Published: November 2013
Urinary tract infection (UTI) is the most common bacterial infection in humans.1 They account for more 8.6 million physician visits (84% by women) and over 1 million hospital admissions in the United States each year.2–4 Acute uncomplicated cystitis remains one of the most common indications for prescribing antimicrobials to otherwise healthy community-dwelling women5 and up to 50% of all women experience one episode by 32 years of age.6
The term uncomplicated urinary tract infection refers to the invasion of a structurally and functionally normal urinary tract by a nonresident infectious organism. Complicated UTI refers to the occurrence of infection in patients with an abnormal structural or functional urinary tract, or both (Box 1). However, this classification scheme does not account for the diversity of complicated UTI syndromes. UTI in men conventionally have been considered complicated because most infections occur in infants or in the elderly in association with urologic abnormalities. Nevertheless, acute uncomplicated UTI can occur in men, especially in those with risk factors like insertive anal intercourse or lack of circumcision.7 UTI also can be classified according to anatomical location as either lower UTI (urethritis and cystitis) or upper UTI (pyelonephritis and perinephric abscess). UTI is differentiated from asymptomatic bacterial colonization by the presence of an inflammatory response, and the associated signs and symptoms that result from bacterial invasion.
|Ureteric and urethral strictures|
|Polycystic kidney disease|
Urinary tract infections are an extremely common diagnosis in women. The UTI incidence ratio in middle-aged women to men is 30:1; yet, during later decades of life, the ratio of infection in women to men with bacteriuria progressively decreases.8 Incidence and prevalence of UTI vary between different reports depending on the criteria used for diagnosis (urine culture vs urine analysis) and the methods used for case ascertainment (self report to a health care provider vs random telephone surveys). However, it has been estimated that at least one-third of all women in the United States are diagnosed with a UTI by the time they reach 24 years of age.9 According to the National Health and Nutrition Examination Survey (NHANES-III), the incidence for UTI is 13,320 per 100,000 adult women per year.10 Among young healthy women with cystitis, the infection recurs in 25% of women within 6 months after the first episode.11
Some people are more likely to develop a UTI than others because of host factors or urothelial mucosal adherence to the mucopolysaccharide lining.12 Any abnormality of the urinary tract that interferes with the drainage of urine (e.g., kidney stones or an enlarged prostate) sets the stage for an infection. The same is true for foreign bodies in the bladder, such as catheters and tubes (see Box 1). Diabetics and other immunocompromised patients are at higher risk for UTI and its complications.
Women are especially susceptible to cystitis for reasons that are poorly understood. One factor may be that a woman's urethra is short, allowing bacteria quick access to the bladder. Also, a woman's urethral opening is near sources of bacteria from the anus and vagina. Sexual intercourse13 and women's use of a diaphragm14 have also been linked to an increased risk of cystitis although the reasons for this linkage are unclear.13 Hormonally induced changes in the vaginal flora associated with menopause are responsible for its higher prevalence in older women.15 Postmenopausal women also may be at increased risk for UTI given their increased prevalence of cystocele and elevated volumes of post-void residual urine. Pregnancy does not increase the risk of cystitis. However, pregnancy does increase the risk of pyelonephritis if UTI does occur.
Bacterial urinary infections usually spread to the urinary tract through an ascending route of fecal flora, from the fecal reservoir through the urethra into the bladder, particularly in patients with intermittent or indwelling catheters. In women, colonization of the mucosa of the vaginal introitus is an essential step in the pathogenesis of UTI. Once the introitus is colonized, sexual intercourse or urethral manipulation can force bacteria into the female bladder. The ascending route of bacterial infection has been proved in animal experiments after unilateral ureteral ligation. Only the unligated kidney develops pyelonephritis once bacterial cystitis ensues.16
Hematogenous dissemination secondary to organisms in the bloodstream is another possible route to the development of UTI (specifically pyelonephritis). Experimental pyelonephritis can be produced by intravenous injection of several species of bacteria and Candida.17 However, the production of pyelonephritis via this method with gram negative enteric bacilli is difficult. Data suggest infection of the kidney by gram negative bacilli rarely occurs by the hematogenous route.
Direct extension from adjacent organs via the lymphatic system, as in the case of retroperitoneal abscesses or severe bowel obstruction has been proposed as a third mechanism for UTI pathogenesis. However, evidence of this pathogenesis is unimpressive and consists of demonstrating lymphatic connections between ureters and kidneys in animals. Furthermore, increased pressure in the bladder can cause lymphatic flow to be directed towards the kidneys.16
Escherichia coli is the most common infecting organism in patients with uncomplicated UTI.18 It causes around 85% of community-acquired infections and approximately 50% of nosocomial infections.16 Other gram-negative microorganisms causing UTI include Proteus, Klebsiella, Citrobacter, Enterobacter, and Pseudomonas spp. Gram-positive pathogens, such as Enterococcus fecalis, Staphylococcus saprophyticus, and group B streptococci, can also infect the urinary tract. Anaerobic microorganisms are frequently encountered in suppurative infections of the genitourinary tract (e.g., periurethral abscess and Fournier gangrene).
The vast majority of recurrent episodes of cystitis in women are thought to be reinfections. Two thirds of such episodes involve the same strain of bacteria as uropathogenic strains can persist in the fecal flora for years after elimination from the urinary tract.19
UTI may be asymptomatic. However, some patients report incontinence, a general lack of well-being, or both.20 Cystitis clinically manifests as irritative voiding symptoms that include frequent and painful urination of small amounts of turbid urine, urgency, suprapubic or lower abdominal pain, and incontinence. Fever tends to be absent in infections limited to the lower urinary tract. In men, urinary retention should be ruled out, because it is frequently associated with cystitis and possible prostatitis. The manifestations of UTI in older adults may include confusion, lethargy, anorexia, and incontinence. The absence of dysuria, and the presence of vaginal discharge significantly decrease the probability of UTI.21
Physical examination, including a pelvic examination, should be carried out in women with lower urinary tract symptoms (LUTS) to exclude gynecologic, neurologic, or colorectal disorders. The only finding in physical examination that increases the probability of UTI is costovertebral angle tenderness, which indicates pyelonephritis.21 The presence of dysuria and frequency without vaginal discharge or irritation has a high likelihood ratio (LR = 24.6) for UTI especially when the onset of symptoms is sudden or severe. On the other hand, the combination of vaginal discharge or irritation without dysuria has a low LR (0.3).21 Physicians should also maintain a high index of suspicion for underlying sexually transmitted infections (STI). Up to 50% of women presenting to an emergency department for symptoms of cystitis were found to have an STI.22
Urine samples are collected for urinalysis in a sterile container through urethral catheterization, especially in women, or by midstream voided urine after the genital area is washed to avoid contamination. The sample is then tested for bacteriuria, pyuria, and hematuria. Pyuria is defined as the presence of at least 10 leukocytes/mm3 of un-centrifuged urine, or more than 5 to 10 leukocytes/high-power field in centrifuged urine. About one third of the women who have acute symptoms of cystitis have sterile urine or some other cause for the symptoms.23 Many diseases of the urinary tract produce significant pyuria without bacteriuria, including staghorn calculi, tuberculosis, and infections caused by Chlamydia and Mycoplasma spp. Indirect dipstick tests are informative, but less sensitive, than microscopic examination of the urine. The dipstick leukocyte esterase test is a rapid screening test for pyuria. It has a sensitivity of 75% to 96% and a specificity of 94% to 96% for detecting more than 10 white blood cells/mm3 of urine.24,25 However, if leukocytes in urine are already reported, then the leukocyte esterase test will not provide any additional information. In addition, dipstick test results provide little useful information when the story is strongly suggestive of UTI, since even negative results do not reliably rule out the infection in such cases.21 Microscopic hematuria is found in 40% to 60% of cystitis patients.26 Associated gross hematuria should be evaluated further by imaging studies. Cystoscopy is indicated for those patients who are older than 50 years or who have other risk factors for concomitant diseases, such as nephrolithiasis or transitional cell carcinoma (e.g., smoking). Mild proteinuria (<2 g/d) is a common but not universal finding in UTI. Excretion of 3 g over 24 hours or more would be suggestive of glomerular disease.16
Although empirical therapies are acceptable for uncomplicated cystitis (Box 2), culture and sensitivity testing should be performed in all other cases, including uncomplicated pyelonephritis. In patients with symptoms of UTI, one titer of 105 or more bacteria/mL of urine carries a 95% probability of true bacteriuria. With titers below 105 colony forming units/mL, but in the presence of frequency, urgency, and dysuria, women have a 33% chance of having a bacterial UTI.16 However, very low titers (<102/mL) of Enterobacteriaceae argues against UTI. It should be noted again that a large percentage of women with cystitis have been found to have STIs. Additional cultures for Neisseria gonorrhea, Chlamydia, Mycoplasma hominis, and Ureaplasma ureolyticus should be considered for women with recurrent LUTS.
|Acute cystitis in women|
|Acute pyelonephritis in young healthy women|
|Acute cystitis in men|
|Acute pyelonephritis in men|
|UTI with pregnancy|
|UTI with gross hematuria|
|UTI associated with nephrolithiasis|
|UTI associated with neurogenic bladder|
|UTI in diabetic or immunocompromised patient|
|Recurrent UTI (>3 episodes per year)|
Radiologic studies are unnecessary for the routine evaluation of patients with cystitis. However, they may be indicated to find the cause of complicated cases, in which UTI are associated with urinary calculi, ureteral strictures, ureteral reflux, urinary tract tumors, and urinary tract diversions.
For the general management of cystitis, the patient is advised to drink plenty of water, which helps cleanse the urinary tract of bacteria. Cranberry juice and vitamin C (ascorbic acid) supplements inhibit the growth of some bacteria by acidifying the urine. Avoiding coffee, alcohol, and spicy foods is also useful. A heating pad and pain relief medication are helpful for pain management.
Cystitis is treated with antibacterial drugs. The choice of medication and length of treatment depend on several factors (Box 3). The sensitivity test is especially useful for selecting the most effective antimicrobial.
|History of drug allergy|
|Medical history (e.g., renal impairment, liver impairment)|
|Presence of urologic abnormalities|
|Spectrum of activity|
|Route of administration|
|Type of Organism|
|Results of Gram staining|
|Results of special culture and sensitivity testing|
Patients who have symptoms of frequency, urgency, pyuria on microscopic examination, and no known functional or anatomic abnormality of the genitourinary tract may be presumed to have acute uncomplicated cystitis. Recommended empirical regimens for acute uncomplicated cystitis by the 2010 update of the Infectious Disease Society of America clinical practice guidelines include nitrofurantoin, trimethoprim-sulfamethoxazole (TMP-SMX), or fosfomycin as alternatives for first-line therapy (Box 4).5 Some regimens, such as a fluoroquinolone or oral third-generation cephalosporins, may produce better results, but may promote emergence of resistance. Given the ecological adverse effects of antimicrobial therapy (collateral damage) these medications have been moved to second line therapy. Generally, for most female patients, short courses of therapy (1 to 5 days depending on the antimicrobial agent) seem warranted. With short courses of therapy, similar efficacy has been demonstrated when compared with longer courses of therapy, and with lower side effects and cost.27 TMP-SMX and quinolones are not recommended for empirical treatment of UTI in areas where resistance is above 20% and 10%, respectively.19
|Nitrofurantoin monohydrate macrocrystals, 100 mg twice daily for 5 days|
|TMP-SMX, 160/800 mg twice daily for 3 days|
|Fosfomycin trometamol, 3g sachet in a single dose|
|Ciprofloxacin, 250 mg twice daily for 3 days|
|Levofloxacin, 250 mg or 500 mg once daily for 3 days|
|Amoxicillin-clavulanate, 500 mg/125 mg twice daily for 7 days|
|Cefpodoxime, 100-mg twice daily for 3 to 7 days|
The most common cause of recurrent UTI in women is reinfection that may occur with varying intervals and different causative organisms. Reinfection in women does not require extensive urologic evaluation. Recurrent episodes of uncomplicated cystitis can be managed by several strategies. Behavioral therapy includes increasing fluid intake, urinating as soon as the need is felt, as well as immediately after intercourse, and changing the method of contraception (for users of a diaphragm or spermicide). In women who use contraception, spermicidal jelly contains nonoxynol 9, which decreases vaginal lactobacillus colonization and increases bacterial adherence. Long-term antimicrobial prophylaxis,28 postcoital prophylaxes with a single-dose antibiotic,29 or short-course (1- or 2-day) antibiotics for each symptomatic episode is recommended for women who have three or more UTI in the past 12 months or two episodes in the last 6 months.19 For postmenopausal women, the use of vaginal estrogen cream may prove an effective preventive measure.15 Patients with bacterial persistence should be evaluated thoroughly to exclude potential structural or functional abnormalities.
Most episodes of uncomplicated pyelonephritis can be treated in the outpatient setting with an empirical regimen of ciprofloxacin (500 mg twice daily for 7 days) or levofloxacin (750 mg once daily for 5 days). Urine culture and susceptibilities need to be collected before starting antimicrobial treatment to guide treatment. If quinolone resistance is a concern, TMP-SMX (160/800 mg twice daily for 14 days) can be used once the antibiogram shows susceptibility to this medication. Indications to hospitalize patients with pyelonephritis include severe presentation, hemodynamic instability, pregnancy, kidney stones, or inability to tolerate oral medications.19
Prostate infections are more challenging to cure because of the altered microenvironment of the inflamed tissue, which may affect antibiotic efficacy. Therefore, men with acute bacterial prostatitis often need long-term treatment (≥30 days) with a carefully selected antibiotic. Severely ill patients need hospitalization and parenteral antimicrobial agents, such as an aminoglycoside-penicillin combination, until culture and susceptibility results provide guidance for alternative, specific antibiotic regimens. In men with urinary retention, a urethral or suprapubic catheter is necessary. Suprapubic catheterization is preferable to decrease the risk of prostatic abscesses. Mild and moderate cases respond well to fluoroquinolones or TMP-SMX, both of which have a cure rate of 60% to 90%.30 Chronic bacterial prostatitis may manifest as episodes of recurrent bacteriuria with the same organism between asymptomatic periods. Episodic treatment may be prescribed using the agents mentioned and, in select patients, may be self-administered as needed. Daily suppressive therapy should be considered in men with frequent cystitis if other causes are excluded, and the culpable organism is localized to the prostate, using the Meares-Stamey technique.31
When evaluating patients with LUTS, it is important to consider gynecologic and colorectal diagnoses as well. STIs in either gender may manifest as LUTS, with or without fever. Female patients, especially those presenting with severe symptoms and pain, should be screened for pregnancy, because complications such as ectopic pregnancy or abortion should be ruled out. Chronic appendicitis and sigmoid diverticulitis may be confused with UTI.
Special cultures are needed to diagnose these infections. Antibiotic therapy should be prescribed accordingly. Longer treatment with tetracycline, doxycycline, or any drug appropriate for the treatment of Mycoplasma hominis and Ureaplasma urealyticum is recommended.32 The patient's sexual partner must be treated simultaneously.
Catheterization for longer than 2 weeks is usually associated with bacteriuria. Prophylactic antimicrobial therapy for cystitis during short-term, indwelling, urethral catheterization is not recommended. Symptomatic UTI in older adults should be treated. Careful consideration should be given to antimicrobial choice and meticulous monitoring of drug levels in this patient population, because the older patient is more susceptible to harmful side effects of many antimicrobial agents. Short-term antimicrobial therapy (5 to 7 days) is indicated only for symptomatic episodes. In patients requiring long-term urinary catheterization, suprapubic catheter placement should be considered. In men, suprapubic catheterization is associated with decreased risk of meatal erosion or prostatitis. In the short term, suprapubic catheterization may be associated with a decreased risk of bacteriuria or UTI. Unfortunately, this difference is not associated with long-term catheterization.
Funguria is a common finding in catheterized patients. Whereas most patients are asymptomatic, interventions should include change in catheter, elimination of unnecessary antimicrobials, and glycemic control. Although amphotericin B may be used for bladder irrigations, it is less effective and more expensive than oral fluconazole therapy, although the latter is a concern in patients with hepatic vulnerability.
Removal of an indwelling catheter should be prompt. Whenever possible, intermittent self-catheterization should be used for patients with transient or long-term urinary retention.
Bacteriuria denotes the presence of bacteria in the urine, which may be symptomatic or asymptomatic. Treatment of asymptomatic bacteriuria is indicated for pregnant women and in those patients requiring urologic surgery.33 Preoperative treatment reduces postoperative complications, including bacteremia.34
Although the prevalence of bacteriuria identified by screening is no higher in pregnant than nonpregnant women, the presence of asymptomatic bacteriuria in a pregnant woman should be treated promptly.35 The gravid uterus causes physiologic alterations that increase the risk of pyelonephritis. Pyelonephritis has been associated with infant prematurity, low birth weight, perinatal mortality, and high blood pressure.36 The recommended regimen is 7-day treatment with ampicillin or nitrofurantoin.
When creatinine clearance is significantly impaired, antibiotic dosage should be decreased since the renal blood flow is decreased and the perfusion of antimicrobial agents into the renal tissue and urine is impaired. Ampicillin, TMP-SMX, and fluoroquinolones are all effective for the treatment of UTI in uremic patients.37,38 Nitrofurantoin and tetracyclines are contraindicated for the treatment of UTI in uremic patients.
Antimicrobial prophylaxis is recommended to ensure the sterility of urine for those who appear susceptible to developing infections. These include immunocompromised patients, patients with heart disease or prosthetic heart valve, and patients who are scheduled for a procedure such as cystoscopy. Oral or vaginal estrogen administered prophylactically to postmenopausal women also reduces the incidence of cystitis.35,38