study of Swedish women showed a higher mortality in women with a history of UTI than in age-matched women without such a history (37% vs 28% in 10 y),[15] but these cohorts were not matched for other mortality-related factors, making it difficult to attribute the increased mortality to UTIs.

In contrast, the morbidity in terms of quality of life and economic measures is tremendous. Each episode of UTI in a young woman results in an average of 6.1 days of symptoms, 1.2 days of decreased class/work attendance, and 0.4 days in bed.

Nosocomial infections develop in about 5% of patients admitted to hospitals, and UTIs account for 40% of these infections. From 2% to 4% of these patients become bacteremic, with a mortality of 12.5%.

Proper adherence to the outpatient medical regimen should be stressed. Behavior modification, such as good oral fluid intake to enhance diuresis and frequent voiding (including postintercourse voiding) may be helpful in reducing recurrent infection. (See Prevention of Urinary Tract Infections.)

For patient education information, see the Infections Center, as well as Urinary Tract Infection (UTI), Blood in the Urine, Birth Control Overview, Birth Control Spermicides, and Birth Control FAQs.

The classic symptoms of urinary tract infection (UTI) in the adult are primarily dysuria with accompanying urinary urgency and frequency along with a sensation of bladder fullness or lower abdominal discomfort.

Because of the referred pain pathways, even simple lower UTI may be accompanied by flank pain and costovertebral angle tenderness. However, assume that the presence of these symptoms represents upper UTI until proven otherwise.

Gross hematuria, hemorrhagic cystitis, develops in up to 10% of heathy women. Fevers, chills, and malaise may be noted in such patients but are associated more frequently with upper UTI (ie, pyelonephritis).

A history of vaginal discharge suggests that vaginitis, cervicitis, or pelvic inflammatory disease is responsible for symptoms of dysuria and necessitate an examination of the pelvis.

Important additional information includes a history of prior sexually transmitted disease (STD) and multiple current sexual partners.

The patient appears uncomfortable but not toxic. The presence of toxic fever, chills, nausea, and vomiting suggests pyelonephritis rather than cystitis; however, immunosuppressed and even immunocompetent patients with pyelonephritis may exhibit few, if any, of these symptoms. In elderly women, 50% of cases of cystitis also involve the upper tracts.[15]

The clinician may appreciate signs of dehydration, such as dry mucous membranes and tachycardia. Clammy extremities and symptomatic orthostasis suggest poor vascular tone due to gram-negative bacteremia rather than simple cystitis.

Most adult women with simple lower UTI have suprapubic tenderness. Pelvic examination should be performed to exclude vaginitis, cervicitis, or pelvic tenderness (eg, cervical motion tenderness, which suggests pelvic inflammatory disease).

The symptoms of acute urethritis overlap with those of cystitis, including acute dysuria and urinary hesitancy. Fever may be a component of urethritis-related syndromes (eg, Reiter syndrome, Behçet syndrome) but rarely is observed in acute cystitis. Urethral discharge is much more suggestive of urethritis, whereas bladder-related symptoms, such as urgency, polyuria, and incomplete voids, are more consistent with cystitis.

The predominant complaints in acute cystitis relate to the inflamed bladder mucosa. Constitutional symptoms, such as fever, nausea, and anorexia, are infrequent and quite mild. The symptoms of dysuria, urgency, hesitancy, polyuria, and incomplete voids may be accompanied by urinary incontinence, gross hematuria, and suprapubic or low back pain. Patients may demonstrate some suprapubic tenderness to palpation.

Abnormal physical examination findings generally are lacking in women with acute cystitis. The pelvic examination reveals no abnormalities unless another process, such as vaginitis, is mimicking or occurring simultaneously with cystitis.

In patients with spinal cord injury, the following signs and symptoms are suggestive of a UTI:

• Malodorous and cloudy urine

• Muscular spasticity

• Fatigue

• Fevers

• Chills

• Autonomic instability

Patients with lesions above T6 may exhibit autonomic dysreflexia to noxious stimuli, such as an overdistended bladder. The sympathetic response below the level of injury is uninhibited, producing severe vasoconstriction and reflexive bradycardia. If the patient is febrile, this may appear as a pulse-temperature dissociation.

For more information on this topic, see the Medscape Reference article Urinary Tract Infections in Spinal Cord Injury.

Symptoms of catheter-related UTI generally are nonspecific; most patients present with fever and leukocytosis. Significant pyuria generally is represented by more than 50 white blood cells per high-power field (WBC/hpf). Colony counts on a urine culture range from 100-10,000 CFU/mL. Infections may be polymicrobial. Pyuria and elevated bacterial colony counts are seen in all patients in whom a catheter has been in place for more than a few days. In this situation, their presence is not synonymous with a UTI.[10]

For more information on this topic, see the Medscape Reference article Catheter-Related Urinary Tract Infection.

Asymptomatic bacteriuria (ASB) occurs in 5% to 10% of pregnant women. More than 100,000 CFU/mL of a single uropathogen is the classic definition of ASB, but more recent data support 10,000 CFU/mL from a clean-catch specimen as a threshold.

ASB most commonly appears between the ninth and 17th weeks of pregnancy. ASB predisposes to preterm labor, intrauterine growth retardation, low-birth-weight infants, anemia, amnionitis, and hypertensive disorders of pregnancy.

Risk factors include sexual activity, increasing age and parity, diabetes, lower socioeconomic class, a history of UTIs, sickle cell disease, and structural/functional abnormalities. Cystitis occurs in 0.3% to 1.3% of pregnancies but does not appear to be related to ASB.

The recommendation is to screen pregnant women at their first prenatal visit and during the third trimester. Further screening is not indicated unless the initial test result is positive or the patient develops symptoms.

For more information, see the Medscape Reference topic Urinary Tract Infections in Pregnancy.

Complicated UTIs in patients who have diabetes include renal and perirenal abscess, emphysematous pyelonephritis, emphysematous cystitis, fungal infections, xanthogranulomatous pyelonephritis, and papillary necrosis. Susceptibility increases with longer duration and greater severity of diabetes.

For more information on this topic, see the Medscape Reference article Urinary Tract Infections in Diabetes Mellitus.

In the 1980s, many experts felt that urine cultures were unnecessary in young women with probable cystitis because almost all of these were caused by pan-susceptible isolates of Escherichia coli. Since then, however, antibiotic resistance in uropathogenic E coli has become a significant concern. Resistance also has been emerging among other common cystitis pathogens, including Enterococcus faecalis, Staphylococcus saprophyticus, Klebsiella pneumoniae, and Proteus mirabilis.

Trimethoprim-sulfamethoxazole (TMP-SMX) resistance reached levels as high as 20% prior to COVID-19. Substitution of fluoroquinolones had led to an increase in resistance to these drugs, as well.[16]

Nevertheless, according to 2010 guidelines from the American College of Obstetricians and Gynecologists, a urine culture is not required for the initial treatment of women with a symptomatic lower urinary tract infection (UTI) with pyuria or bacteriuria or both.[17] In a UK study, dipstick diagnosis proved more cost-effective than positive midstream urine culture for targeting antibiotic therapy.[5]

During the COVID -19 epidemic, there has been an outstanding increase in a variety of bacterial and fungal cultiures.[18, 19, 20]

Urine cultures should be obtained in all cases of cystitis in immunosuppressed patients and in those with a recent history of instrumentation, exposure to antibiotics, or recurrent infection. Obtaining cultures also is advisable in elderly women, who have a high rate of upper tract involvement.

Microscopic hematuria is found in about half of cystitis cases; when found without symptoms or pyuria, it should prompt a search for malignancy. Other possibilities to be considered in the differential diagnosis include calculi, vasculitis, renal tuberculosis, and glomerulonephritis.

In a developing country, hematuria is suggestive of schistosomiasis. Retention of Schistosoma haematobium eggs and formation of granulomas in the urinary tract can lead not only to hematuria but also to dysuria, bladder polyps and ulcers, and even obstructive uropathies. Schistosomiasis also can be associated with salmonellosis and squamous cell malignancies of the bladder.

Bacteremia is associated with pyelonephritis, corticomedullary abscesses, and perinephric abscesses. Approximately 10% to 40% of patients with pyelonephritis or perinephric abscesses have positive results on blood culture. Bacteremia is not necessarily associated with a higher morbidity or mortality in women with uncomplicated UTI.

Cervical swabs may be indicated in cases of possible pelvic inflammatory disease.

Visual inspection of the urine is not helpful. Cloudiness of the urine most often is due to protein or crystal presence, and malodorous urine may be due to diet or medication use.

No imaging studies are indicated in the routine evaluation of cystitis. Renal function testing is not indicated in most episodes of UTI, but it may be helpful in patients with known urinary tract structural abnormality or renal insufficiency. Renal function testing also may be helpful in older, particularly ill-appearing hosts or in hosts with other complications.

A study of 196 women with painful and/or frequent urination found that most could be classified as having a low or high risk for UTI by asking the following questions[21, 22] :

• Does the patient think they have a UTI?

• Is there at least considerable pain on urination?

• Is there vaginal irritation?

History correctly classified 56% of patients as having a UTI risk of either less than 30% or more than 70%, and adding urine dipstick results increased this correct classification rate to 73%. Correct classification increased to 83% when patients with intermediate risk (30-70%) after history alone underwent an additional test. The strongest indicators of UTI were the patient's suspicion of having a UTI and a positive nitrite test.[21, 22]

The most accurate method to measure pyuria is counting leukocytes in unspun fresh urine using a hemocytometer chamber; greater than 10 white blood cells (WBCs)/mL is considered abnormal. Counts determined from a wet mount of centrifuged urine are not reliable measures of pyuria. A noncontaminated specimen is suggested by a lack of squamous epithelial cells. Pyuria is a sensitive (80-95%) but nonspecific (50-76%) sign of UTI.

White cell casts may be observed in conditions other than infection and may not be present in all cases of pyelonephritis. A spun sample (5 mL at 2000 revolutions per min [rpm] for 5 min) is best used for evaluation of cellular casts.

Proteinuria commonly is observed in infections of the urinary tract, but the proteinuria usually is low grade. More than 2 g of protein per 24 hours suggests glomerular disease.

Approximately 70% of patients with corticomedullary abscesses have abnormal urinalysis findings, whereas those with renal cortical abscesses usually have normal findings. Two thirds of patients with perinephric abscesses have an abnormal urinalysis.

Urine specimen collection

Urine specimens may be obtained by midstream clean catch, suprapubic aspiration, or catheterization.

The midstream-voided technique is as accurate as catheterization if proper technique is followed. Instruct the woman to remove her underwear and sit facing the back of the toilet. This promotes proper positioning of the thighs.

Instruct the patient to spread the labia with one hand and cleanse from front to back with povidone-iodine or soaped swabs with the other hand; then pass a small amount of urine into the toilet; and finally urinate into the specimen cup. The use of a tampon may allow a proper specimen if heavy vaginal bleeding or discharge is present.

Midstream urine specimens may become contaminated, particularly if the woman has difficulty spreading and maintaining separation of the labia. The presence of squamous cells and lactobacilli on urinalysis suggests contamination or colonization (see image below). Catheterization may be needed in some women to obtain a clean specimen, although it poses the risk for iatrogenic infection.[23]

Lactobacilli and a squamous epithelial cell are evident on this vaginal smear. The presence of squamous cells and lactobacilli on urinalysis suggests contamination or colonization. Source: Centers for Disease Control and Prevention, Dr. Mike Miller

Although the use of midstream urine specimens is widely advocated, one randomized trial in young women showed that the rate of contamination was nearly identical among those who used midstream clean-catch technique and those who urinated into a container without cleansing the perineum or discarding the first urine output. Use of a vaginal tampon in addition to clean-catch technique had no significant effect on the contamination rate.[24]

Dipstick testing

Dipstick testing should include glucose, protein, blood, nitrite, and leukocyte esterase. Leukocyte esterase is a dipstick test that can rapidly screen for pyuria; it is 57% to 96% sensitive and 94% to 98% specific for identifying pyuria. Given this broad range of sensitivity, it is important to consider the possibility of false-positive results, particularly with asymptomatic patients undergoing evaluation for recurrent UTI.

Pyuria, as indicated by a positive result of the leukocyte esterase dipstick test, is found in the vast majority of patients with UTI. This is an exceedingly useful screening examination that can be performed promptly in any ED setting. If pyuria is absent, the diagnosis of UTI should be questioned until urine culture results become available.

In a United Kingdom study, dipstick diagnosis based on findings of nitrite or both leukocyte esterase and blood was 77% sensitive and 70% specific, with a positive predictive value of 81% and a negative predictive value of 65%.[5] Diagnosis on clinical grounds proved less sensitive.

Urine microscopy

A microscopic evaluation of the urine sample for WBC counts, RBC counts, and cellular or hyaline casts should be performed. In the office, a combination of clinical symptoms with dipstick and microscopic analysis showing pyuria and/or positive nitrite and leukocyte esterase tests can be used as presumptive evidence of UTI.

Low-level pyuria (6-20 WBCs per high-power field [hpf] microscopy on a centrifuged specimen) may be associated with an unacceptable level of false-negative results with the leukocyte esterase dipstick test, as Propp et al found in an ED setting.[25]

In females with appropriate symptoms and examination findings suggestive of UTI, urine microscopy may be indicated despite a negative result of the leukocyte esterase dipstick test. Current emphasis in the diagnosis of UTI rests with the detection of pyuria. As noted, a positive leukocyte esterase dipstick test suffices in most instances.

According to Stamm et al, levels of pyuria as low as 2-5 WBCs/hpf in a centrifuged specimen are important in females with appropriate symptoms. The presence of bacteriuria is significant. However, the presence of numerous squamous epithelial cells raises the possibility of contamination.[23] Low-level or, occasionally, frank hematuria may be noted in otherwise typical UTI; however, its positive predictive value is poor.

Nitrite test

Nitrite tests detect the products of nitrate reductase, an enzyme produced by many bacterial species. These products are not present normally unless a UTI exists. This test has a sensitivity and specificity of 22% and 94% to 100%, respectively. The low sensitivity has been attributed to enzyme-deficient bacteria causing infection or low-grade bacteriuria.

A positive result on the nitrite test is highly specific for UTI, typically because of urease-splitting organisms, such as Proteus species and, occasionally, E coli; however, it is very insensitive as a screening tool, as only 25% of patients with UTI have a positive nitrite test result.

Urine culture remains the criterion standard for the diagnosis of UTI. Collected urine should be sent for culture immediately; if not, it should be refrigerated at 4°C. Two culture techniques (dip slide, agar) are widely used and accurate.

The 2010 Infectious Disease Society of America (IDSA) consensus limits for cystitis and pyelonephritis in women are more than 1000 colony-forming units (CFU)/mL and more than 10,000 CFU/mL, respectively, for clean-catch midstream urine specimens. Historically, the definition of UTI was based on the finding at culture of 100,000 CFU/mL of a single organism. However, this misses up to 50% of symptomatic infections, so the lower colony rate of greater than 1000 CFU/mL now is accepted.[26]

The definition of asymptomatic bacteriuria still uses the historical threshold. Asymptomatic bacteruria in a female is defined as a urine culture (clean-catch or catheterized specimen) growing greater than 100,000 CFU/mL in an asymptomatic individual.

Note that any amount of uropathogen grown in culture from a suprapubic aspirate should be considered evidence of a UTI. Approximately 40% of patients with perinephric abscesses have sterile urine cultures.

An uncomplicated UTI (cystitis) does not require a urine culture unless the woman has experienced a failure of empiric therapy. Obtain a urine culture in patients suspected of having an upper UTI or a complicated UTI, as well as those in whom initial treatment fails.

If the patient has had a UTI within the last month, relapse probably is caused by the same organism. Relapse represents treatment failure. Reinfection occurs in 1-6 months and usually is due to a different organism (or serotype of the same organism). Obtain a urine culture for patients who are reinfected.

If a Gram stain of an uncentrifuged, clean-catch, midstream urine specimen reveals the presence of 1 bacterium per oil-immersion field, it represents 10,000 bacteria/mL of urine. A specimen (5 mL) that has been centrifuged for 5 minutes at 2000 rpm and examined under high power after Gram staining will identify lower numbers. In general, a Gram stain has a sensitivity of 90% and a specificity of 88%.

A CBC is not helpful in differentiating upper from lower UTI or in making decisions regarding admission. Significant leukopenia in hosts who are older or immunocompromised may be an ominous finding.

The WBC count may or may not be elevated in patients with uncomplicated UTI, but it usually is elevated in patients with complicated UTIs. Patients with complicated UTIs may have anemia; for example, anemia is observed in 40% of patients with perinephric abscesses.

Catheterization is indicated if the patient cannot void spontaneously, if the patient is too debilitated or immobilized, or if obesity prevents the patient from obtaining a suitable specimen. Measurement of postvoiding residual urine volume by catheterization may reveal urinary retention in a host with a defective bladder-emptying mechanism.

Measurement of the postvoid residual volume should be strongly considered in all patients who require hospital-level care. Handheld portable bladder scans also may be used as a noninvasive alternative.

Guidelines from the Centers for Disease Control and Prevention (CDC) advise that in acute care hospital settings, aseptic technique and sterile equipment for catheter insertion must be used to minimize the risk for catheter-associated UTI. Only properly trained individuals who are skilled in the correct technique of aseptic catheter insertion and maintenance should take on this task.[27]

For more information on this procedure, see the Medscape Reference article Urethral Catheterization in Women.

Diagnosing a UTI in a patient with a spinal cord injury is difficult. In these patients, signs and symptoms suggestive of a UTI are malodorous and cloudy urine, muscular spasticity, fatigue, fevers, chills, and autonomic instability.

In these patients, suprapubic aspiration of the bladder is the criterion standard for diagnosing a UTI, although it is not performed often in clinical practice.

For more information on this topic, see the Medscape Reference article Urinary Tract Infections in Patients with Spinal Cord Injury.

Patients with diabetes are at risk for complicated UTIs, which may include renal and perirenal abscess, emphysematous pyelonephritis, emphysematous cystitis, fungal infections, xanthogranulomatous pyelonephritis, and papillary necrosis.

For more information, see the Medscape Reference topic Urinary Tract Infections in Diabetes Mellitus.

Cystitis caused by Candida is clinically similar to cystitis from other pathogens. The presence of fungus in the urine should be verified by repeating the urinalysis and urine culture. Other features of diagnosis are as follows[28] :

• Pyuria is a nonspecific finding

• C glabrata may be differentiated from other species by morphology

• Candida casts in the urine indicate renal candidiasis but rarely are seen

• Colony counts have not proved diagnostically useful

Ultrasonography of the kidneys and collecting systems is the preferred initial study in symptomatic or critically ill patients with candiduria, but computed tomography is better for detecting pyelonephritis or perinephric abscess.[28]

Appropriate antibiotic treatment leads to significantly higher symptomatic and bacteriologic cure rates and better prevention of reinfection in women with uncomplicated cystitis.[29]  Its negative consequences include promotion of the development of antibiotic resistance in uropathogens and commensal bacteria as well as adverse effects on the gut and vaginal flora.[30]

Consequently, evolving practice seeks to achieve good symptom control for uncomplicated acute cystitis while reducing antibiotic use. For example, European practice increasingly includes the option of offering a 48-hour delayed antibiotic prescription to be used at the patient's discretion.[31]

The first-choice agents for treatment of uncomplicated acute cystitis in women include nitrofurantoin monohydrate/macrocrystals, trimethoprim-sulfamethoxazole (TMP-SMX), or fosfomycin. Beta-lactam antibiotics may be used when other recommended agents cannot be used.[2, 3] Fosfomycin and nitrofurantoin monohydrate/macrocrystals should be avoided in patients with possible early pyelonephritis.[2] Fluoroquinolones typically are reserved for complicated cystitis.

Empiric antibiotic selection should be based on local resistance patterns. In addition, clinicians may wish to limit use of TMP-SMX in order to reduce the emergence of resistant organisms.

Resistance to TMP-SMX has been associated with concomitant resistance to other antibiotics. Because of the importance of maintaining the effectiveness of TMP-SMX for treatment of serious infections, German national guidelines no longer recommend this agent as first-line empiric treatment for uncomplicated cystitis.[3]

Patients who have been hospitalized in urology units tend to have uropathogenic E coli infections with higher antimicrobial resistance, especially ESBL isolates.[32]

On average, women with cystitis who receive effective antibiotic treatment experience severe symptoms for somewhat longer than 3 days.[14] Complete resolution of symptoms may require approximately 6 days. Features associated with a more prolonged course include a history of somatization, previous cystitis, urinary frequency, and more severe symptoms at baseline.[14] Patients who respond to antibiotics do not require follow-up urine cultures.

Without treatment, 25% to 42% of uncomplicated acute cystitis cases in women will resolve spontaneously.[29] Even without effective treatment, the likelihood that uncomplicated acute cystitis will progress to pyelonephritis is only around 2%.[33]

German investigators reported that symptomatic treatment with ibuprofen (400 mg 3 times daily) did not prove to be inferior to antibiotic treatment with ciprofloxacin.[34] This randomized, controlled pilot trial in 79 women with uncomplicated acute cystitis found no significant difference in symptom resolution between the 2 groups. A notable but statistically insignificant difference was that 33.3% of patients in the ibuprofen group and 18% in the ciprofloxacin group required secondary antibiotic treatment.

Unfortunately, there is a low level of adherence to IDSA guidelines by primary care physicians in terms of antibiotic selection and therapy duration for treatment of uncomplicated acute cystitis. Appropriate antibiotics were administered in most (97.6%) cases of uncomplicated UTI, but the recommended treatment duration was followed in only 71.9% of cases.[35, 36]

Patient disposition

With few exceptions, the vast majority of women with urinary tract infection (UTI) present on an ambulatory basis and can be treated as outpatients. Exceptions include immunocompromised or elderly patients who have a UTI manifesting as a sepsis syndrome with circulatory insufficiency. In this situation, mental status changes (eg, confusion) or profound weakness may prompt paramedical transport to the hospital. Patients with hypotension, tachycardia, and delayed capillary refill require intravenous (IV) fluid resuscitation in the field.

Hospital admission may be indicated for some patients with complicated UTI. Complicating factors include the following:

• Structural abnormalities (eg, calculi, tract anomalies, indwelling catheter, obstruction)

• Metabolic disease (eg, diabetes, renal insufficiency)

• Impaired host defenses (eg, HIV, current chemotherapy, underlying active cancer)

Adequate fluid resuscitation restores effective circulating volume and generous urinary volumes. Antipyretic pain medications may be administered, as appropriate.

Uncomplicated cystitis occurs in patients who have a normal, unobstructed genitourinary tract; who have no history of recent instrumentation; and whose symptoms are confined to the lower urinary tract. Uncomplicated cystitis is most common in young, sexually active women. Patients usually present with dysuria, urinary frequency, urinary urgency, and/or suprapubic pain. Treatment regimens for uncomplicated cystitis in nonpregnant women are provided in Table 1, below.

Table 1. Treatment Regimens for Uncomplicated Cystitis in Nonpregnant Women ^[2] (Open Table in a new window)

Complicated cystitis is associated with an underlying condition that increases the risk for therapeutic failure. Some underlying conditions include diabetes, symptoms for 7 days or longer before seeking care, renal failure, functional or anatomic abnormality of the urinary tract, renal transplantation, an indwelling catheter stent, or immunosuppression. Treatment regimens for complicated cystitis in nonpregnant women are provided in Table 2, below.

Table 2. Treatment Regimens for Complicated Cystitis in Nonpregnant Women ^[17] (Open Table in a new window)

Oral therapy with an antibiotic effective against gram-negative aerobic coliform bacteria, such as E coli, is the principal treatment intervention in patients with lower urinary tract infections.

For women with acute bacterial cystitis who are otherwise healthy and not pregnant, 3 days of therapy with most antimicrobial agents generally is more effective than single-dose therapy and as effective as the same drug administered for a longer duration. Exceptions are nitrofurantoin monohydrate/macrocrystals and beta-lactams as a group. Cystitis in older women or infection caused by Staphylococcus saprophyticus is less responsive to 3 days of therapy; therefore, 7 days of therapy is suggested.

IDSA guidelines recommend TMP-SMX (160 mg/800 mg [1 double-strength tablet] orally given twice daily for 3 days) as an appropriate choice for treatment of acute uncomplicated cystitis if local resistance rates of uropathogens do not exceed 20% or if the infecting strain is known to be susceptible. TMP-SMX should not be used empirically if the patient has received this agent for treatment of UTI during the previous 3 months.[2]

Nitrofurantoin monohydrate/macrocrystals has the advantage of taking resistance pressure off the much-used quinolone class. In a 2009 analysis by Olson et al, 29.6% of 176 urinary isolates with E coli studied were resistant to TMP-SMX; none was resistant to nitrofurantoin macrocrystals. Resistance to ciprofloxacin was 1.8% in first-time UTIs, versus 11.8% in recurrent UTIs. The authors recommended considering nitrofurantoin as a first-line agent for uncomplicated lower UTIs.[37]

Similarly, a decision and cost analysis by McKinnell et al found that nitrofurantoin minimized cost when the prevalence of fluoroquinolone resistance exceeded 12% or the prevalence of TMP-SMX resistance exceeded 17%.[38] On the basis of efficacy, cost, and low impact on promoting antimicrobial resistance, these researchers recommended that clinicians consider nitrofurantoin as a reasonable alternative to TMP-SMX and fluoroquinolones for first-line therapy for uncomplicated UTIs.

Fosfomycin (a single dose of 3 g with 3-4 oz of water) also is an appropriate choice for therapy, where available, because of minimal resistance and propensity for collateral damage. Fosfomycin is approved by the US Food and Drug Administration (FDA) for single-dose treatment in adult women with uncomplicated UTI caused by Escherichia coli or Enterococcus faecalis.

It has been reported that the efficacy of single-dose fosfomycin is inferior to that of standard short-course regimens.[2] However, a recent meta-analysis of 27 trials found no difference in efficacy between fosfomycin and other antibiotics for treatment of cystitis and found that fosfomycin was associated with significantly fewer adverse reactions in pregnant women.[39]

Fluoroquinolones (eg, ofloxacin, ciprofloxacin, levofloxacin) are highly effective in UTIs, but these agents have a propensity for causing collateral damage and should be reserved for important uses other than acute uncomplicated cystitis.[2] IDSA guidelines recommend that fluoroquinolones be used as second-line agents for acute uncomplicated cystitis and as first-line oral therapy for complicated cystitis.

According to the IDSA guidelines, beta-lactam agents (eg, amoxicillin-clavulanate, cefdinir, cefaclor, cefpodoxime-proxetil) in 3–7-day regimens are appropriate second-line choices when other recommended agents cannot be used. The IDSA advises against using amoxicillin or ampicillin for empiric treatment, because these agents have relatively poor efficacy and high rates of resistance.[2]

Patients with intense dysuria may obtain symptomatic relief from a bladder analgesic, such as phenazopyridine, to be used for 1-2 days. Avoid long-term use, as this agent may mask symptoms of therapeutic failure or recurrence. Many authors advise stressing the intake of plenty of fluids to promote a dilute urine flow.

In catheterized patients, removal of the catheter is essential for clearance of funguria. If the catheter is still needed, replace it (preferably a day later).

Treatment options vary from topical treatment to systemic therapy. A regimen of amphotericin-B bladder washes for 7 days provides a prompt but nonsustained response. It does not treat systemic mycoses and is inconvenient to administer. Amphotericin B, 0.3 mg/kg IV for 1 dose, is an option that provides a more sustained and systemic response.

Fluconazole 200 mg orally, followed on subsequent days by 100 mg orally once a day for 4-7 days, is a simpler option. This drug is effective against azole-responsive Candida organisms. Generally, azole resistance is observed only in C krusei and C glabrata. Fluconazole provides a good long-term effect but takes a few days to clear the urine.

As mentioned above, Candida auris has become a rapidly growing nosocomial probllem. It is highly contagious and most patients are asymptomatic. The primary route of infection is by contaminated equipment. It can live on all surfaces of the institution (equipment, skin, water) for long periods of time.[19, 40]

Once a urethral catheter is in place, the daily incidence of bacteriuria is 3% to 10%. Antibiotics should be reserved for patients with clear signs and symptoms of UTI. In these patients, suprapubic aspiration of the bladder is the criterion standard for diagnosing a UTI, although it is not performed often in clinical practice.

Oral fluoroquinolones are the drugs of choice for empiric treatment of acute UTIs. However, these drugs have a propensity for collateral damage and should be reserved for important uses other than acute cystitis.

For more information on this topic, see the Medscape Reference article Urinary Tract Infections in Patients with Spinal Cord Injury.

The physiologic changes associated with pregnancy increase the risk for serious infectious complications from symptomatic and asymptomatic urinary tract infections, even in healthy pregnant women. Consequently, treatment is indicated for pregnant women with asymptomatic bacteriuria, as well as for those with symptomatic UTIs; antibiotic selection may differ, and regimens typically are more prolonged.

For more information, see the Medscape Reference topic Urinary Tract Infections in Pregnancy.

Treatment of UTIs in renal transplant patients is preferably with a fluoroquinolone. TMP-SMX poses the risk of inducing renal failure in the transplanted kidney and consequently should be avoided unless the patient’s creatinine clearance is normal.

Asymptomatic bacteriuria should be treated for 10 days. Parenteral antibiotics should be used for severe infections. The duration of antibiotics for severe infections is 4-6 weeks.

Although asymptomatic bacteriuria is highly contagious, in most patient populations it has not been shown to be harmful. Furthermore, although persons with bacteriuria are at increased risk for symptomatic urinary tract infections, treatment of asymptomatic bacteriuria does not decrease the frequency of symptomatic infections or improve other outcomes. Consequently, screening for or treatment of asymptomatic bacteriuria is not appropriate and should be discouraged.[41]

Asymptomatic bacteriuria in women should be treated only in pregnant patients, in patients undergoing a urologic procedure that may produce mucosal bleeding, and in the significantly immunosuppressed (eg, renal transplantation patients). It should not be treated in diabetic persons, elderly individuals, and patients with indwelling catheters. Diabetic women have a high rate of asymptomatic bacteriuria with nonpathogenic strains, which can persist for long periods without progressing to infection.[42]

For a full discussion of this topic, see the Medscape Reference article Asymptomatic Bacteriuria. 

Hydration to accentuate unidirectional clearance of bacteriuria is recommended, especially if an obstruction was relieved recently. Drinking cranberry juice (10 oz/day) or taking cranberry tablets may offer some benefit in reducing recurrent UTI and does not appear to be harmful.[43, 44]

Cranberries contain type A proanthocyanidins. This compound and its urinary metabolites interfere with the adhesiveness of uropathogenic bacteria to the bladder epithelium.[45] Their effect is not as significant as antibiotics, but they do not induce bacterial resistance. Because of their variable intestinal absorption, it is difficult to design a valid study comparing them head-to-head with antimicrobials.[43]

Urologic consultation is essential in patients with UTIs complicated by obstruction, renal cysts, perinephric abscess, renal carbuncle, or unknown renal masses. Other consultations depend on the patient's underlying state of health and may include an obstetrician, gynecologist, endocrinologist, nephrologist, neurologist, or neurosurgeon. In patients who present to the emergency department, consultation with the patient's primary care provider is suggested.

In the patient with a complicated UTI, coverage for unusual or multiple antibiotic–resistant organisms (eg, Pseudomonas aeruginosa) must be considered. An infectious disease consultation may be helpful in selecting the appropriate antimicrobial agent. Infectious disease input is essential for immunocompromised patients and those infected with unusual or resistant pathogens. A pharmacokinetics consultation is suggested when using aminoglycosides.

The team approach is absolutely required in dealing with C auris infections.

Prophylactic measures are indicated for patients with any of the following:

• Recurrent UTIs

• Spinal cord injury

• Urinary catheters

• Renal transplants

A study of 140 women with recurrent UTIs showed that increased fluid intake reduces the risk for repeat infections. The study participants were otherwise healthy premenopausal women who had experienced three or more UTIs in the preceding year and who self-reported low fluid intake (< 1.5 liters/day). The intervention group was instructed to increase their water intake by an additional 1.5 liters per day, whereas the control group was instructed to continue with their usual intake. At 1 year, the intervention group had experienced 48% fewer UTIs than the control group. The only fluid involved in the study was water, although other fluids would probably provide similar results, and the benefits would probably also apply to postmenopausal women. In addition, the intervention group used 47% fewer courses of antibiotics than the control group (1.8 vs 3.5; P< 0.0001).[46]

Sexually active women may attempt voiding immediately after intercourse to lessen the risk for coitus-related introduction of bacteria into the bladder. Some authors recommend large urinary flow volumes as a measure that will reduce the risk for UTI.

Prophylactic regimens for women with frequent recurrent UTIs include postcoital or continuous antibiotics. Women with fewer than 3 UTIs per year may benefit from self-initiated antibiotic therapy. For more information, see the Medscape Reference topic Prevention of Urinary Tract Infections.

In a 12-month randomized study of 28 women with recurrent bacterial cystitis, treatment with intravesical hyaluronic acid and chondroitin sulfate significantly reduced cystitis recurrence and improved urinary symptoms, quality of life, and cystometric capacity, as compared with antibiotic prophylaxis. Intravesical treatment was given once weekly for 4 weeks, then once every 2 weeks twice more. Antibiotic prophylaxis consisted of sulfamethoxazole and trimethoprim once weekly for 6 weeks.[47]

The American Urological Association (AUA) has issued its first guideline for the diagnosis and treatment of uncomplicated recurrent urinary tract infections (UTIs), emphasizing the importance of cultures and antibiotic stewardship.[48]

Evaluation

Women presenting with recurrent lower urinary tract infections (rUTI) should undergo a complete patient history and pelvic examination.

A diagnosis of rUTI must be based on documented positive urine culture results in association with prior symptomatic episodes.

An initial urine specimen that may be contaminated should prompt a repeat urine study; collection of a catheterized specimen should be considered.

Index patients presenting with rUTI should not routinely undergo upper tract imaging and cystoscopy.

Before beginning treatment in patients with rUTI, urinalysis, urine culture, and sensitivity should be performed for each symptomatic acute cystitis episode.

Select patients with rUTI with acute episodes may be offered patient-initiated treatment (self-start treatment) while urine culture results are pending.

Asymptomatic bacteriuria

Surveillance urine testing, including urine culture, should not be performed in asymptomatic patients with rUTI.

Asymptomatic bacteriuria should not be treated.

Antibiotic treatment

Symptomatic UTIs in women should be treated with first-line therapy (ie, nitrofurantoin, TMP-SMX, fosfomycin) and should depend on local antibiogram.

The duration of antibiotic therapy for rUTI in patients with acute cystitis episodes should be as short as is reasonable (typically no longer than 7 days).

rUTIs in patients with acute cystitis that has shown resistance to oral antibiotics on urine culture may be treated with culture-directed parenteral antibiotics for as short a course as is reasonable (typically no longer than 7 days).

Antibiotic prophylaxis

After discussing the risks, benefits, and alternatives, antibiotic prophylaxis may be prescribed to reduce the risk for future UTIs in women of all ages previously diagnosed with UTI.

Nonantibiotic prophylaxis

Cranberry prophylaxis may be offered to women with rUTI.

Follow-up evaluation

Posttreatment urinalysis or urine culture to test for cure should not be performed in asymptomatic patients.

UTI symptoms that persist after antimicrobial therapy should prompt repeat urine culture to guide further treatment.

Estrogen therapy

Vaginal estrogen therapy with no contraindications should be recommended to perimenopausal and postmenopausal women with rUTIs to reduce the risk of future UTI.

The goals of pharmacotherapy are to eradicate the infection, prevent complications, and provide symptomatic relief to patients. Early treatment is recommended to reduce the risk for progression to pyelonephritis.

It is important to identify antimicrobial resistance patterns when considering empiric antimicrobial selection. Oral therapy with an empirically chosen antibiotic that is effective against gram-negative aerobic coliform bacteria, such as Escherichia coli, is the principal treatment intervention in patients with lower urinary tract infections. Appropriate antimicrobials for the treatment of cystitis include trimethoprim-sulfamethoxazole (TMP-SMX), nitrofurantoin, fluoroquinolones, or cephalosporins. Some patients may require a urinary analgesic such as oral phenazopyridine, which is useful to relieve discomfort due to severe dysuria.

Class Summary

Sulfonamides inhibit bacterial dihydropteroate synthase by competing with para-aminobenzoic acid (PABA). This action interferes with the uptake of PABA into folic acid, an essential component of bacterial development.

Trimethoprim-sulfamethoxazole (Bactrim, Bactrim DS, Septra, Septra DS)

Trimethoprim-sulfamethoxazole (TMP-SMX) is designed to take advantage of the synergy between trimethoprim and sulfonamides. TMP-SMX activity includes common urinary tract pathogens, both aerobic gram-positive and gram-negative bacteria, except Pseudomonas aeruginosa. Empiric therapy with TMP-SMX should be avoided if the prevalence of resistance is greater than 20%. This agent has been given an A-I rating in the 2010 Infectious Disease Society of America (IDSA) guidelines for treating cystitis.[1] General dosing recommendations include administering 1 tablet (160 mg/800 mg) twice a day for 3 days in patients with uncomplicated cystitis.

Class Summary

Empiric antimicrobial therapy should cover all likely pathogens in the context of this clinical setting. Antibiotics that have been used include nitrofurantoin, fosfomycin, or trimethoprim.

Nitrofurantoin (Furadantin, Macrobid, Macrodantin)

Nitrofurantoin is bactericidal in urine at therapeutic doses. It is indicated for the treatment of cystitis when caused by susceptible strains of E coli, enterococci, Staphylococcus aureus, and certain strains of Klebsiella and Enterobacter species. It is a good treatment option because of minimal resistance and propensity for collateral damage.

This agent has been given an A-I rating in the 2010 Infectious Disease Society of America (IDSA) guidelines for treating cystitis.[1] Nitrofurantoin should be avoided if there is suspicion for early pyelonephritis, and it is contraindicated when creatinine clearance is less than 60 mL/min.

Nitrofurantoin is manufactured in different forms to facilitate durable concentrations in the urine: macrocrystals (Macrodantin) and microcrystal suspension (Furadantin). A combined preparation of monohydrate/monocrystals (Macrobid) is indicated only for the treatment of acute cystitis caused by susceptible strains of E coli or S saprophyticus in patients 12 years of age and older.

General dosing recommendations for patients with uncomplicated cystitis include nitrofurantoin monohydrate/macrocrystals, 100 mg twice a day for 5-7 days, or

nitrofurantoin macrocrystals, 50-100 mg 4 times a day for 7 days.

Fosfomycin (Monurol)

Fosfomycin is a bactericidal agent that is used for the treatment of uncomplicated cystitis in susceptible strains of E coli and Enterococcus faecalis. Little cross-resistance between fosfomycin and other antibacterial agents exists. It is primarily excreted unchanged in the urine, and concentrations remain high for 24-48 hours after a single dose. This agent has been given an A-I rating in the 2010 IDSA guidelines for treating cystitis.[1] Fosfomycin can be administered at a dose of 3 g as a single dose with 3-4 oz of water for uncomplicated cystitis.

Trimethoprim (Primsol)

Trimethoprim inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. It is active in vitro against a broad range of gram-positive and gram-negative bacteria, including uropathogens, such as Enterobacteriaceae and S saprophyticus. Resistance usually is mediated by decreased cell permeability or alterations in the amount or structure of dihydrofolate reductase. It demonstrates synergy with the sulfonamides, potentiating the inhibition of bacterial tetrahydrofolate production.

Class Summary

Fluoroquinolones are highly effective against gram-negative and gram-positive bacteria. A major concern with fluoroquinolones is the development of resistance among uropathogens and other organisms.[49] For that reason, these agents should be reserved as alternative therapies for acute cystitis. Fluoroquinolones are effective in 3-day regimens. In the 2010 IDSA guidelines, quinolones have an A-III rating for treating cystitis.[2]

Ciprofloxacin (Cipro. Proquin XR)

Ciprofloxacin is used to treat cystitis that is caused by E coli or S saprophyticus. For acute uncomplicated cystitis, the recommended dosage is 250 mg twice daily for 3 days. As the severity of the condition worsens, the duration of therapy is extended.

Ofloxacin

Ofloxacin is indicated for the treatment of both uncomplicated and complicated cystitis. Like other fluoroquinolones, it is most effective against gram-negative organisms such as E coli, Citrobacter diversus, C freundii, Enterobacter cloacae, Klebsiella species, Proteus species, and Shigella species. The usual regimen for uncomplicated cystitis is 200 mg given twice daily for 3 days. Complicated cystitis can be treated for 10 days.

Levofloxacin (Levaquin)

Levofloxacin is indicated for the treatment of uncomplicated and complicated cystitis. It is used to treat cystitis caused by E coli, S saprophyticus, or Klebsiella species. Levofloxacin can be given for uncomplicated cystitis at a dose of 250 mg every 24 hours for 3 days. It also can be given for complicated cystitis at a dose of 750 mg daily for 5 days or a dose of 250 mg daily for 10 days.

Class Summary

Penicillins such as amoxicillin and ampicillin are not recommended as empiric therapy for uncomplicated cystitis. However, amoxicillin-clavulanate may be used in uncomplicated cystitis as an alternative therapy.

Amoxicillin-clavulanate (Augmentin, Augmentin XR)

A beta-lactam antibiotic such as amoxicillin-clavulanate in 3-7 day regimens is recommended for the treatment of uncomplicated cystitis when other agents are not appropriate. In the 2010 IDSA guidelines, amoxicillin-clavulanate has a B-I rating for treating cystitis.[1]

Ampicillin

Ampicillin has activity against anaerobes and gram-negative aerobes. Ampicillin can be given intravenously or intramuscularly and generally is used in combination with an aminoglycoside (gentamicin) for empiric or directed activity against E faecalis in patients with complicated cystitis who cannot tolerate oral therapy or in patients in whom infection with resistant organisms is suspected.

Class Summary

Cephalosporins represent the majority of antibiotics known as beta-lactam antibiotics. The 2010 IDSA guidelines for treating cystitis give beta-lactams, in general, a B-I rating, listing them as second-line agents.[2] Cephalosporin antibiotics are classified into “generations” that somewhat correspond to their spectrum of action.

Cefaclor

Cefaclor is indicated for the treatment of cystitis and pyelonephritis that is caused by E coli, Proteus mirabilis, Klebsiella species, and coagulase-negative staphylococci. Cefaclor has been used at a dose of 500 mg 3 times a day for 7 days in patients with uncomplicated cystitis.

Cefuroxime (Ceftin, Zinacef)

Cefuroxime is indicated for the treatment of uncomplicated cystitis that is caused by E coli or Klebsiella pneumoniae. The general dosing recommendation is 250 mg given twice daily for 7-10 days.

Class Summary

Third-generation cephalosporins are broad-spectrum and have bactericidal activity. These drugs are the most active against serious gram-negative pathogens but have some activity against gram-positive pathogens. The 2010 IDSA guidelines for treating cystitis give beta-lactams, in general, a B-I rating, listing them as second-line agents.[2]

Cefpodoxime

Cefpodoxime is approved for the treatment of uncomplicated cystitis. It is an extended-spectrum oral cephalosporin with bactericidal activity against a wide spectrum of gram-positive and gram-negative bacteria, including E coli, S saprophyticus, and K pneumoniae. Patients with uncomplicated cystitis can be treated with cefpodoxime, 100 mg twice a day for 7 days.

Cefdinir

Cefdinir has been used an alternative therapy for uncomplicated cystitis when other therapies cannot be used. Dosing recommendations include 300 mg twice daily given for 7 days.

Ceftazidime (Fortaz, Tazicef)

Ceftazidime has broad-spectrum gram-negative activity and lower efficacy against gram-positive organisms. It is approved for both complicated and uncomplicated cystitis caused by Pseudomonas aeruginosa; Enterobacter species; Proteus species, including P mirabilis and indole-positive Proteus; Klebsiella species; and E coli. Ceftazidime, 500 mg IV or IM every 8-12 hours for 7-14 days, can be administered to patients with complicated cystitis. For patients with uncomplicated cystitis, a dose of 250 mg IV or IM can be given every 12 hours.

Class Summary

Cefepime is a fourth-generation drug that has the gram-negative activity of the third-generation agents and the gram-positive activity of the first-generation drugs.

Cefepime (Maxipime)

Cefepime is a zwitterion; this property is thought to enhance the ability of this agent to penetrate porin channels in the cell walls of gram-negative bacteria. Cefepime is ideal for intramuscular administration.

Cefepime is indicated for the treatment of complicated and uncomplicated cystitis caused by E coli or K pneumoniae when the infection is severe or caused by E coli, K pneumoniae, or P mirabilis when the infection is mild to moderate, including cases associated with concurrent bacteremia with these microorganisms. Cefepime can be administered at a dose of 2 g IV every 12 hours for 10 days for patients with severe complicated cystitis.

Cefiderocol (Fetroja)

Cephalosporin antibiotic with a novel mechanism for penetrating the outer cell membrane of gram-negative pathogens by acting as a siderophore by binding to extracellular free ferric iron. Elicits bactericidal action by inhibiting cell wall biosynthesis through binding to penicillin-binding proteins. It is indicated for complicated UTIs, including pyelonephritis, caused by susceptible gram-negative microorganisms in adults who have limited or no alternative treatment options.

Class Summary

Extended-spectrum penicillins have a broad spectrum of bactericidal activity. They are used mainly in the treatment of infections suspected or known to be caused by gram-negative aerobes.

Piperacillin-tazobactam (Zosyn)

Piperacillin-tazobactam is useful because of its broad spectrum of bactericidal activity against gram-positive and gram-negative aerobic and anaerobic organisms. Piperacillin is a beta-lactam antibiotic and is mainly bactericidal. Tazobactam is an irreversible inhibitor of bacterial beta-lactamases.

Class Summary

Aminoglycosides are bactericidal antibiotics used primarily in the treatment of gram-negative infections. They irreversibly bind to the 30S subunit of bacterial ribosomes, blocking the recognition step in protein synthesis and causing misreading of the genetic code. The ribosomes separate from the messenger RNA; cell death ensues.

The FDA approved a new aminoglycoside, plazomicin, in June 2018. Approval was based on the Phase 3 Evaluating Plazomicin in cUTI (EPIC) clinical trial (n=388). Plazomicin was noninferior to meropenem in terms of clinical cure and microbiological eradication at Day 5 and test-of-cure at about Day 17.[50]

Gentamicin

Gentamicin has activity against various aerobic gram-negative bacteria, as well as E faecalis and staphylococcal species. It is the only aminoglycoside with appreciable activity against gram-positive organisms. Gentamicin is used with ampicillin to treat patients with complicated cystitis who cannot tolerate oral therapy or patients in whom infection with resistant organisms is suspected.

Plazomicin (Zemdri)

Semisynthetic aminoglycoside antibacterial derived from sisomicin. Plazomicin has been engineered to overcome aminoglycoside-modifying enzymes (AMEs), the most common aminoglycoside-resistance mechanism in Enterobacteriaceae, and has in vitro activity against extended-spectrum beta-lactamase–producing, aminoglycoside-resistant, and carbapenem-resistant isolates. It is indicated for complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible microorganism(s): E coli, K pneumoniae, P mirabilis, and E cloacae. Limited clinical safety and efficacy data are available; therefore, the prescribing information recommends to reserve treatment for use in patients with cUTI who have limited or no alternative treatment options.

Class Summary

These agents relieve pain, discomfort, and spasms of the bladder.

Phenazopyridine (Azo Standard, Azo Standard Maximum Strength, Baridium, Pyridium, UTI Relief)

Phenazopyridine is an azo dye excreted in urine, where it exerts a topical analgesic effect on urinary tract mucosa. It is compatible with antibacterial therapy and can help relieve pain and discomfort before antibacterial therapy controls infection. Its analgesic action may reduce or eliminate the need for systemic analgesics or narcotics.

Class Summary

Carbapenem antibiotics are broad-spectrum antibiotics that are structurally related to beta-lactam antibiotics. The bactericidal activity of carbapenems results from the inhibition of cell wall synthesis and is mediated through the binding to penicillin-binding proteins (PBPs). Parenteral therapy may be warranted for treatment of patients with complicated cystitis who cannot tolerate oral therapy. Parenteral regimens that can be used include carbapenem antibiotics.

Doripenem (Doribax)

Doripenem is indicated as a single agent for the treatment of complicated cystitis and pyelonephritis caused by E coli (including cases with concurrent bacteremia), K pneumoniae, P mirabilis, P aeruginosa, and Acinetobacter baumannii. The general dosing recommendation is 500 mg IV every 8 hours for 10 days.

Imipenem/cilastatin (Primaxin)

Imipenem is a carbapenem antimicrobial agent. It is mainly bactericidal, and it inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific PBPs that are located inside the bacterial cell wall.

Cilastatin is a reversible, competitive inhibitor of dehydropeptidase-1 (DHP-1), an enzyme found in the brush border of the proximal tubular cells of the kidneys that breaks down imipenem to inactive metabolites. Cilastatin prevents the renal metabolism of imipenem, which results in an increase in urinary concentrations of imipenem and minimizes the nephrotoxicity observed when imipenem is administered alone. Imipenem can be administered at a dose of 500 mg IV every 6 hours for 7-14 days.

Imipenem/cilastatin/relebactam (Recarbrio)

Three-drug combination containing previously approved imipenem/cilastatin and relebactam, a beta-lactamase inhibitor. It is indicated for complicated urinary tract infections, including pyelonephritis, and complicated intra-abdominal infections in adults with limited or no other treatment options. Dosage modifications are necessary for patients who have renal impairment.

Meropenem (Merrem)

Meropenem is indicated for the treatment of bacterial meningitis, complicated skin and skin-structure infections, and intra-abdominal infections. However, it can also be used for the treatment of complicated cystitis. It inhibits cell wall formation, facilitates bacterial cell lysis, and is primarily a bactericidal agent. It inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific PBPs that are located inside the bacterial cell wall.