Urinary Tract Infections

N.R. Chamberlain. The Big Picture Medical Microbiology, 2009. Chapter 34, pg. 341-346 McGraw-Hill
Colgan R, and M Williams. 2011. Diagnosis and Treatment of Acute Pyelonephritis in Women. American Family Physician. 84(5):519-526.
Kasper DL, and AS Fauci. 2013. Harrison’s Infectious Disease. 2nd Edition. McGraw Hill Education. New York, NY.

Infections of the urinary tract result in over 8 million office visits per year with over 1 million hospitalizations. Most infections in this system are endogenous infections. Uropathogenic strains of Escherichia coli cause most of the uncomplicated UTI’s. Around 50-80% of women will have a UTI at some point in their life. Sexually active females are disproportionally affected. Other patients more likely to get a UTI include the elderly and those needing genitourinary catheterization or instrumentation.

UTI’s are defined as a significant bacteriuria in the presence of symptoms. The bacteria most often seen in UTI’s are of fecal origin. These organisms are a subset of the organisms found in the feces. Strict anaerobic bacteria rarely cause UTI’s. 75-90% of acute UTI’s in patients with normal anatomic structure and function are caused by uropathogenic strains of E coli. Ten to 20% of acute UTI’s are caused by coagulase-negative Staphylococcus saprophyticus (young sexually active females) and 5% or less are caused by other gram negative rods (Klebsiella, Proteus, Citrobacter) or Enterococcus species. A high pH in the urine is indicative of a Proteus infection.

Staphylococcus saprophyticus is a common inhabitant of the gastrointestinal tract. Young women are more susceptible than other ages of women. Sexual intercourse promotes colonization and infections are more common in the late summer to fall seasons. S saprophyticus is the second most common cause of uncomplicated urinary tract infections (UTI) in sexually active young (13-40 years of age) women following E coli.

In complicated cases of UTI, such as UTI's resulting from anatomic obstructions, from catheterization, or diabetes the most common cause of UTI is E. coli. Klebsiella, Proteus, Citrobacter, Acinetobacter, Morganella and Pseudomonas aeruginosa are less common causes of UTI in these patients. Enterococcus, Staphylococcus aureus and Candida albicans can also cause complicated UTI’s.

Urethritis - Most of the cases of purulent urethritis without cystitis are sexually transmitted. The inflammation and infection is limited to the urethra. Chlamydia trachomatis and Neisseria gonorrhoeae are common causes in women. Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium, Ureaplasma urealyticum, and Trichomonas vaginalis are the common causes in men. Complaints include discomfort during voiding (dysuria) and pyuria. There are usually NO symptoms of suprapubic pain or urinary urgency or frequency. Urine samples contain small numbers of uropathogens (less than 100 colony forming units (CFU)/ml).

Asymptomatic bacteriuria (ABU) – Patients have NO symptoms however, they do have bacteriuria (For women, two consecutive specimens with isolation of the same species in quantitative counts of at least 100,000 CFUs per mL of urine. For men, a single specimen with one bacterial species isolated in a quantitative count of at least 100,000 CFUs per mL.)

Cystitis-urethritis - Results from an irritation of the lower urinary tract mucosa. This infection as such is not invasive. These infections can be uncomplicated or complicated (pregnant women, nosocomial infections, patients with anatomic abnormalities, patients with instrumentation in the urinary tract). Symptoms include (1-4 are called irritative voiding symptoms):

Dysuria (painful urination; females; painful internal urination)
Urgency (the need to urinate without delay)
Increased frequency of urination
Suprapubic tenderness, pelvic discomfort especially pre- and immediately postvoid. Occurs in 20% of women with uncomplicated UTI.
Small volume voiding.
Increased number of white blood cells in the urine (pyuria)

Hemorrhagic cystitis is characterized by large quantities of blood in the urine. It can be caused by an infection (bacterial or adenovirus types 1-47) or as a result of radiation, cancer chemotherapy, or immunosuppressive medication. Clinical presentation usually depends on its origin. All causes result in irritative voiding symptoms. When infectious in origin, signs and symptoms of infection may also be encountered. Adenovirus is a common cause and is self-limiting in nature. Hemorrhagic cystitis is often confused with glomerulonephritis, but hypertension and abnormal renal function are absent in hemorrhagic cystitis.

Pyelonephritis - This infection usually results from ascension of the bacteria to the kidney from the lower urinary tract, but also can arise by hematogenous spread (e.g., from lungs in patients with pneumonia). In contrast to cystitis, pyelonephritis is an invasive disease. Blood cultures are positive in 20-30% of women who have this infection. The patient may experience many of the symptoms of cystitis as well as:

Symptoms of cystitis (see above) may be present or absent.
Fever- low grade in mild disease; high spiking “picket-fence” pattern in severe disease
Lower back pain
Costovertebral angle tenderness (CVA tenderness)
Nausea and vomiting
Peripheral leukocytosis
Urine contains white blood cell casts- elongated structures composed of cells that were tightly packed in the tubules and excreted in a proteinaceous matrix.

UTI's rank second only to respiratory infections in their incidence in the US. UTI’s account for over 8 million physician visits per year.
Males during the neonatal time of life (first three months) are slightly more likely than females to present with UTI’s and are oftentimes septic due to infection with gram-negative bacteria (E coli).
The incidence in preschool children is approximately 2% and is 10 times more common in females.
About 5% of school-aged females experience UTI’s. These infections are rare in school-aged males.
The large majority of the cases seen in the doctor's office are in adult females (30:1, female:male ratio).
Up to 20% of young females with acute cystitis develop recurrent UTI's. A recurrent UTI occurs > 2 wks after the preceding UTI. If the antecedent UTI occurs less than 2 wks before the current UTI it would be considered a relapse NOT a recurrence.
Incidence of infection increases with age and sexual activity.

Women; recent use of a diaphragm with spermicide, frequent sexual intercourse, and a history of UTI are each risk factors for acute cystitis.
Pregnant women are more susceptible to UTI's.
There is a 60-fold increase in the relative odds of a woman getting acute cystitis in the first 48 h after intercourse.
In healthy postmenopausal women sexual activity, diabetes mellitus, and incontinence are risk factors for UTI.
Men; experience a rapid increase in the incidence of UTI's in their 50’s following development of benign prostatic hypertrophy (BPH).
Any abnormality of the urinary tract that obstructs or slows the flow of urine. A stone in the kidney or any part of the urinary tract can form a blockage, creating the conditions for a UTI.
One of the most common sources of complicated UTI is placement of a catheter in the bladder.
Immunosuppressed patients.
UTI's occur in a small percentage of infants due to congenital abnormalities.
Patients with a neurogenic bladder or bladder diverticula.
Postmenopausal women with bladder or uterine prolapse

Entry is normally by ascent from the urethra. The organisms that cause UTI’s are usually fecal organisms. Blood borne infections are infrequent, usually leading to renal abscesses.

Host factors - Host factors important in protection from cystitis include the normal flow of urine, complete emptying of the bladder, and constant sloughing of the uroepithelial cells. Anything that prevents urination or results in incomplete emptying of the bladder allows uropathogens that get into the bladder time to colonize the uroepithelial cells.

The kidneys are protected from infection by the ureterovesical valves that prevent reflux of urine from the bladder and the constant peristalsis of the ureters.

The larger number of UTI's seen in women is due to the shorter urethra and the much closer association of the urethra to the anus. Sexual intercourse contributes to the increased number of UTI's seen in women. Celibate women have fewer UTI’s.

Some women have more bacterial receptors on their uroepithelial cells resulting in them having more UTI’s. Any anatomic obstruction or neurological disorder leading to failure to completely eliminate urine from the bladder can lead to UTI. More UTI’s are seen in postmenopausal women with diabetes mellitus.

In women, organisms on the mucosal surface of the vagina and on the periurethral area are colonized with predominantly, Lactobacillus species. These organisms prevent the uropathogens (e.g., Escherichia coli) from colonizing these areas. Colonization of these areas with uropathogens from the intestines is the first step in the pathogenesis of UTI’s. Sexual intercourse increases the risk of colonization of the vagina and periurethral areas with uropathogens. Nonoxynol-9 in spermicide is toxic to lactobacilli and increases the chances intestinal uropathogens will colonize the vagina. In postmenopausal women, vaginal lactobacilli are replaced with gram-negative organisms from the intestines. This increases their chances of developing a UTI.

Men in their 50's and above have problems with prostate gland enlargement resulting in obstruction of the urethra followed by incomplete elimination of urine from the bladder and UTI's.

Bacterial factors - The ability of an organism to produce fimbriae (Type 1, P, S, and Dr) is important in that it enables the bacteria to attach to the uroepithelial cells and thereby avoid elimination. Uropathogenic strains of E coli can also resist killing by complement.

Human epithelial cells of the bladder and the kidney can internalize E coli cells. The Type 1 fimbriae are important in attachment of the bacteria to the host epithelial cells and in promoting reorganization of the epithelial cell’s intracellular cytoskeleton to then internalize the bacteria. Internalization of the bacterial cells in epithelial cell vacuoles enhances bacterial cell survival by providing protection from host immune defenses and allows the pathogen greater access to deeper tissues. Once internalized the bacteria can grow in the epithelial cell and form pod-like structures. Intracellular E coli can form a reservoir within the bladder mucosa that may serve as a source for recurrent acute infections (20% of all UTI’s).

The Type 1 fimbriae mediated internalization of E coli is rather slow and the rate of internalization can be increased by 10 fold if the bacteria have first been opsonized by complement component C3. Since uropathogenic E coli are resistant to killing by complement they can then use C3 to gain entry into the host epithelial cells. Not much complement is in the urine in normal conditions. However, during infection LPS from E coli may induce the production of cytokines in the kidney that then causes increased amounts of C3 to get into the bladder. C3 binds to the surface of the bacterial cells. This surface bound C3 then binds to human complement regulatory protein, CD46, on the surface of the epithelial cell. The CD46 protein then mediates internalization of E coli.

Spread to the kidney - Infection of the kidney is usually due to ascent from the lower urinary tract and so any factor leading to retrograde flow of the urine to the kidney will predispose the host to pyelonephritis. Such factors include:

Cystitis due to a strain of E coli that produces the mannose resistant fimbriae (P fimbriae) that binds to the receptor for the P blood group found on epithelial cells and red blood cells.
Internalization of E coli in the proximal tubular epithelial cells of the kidney can also occur helping the bacteria avoid the immune response of the host. C3 bound to the surface of E coli cells appears to also be important in internalization of the bacteria in the kidney epithelial cells.
Reflux of urine to the kidney - usually due to incomplete development of ureterovesical valves.
Physiological malfunctions - disorders leading to poor emptying of the bladder. Changes during pregnancy leading to dilatation and decreased peristalsis of the ureters.
Urethral catheters - can serve as a conduit for the bacteria to ascend into the bladder and a source of bacteria for persistent infection.
Urinary tract stones - These stones serve as a place in which bacteria can escape antibiotics and cause further infections. Proteus sp. is an example of an organism, which can cause stone formation. Proteus sp. produces an enzyme called urease that splits urea to ammonia and carbon dioxide. This raises the pH of the urine and facilitates the formation of "struvite" calculi. A high pH in the urine is indicative of a Proteus infection.

Kidney damage is due to the ability of the organism to produce polysaccharide (which inhibits phagocytosis), alpha hemolysin and cytotoxic necrotizing factor 1 (causes tissue damage directly), endotoxin that contributes to inflammation and damage of renal parenchyma and internalization of the bacterial cells in kidney epithelial cells.

The diagnosis of UTI WAS based on a quantitative urine culture yielding greater than 100,000 colony-forming units per milliliter (105 CFU/ml) of urine, which WAS termed "significant bacteriuria." This value was chosen because of its high specificity for the diagnosis of true infection, even in asymptomatic persons. However, several studies have established that 50% or more of symptomatic women have CFU counts below this level (low-coliform-count infections). They have also shown that a bacterial count of 100 CFU/ml of urine has a high positive predictive value for cystitis in symptomatic women. In men the minimal level indicating an infection of the bladder is 103 CFU/ml.

Asymptomatic bacteriuria (ABU) – no signs or symptoms of a UTI. For women, two consecutive specimens with isolation of the same species in quantitative counts of at least 100,000 CFUs per mL of urine. For men, a single specimen with one bacterial species isolated in a quantitative count of at least 100,000 CFUs per mL. In catheter associated UTIs the patient should have no signs or symptoms of a UTI and > 102 CFU/ml.

Pregnant women- Between 2 and 10% of pregnancies are complicated by UTI’s. If left untreated, 25 to 30% of these women develop pyelonephritis. Pregnancies that are complicated by pyelonephritis have been associated with low-birth-weight infants and prematurity. Thus, pregnant women should be screened for bacteriuria by urine culture at 12 to 16 weeks of gestation.
Patients with renal transplants
Patients who are about to undergo genitourinary tract procedures.

Uncomplicated cystitis in women- make diagnosis on history alone; female patient presents with at least one symptom of UTI (dysuria, frequency, hematuria, urgency, or back pain) has a risk factor for UTI (e.g., sexual intercourse, diabetes mellitus, diaphragm with spermicide) and NO vaginal discharge or complicating factors present (catheter, pregnancy, neurologic or anatomical abnormalities).

If symptoms are not specific to the urinary tract or if a reliable history cannot be obtained, then do urine dipstick tests or urinalysis. A positive dipstick test (positive nitrite or leukocyte esterase) in a woman with one symptom of UTI makes the diagnosis of cystitis highly likely. If the dipstick test is negative it does not rule out UTI. A urine culture should be done (> 102 CFU/ml) and close clinical followup. If possible a pelvic examination is recommended.

Dipstick tests and urinalysis are performed to confirm pyuria and bacteriuria in a properly obtained midstream clean-catch urine specimen. Pyuria is confirmed by traditional urinalysis (wet mount examination of spun urine) using an automated method to count white blood cells, by counting the cells in a cell-counting chamber (>5-10 white blood cells per high powered field) or a dipstick test for leukocyte esterase.

Gram stains of urine can be used to detect bacteriuria. The presence on Gram stain of ≥ 1 bacterium/high-power field, performed on a midstream clean-catch urine specimen, correlates with ≥ 105 CFU/mL of uncentrifuged urine. Because the procedure is time-consuming and has low sensitivity, it is not routinely performed in most clinical laboratories unless it is specifically requested.

In today's office practice, the dipstick test for nitrite is used as a surrogate marker for bacteriuria. In some cases, women will consume a lot of fluids to increase their urinary output. This can result in a negative nitrite test. It should also be noted that not all uropathogens reduce nitrates to nitrite. For example, Enterococcus, S saprophyticus and Acinetobacter species do not and therefore give false-negative results. A negative nitrite test, positive leukocyte esterase test and at least one urinary tract specific symptom makes the diagnosis of cystitis in an uncomplicated case.

The dipstick test also measures pH of the urine. A high pH in the urine is indicative of a Proteus infection.

Cystitis in men- signs and symptoms similar to those in women. Collection of urine (midstream clean-catch) for culture is strongly recommended when a male has symptoms of UTI. If the culture contains >103 CFU/ml then they have cystitis. If organisms are not present, the patient may have chronic pelvic pain syndrome. If the patient has a fever and bacteriuria, then they have cystitis but may also have acute bacterial prostatitis (more on this later). If they have had several episodes of cystitis, then they may have chronic bacterial prostatitis (more on this later).

Pyelonephritis- Female- signs and symptoms of cystitis with fever. Can also have back pain, costovertebral angle tenderness, nausea and vomiting. Male- signs and symptoms of cystitis, fever and back pain or costovertebral angle tenderness. Hard to differentiate acute bacterial prostatitis from pyelonephritis in males.

If culture of the urine is required, it must be preformed using a mid-stream catch (clean-catch specimen). If the patient can't or won't comply, use percutaneous bladder aspiration or ureter catheterization. Bacteria grow rapidly in urine therefore urine samples should be processed immediately or refrigerated. Cultures refrigerated for more than 2 hours are usually of no value in making the diagnosis.

Diagnosis should also involve the determination of the site of infection (i.e., kidney or bladder-urethra). This may be suggested by the clinical manifestations and preliminary lab tests.

There are a number of tests that may help in establishing the site(s) of infection.

An antibody-coated bacterium in urine test is based upon the principal that bacteria originating in the kidney are coated with specific antibody (detect by fluorescent microscopy following staining with FITC-conjugated, goat anti-human gamma globulin) but those bacteria originating from the bladder are not coated with antibodies. Not always reliable.
Presence of white blood cell casts indicates the patient has pyelonephritis.
Ureteral catheterization under cystoscopic visualization to culture urine directly obtained from each kidney.

If a patient is experiencing recurrent UTI's (UTI’s 2 wks or more apart) the causative organism should be identified by urine culture. Multiple infections caused by the same organism are, by definition, complicated UTIs and require longer courses of antibiotics (e.g., 7 to 10 days) and possibly further diagnostic tests.

Complicated UTI’s- Between 10 and 20% of patients who are hospitalized receive an indwelling Foley catheter. Once this catheter is in place, the risk of bacteriuria is approximately 5% per day. With long-term catheterization, bacteriuria is inevitable. Catheter-associated urinary tract infections account for 40% of all nosocomial infections and are the most common source of gram-negative bacteremia in hospitalized patients.

Afebrile patients experiencing symptoms of lower UTI are treated on an outpatient basis.
Patients experiencing high fever, shaking chills and flank pain, in addition to symptoms of lower UTI, may need to be hospitalized.

Uncomplicated symptomatic acute cystitis and/or urethritis are usually treated with nitrofurantoin (5-7 days) or trimethoprim-sulfamethoxazole (TMP-SMX; 3 days).
Pyelonephritis is more difficult to treat than urethritis-cystitis and reoccurrence due to relapse (i.e., treatment failure) or reinfection is more common.

Three-day therapy is inappropriate.
Give intravenous antibiotics (ciprofloxacin) until the patient can tolerate oral treatment with fluoroquinolone and then give oral antibiotic for a total treatment time of 7 days.
Oral 7-day therapy with a ciprofloxacin can be considered in women with mild to moderate symptoms that are compliant with therapy and can tolerate oral antibiotics but do not have other significant conditions, including pregnancy and gastrointestinal upset.
Do bacteriologic culturing as a follow-up to insure treatment success.
Candida and torulopsis yeast infections of the urinary tract are treated with flucytosine.

Underlying uropathies requiring surgical correction are much more common, particularly in males with pyelonephritis, so a more extensive workup is required to prevent reoccurrence.

3. A seven-day course should be considered in pregnant women (nitrofurantoin, ampicillin or cephalosporin), diabetic women (same antibiotics as uncomplicated) and women who have had symptoms for more than one week and thus are at higher risk for pyelonephritis because of the delay in treatment (same antibiotics as uncomplicated).

4. Women who have more than two UTI recurrences documented by urine culture within one year can be managed using one of three preventive strategies:

Acute self-treatment with a three-day course of standard therapy.
Postcoital prophylaxis with one-half of a trimethoprim-sulfamethoxazole double-strength tablet (40/200mg) if the UTIs have been clearly related to intercourse.
Continuous daily prophylaxis with one of these regimens for a period of six months: trimethoprim-sulfamethoxazole, one-half tablet per day (40/200 mg); nitrofurantoin, 50 to 100 mg per day; norfloxacin, 200 mg per day; cephalexin (Keflex), 250 mg per day; or trimethoprim, 100 mg per day.

Long-term studies have shown antibiotic prophylaxis to be effective for up to five years with trimethoprim, trimethoprim-sulfamethoxazole or nitrofurantoin, without the emergence of drug resistance. Antibiotic prophylaxis does not appear to alter the natural history of recurrences since 40 to 60% of these women reestablish their pattern or frequency of UTI's within six months of stopping prophylaxis.

5. Complicated UTI's occur because of anatomic, functional or pharmacologic factors that predispose the patient to persistent infection, recurrent infection or treatment failure. These factors include conditions often encountered in elderly men, such as enlargement of the prostate gland, blockages and other problems necessitating the placement of indwelling urinary devices, and the presence of bacteria that are resistant to multiple antibiotics. Although antibiotic-susceptible E coli strains are responsible for more than 80% of uncomplicated UTI's, it accounts for fewer than 33% of complicated cases. Clinically, the spectrum of complicated UTI's may range from cystitis to urosepsis with septic shock.

Maintain a high fluid intake to be sure you have good urine output-at least one to two quarts of fluid in 24 hours.
Empty their bladder as soon as they feel the urge to urinate, even if it does not feel full.
Avoid foods that may irritate the bladder, such as spicy foods, alcohol, or beverages containing caffeine.
Take medications prescribed by the doctor exactly as instructed, and be sure to take all of the medication prescribed.
Call the doctor or clinic if signs and symptoms of the infection do not subside after two or three days.

Sexually active women may prevent recurrent UTI’s by switching to contraception that does NOT utilize diaphragms or spermicides.

Asymptomatic bacteriuria
A large number of pregnant women develop asymptomatic bacteriuria. Up to 30% of pregnant women with asymptomatic bacteriuria will develop acute pyelonephritis if not treated. Asymptomatic bacteriuria may also have a role in preterm birth. Drug treatment of asymptomatic bacteriuria in pregnant women substantially decreases the risk of pyelonephritis (Nitrofurantoin, amoxicillin, or TMP-SMX). Urine samples should be obtained periodically from pregnant women to determine if they have asymptomatic bacteriuria.
Renal transplant/genitourinary surgery patients treat with TMP-SMX

URINARY TRACT INFECTIONS (Urethritis, Cystitis, Pyelonephritis)