URINARY TRACT INFECTIONS (Urethritis, Cystitis, Pyelonephritis)

1. The UTI Zone; Medscape.

2. Medscape UTI Clinical Update 

3. R. ORENSTEIN and E. S. WONG. Urinary Tract Infections in Adults. American Family Physician. March 1, 1999.

4. Wilson ML, Gaido L. Laboratory diagnosis of urinary tract infections in adult patients. Clin Infect Dis. 2004;38:1150-1158.

UTI is defined as a significant bacteriuria in the presence of symptoms. The bacteria most often seen in UTIs are of fecal origin. These organisms are a subset of the organisms found in the feces. Strict anaerobic bacteria rarely cause UTIs. More than 90% of acute UTIs in patients with normal anatomic structure and function are caused by certain strains of E. coli. 10 to 20 percent are caused by coagulase-negative Staphylococcus saprophyticus and 5 percent or less are caused by other enterobacteriaceae organisms or enterococci. In complicated cases of UTI, such as UTI's resulting from anatomic obstructions, or from catheterization the most common causes of UTI are E. coli, Klebsiella pneumoniae, Proteus mirabilis, Enterococcus sp., Pseudomonas aeruginosa. In rare cases Candida albicans can cause UTI (ex. diabetic patients). S. saprophyticus is the second most common cause in young sexually active women.

EPIDEMIOLOGY

Males experience a rapid increase in the incidence UTI's sometime in their 40s. This is about the time that males are experiencing prostate gland hypertrophy. Women generally don't have many problems with UTI's until they become sexually active.

Risk factors:

1. Any abnormality of the urinary tract that obstructs or slows the flow of urine makes it easier for bacteria to grow. A stone in the kidney or any part of the urinary tract can form such a blockage, creating the conditions for a UTI. In men, an enlarged prostate gland can obstruct urine flow and make infection difficult to treat.
2. One of the most common sources of infection is catheters, or tubes, placed in the bladder.
3. People who have diabetes mellitus
4. Immunosuppressed patients
5. UTI's occur in a small percentage of infants due to congenital abnormalities that sometimes require surgery.
6. For many women, sexual intercourse seems to precipitate UTI's.
7. Women who use the diaphragm and/or spermicides are more likely to develop a UTI than women who use other forms of contraception.
8. Patients with a neurogenic bladder or bladder diverticulum.
9. Postmenopausal women with bladder or uterine prolapse
10. Pregnant women are more susceptible to UTI's

B. Host factors - Host factors important in protection from cystitis include the normal flow of urine and the constant sloughing of the epithelial cells lining the urinary tract. The kidneys are protected due to the presence of the ureterovesical valves that prevent reflux of urine from the bladder, and constant peristalsis of the ureters.

The larger number of UTI's present in women than in men is probably due to the much 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 a lower frequency of bacteriuria.

Some women have been shown to have a much higher number of bacterial receptors on their uroepithelial cells leading to recurrent UTIs. Also, any anatomic obstruction, or neurological disorder leading to the failure to completely eliminate the urine can lead to UTI. Men in their 40's have problems with the prostate gland enlarging resulting in obstruction of the urethra followed by incomplete elimination of urine from the bladder and UTI's.

C. Bacterial factors - The ability of an organism to produce pili is important in that it enables the bacteria to attach to the epithelial cells and thereby avoid elimination. Damage to the kidney appears to result from the ability of the organism to produce polysaccharide which inhibits phagocytosis, hemolysins that can cause tissue damage directly, and endotoxin from Gram negative organisms that appear to contribute to inflammation and damage of renal parenchyma.

D. Spread to the kidney - Infection of the kidney is 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:

1. Reflux of urine to the kidney - usually due to incomplete development of ureterovesical valves.
2. Physiological malfunctions - disorders leading to poor emptying of the bladder. Changes in pregnancy leading to dilatation and decreased peristalsis of the ureters.
3. Urethral catheters - can serve as a conduit for the bacteria to ascend into the bladder and a source of bacteria for persistent infection.
4. 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 stones to form. Proteus sp. produce an enzyme called urease that can split urea to ammonia and carbon dioxide. This will raise the pH of the urine and facilitate the formation of "struvite" calculi. A high pH of the urine is indicative of a Proteus sp. infection.

A. Urethritis - Most of the cases of purulent urethritis without cystitis are sexually transmitted and will be discussed later. the inflammation and infection is limited to the urethra. It is usually sexually transmitted. Pathogens such as Chlamydia trachomatis, Ureaplasma urealyticum, Neisseria gonorrhoeae, or Trichomonas vaginalis are the common causes of urethritis. Found in men and women, complaints include discomfort during voiding, but there are usually no symptoms of postvoid suprapubic pain or urinary frequency.

B. Cystitis - Results from an irritation of the lower urinary tract mucosa. This infection as such is not invasive. Frequently, one will see:

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

Symptoms 1-4 are sometimes called irritative voiding symptoms.

D. 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 (ex. from lungs in patients with pneumonia). In contrast to cystitis, pyelonephritis is an invasive disease. Blood cultures are positive in up to 20 percent of women who have this infection. Unfortunately, despite appropriate intervention, 1-3% of patients with acute pyelonephritis die. Symptoms in addition to those seen in cystitis are:

1. Suprapubic tenderness 
2. Urinary urgency and frequency may be present or absent.
3. Fever
4. Flank pain and tenderness (back pain)
5. Costovertebral angle tenderness (CVA tenderness)
6. Nausea and vomiting
7. Peripheral leukocytosis
8. Urine contains white blood cell casts (elongated structures) composed of cells that were tightly packed in the tubules and excreted in a proteinaceous matrix.

1. Sepsis
2. Septic shock (if a Gram-negative organism).
3. Death

DIAGNOSIS

Since very few organisms cause UTI in acute uncomplicated cystitis in young women and since their antibiotic sensitivity is relatively predictable, urine cultures and susceptibility testing add little to the choice of antibiotic. Therefore, urine cultures are no longer advocated as part of the routine work-up of these patients. Instead, these patients should undergo an abbreviated laboratory work-up in which the presence of pyuria is confirmed by traditional urinalysis (wet mount examination of spun urine), the cell-counting chamber technique (looking for more than 8 white blood cells per mm³⁾ or a dipstick test for leukocyte esterase. A positive leukocyte esterase test has a reported sensitivity of 75 to 90 percent in detecting pyuria associated with a UTI.

Gram staining unspun urine can be used to detect bacteriuria. In this semiquantitative test, one organism per oil immersion field correlates with 100,000 CFU per mL by culture. 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. It should be noted that not all uropathogens reduce nitrates to nitrite. For example, enterococci, S. saprophyticus and Acinetobacter species do not and therefore give false-negative results.
 

TABLE 1 Urinary Tract Infections in Adults
Category	Diagnostic criteria	Principal pathogens	First-line therapy	Comments
Acute uncomplicated cystitis	Urinalysis for pyuria, bacteriuria and hematuria (culture not required)	Escherichia coli Staphylococcus saprophyticus Proteus mirabilis Klebsiella pneumoniae	TMP-SMX DS (Bactrim, Septra) Trimethoprim (Proloprim) Ciprofloxacin (Cipro) Ofloxacin (Floxin)	Three-day course is best Quinolones may be used in areas of TMP-SMX resistance or in patients who cannot tolerate TMP-SMX
Recurrent cystitis in young women	Symptoms and a urine culture with a bacterial count of more than 100 CFU per mL of urine	Same as for acute uncomplicated cystitis	If the patient has more than three cystitis episodes per year, treat prophylactically with postcoital, patient- directed* or continuous daily therapy	Repeat therapy for seven to 10 days based on culture results and then use prophylactic therapy
Acute cystitis in young men	Urine culture with a bacterial count of 1,000 to 10,000 CFU per mL of urine	Same as for acute uncomplicated cystitis	Same as for acute uncomplicated cystitis	Treat for seven to 10 days
Acute uncomplicated pyelonephritis	Urine culture with a bacterial count of 10,000 CFU per mL of urine	Same as for acute uncomplicated cystitis	If gram-neg organism, oral fluoroquinolone. If gram-pos organism, amoxicillin. If parenteral administration is required, ceftriaxone (Rocephin) or a fluoroquinolone. If Enterococcus species, add oral or IV amoxicillin	Switch from IV to oral administration when the patient is able to take medication by mouth; complete a 14-day course
Complicated urinary tract infection	Urine culture with a bacterial count of more than 10,000 CFU per mL of urine	E. coli  K. pneumoniae P. mirabilis Enterococcus species Pseudomonas aeruginosa	If gram-negative organism, oral fluoroquinolone. If Enterococcus species, ampicillin or amoxicillin with or without gentamicin (Garamycin).	Treat for 10 to 14 days
Asymptomatic bacteriuria in pregnancy	Urine culture with a bacterial count of more than 10,000 CFU per mL of urine	Same as for acute uncomplicated cystitis	Amoxicillin  Nitrofurantoin (Macrodantin) Cephalexin (Keflex)	Avoid tetracyclines and fluoroquinolones. Treat for three to seven days
Catheter-associated urinary tract infection	Symptoms and a urine culture with a bacterial count of more than 100 CFU per mL of urine	Depends on duration of catheterization	If gram-negative organism, a fluoroquinolone. If gram-positive organism, ampicillin or amoxicillin plus gentamicin.	Remove catheter if possible, and treat for seven to 10 days. For patients with long-term catheters and symptoms, treat for five to seven days
TMP-SMX=trimethoprim-sulfamethoxazole; CFU=colony-forming unit; IV=intravenous.  *--Patient is given a prescription for an antibiotic to take if symptoms develop.  Information from Stamm WE, Hooton TM. Management of urinary tract infections in adults. N Engl J Med 1993;329:1328-34.

If culture of the urine is required it must be done 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 no good.

Methods to establish bacteriuria:

1. Direct microscopic examination:
• Place 1 drop of uncentrifuged urine dry on a microscope slide and Gram stain it.
• If you see >1 bacterium per oil immersion field the specimen has >10⁵ bacteria/ml.
• If you have to look at 3-4 fields to find 1 bacterium, the specimen has <10⁴ bacteria/ml.
• Centrifuged urine: a finding of 2-5 WBCs or >/= 15 bacteria per hpf in the urine sediment is consistent with UTI.

2. Quantitative loop method:

• Use calibrated platinum loops which hold 10^-3 or 10^-2 ml and inoculate plates directly; count colonies and multiply by dilution factor to get the number of microorganisms per ml.

3. Dip cultures:
• Purchase special slides coated with media, dip in urine specimen and incubate; count colonies directly.

4. Chemical tests using dip sticks coated with specific chemicals and/or substrates; simply dip the sticks in urine and look for color changes in a few minutes.

• NO₃ sticks = Nitrite- (establishes bacteriuria)- Best results if used on for first-void urine (first urination in morning) specimens because at least 4 hours are required for coliforms to convert nitrate to nitrite
• Leukocyte esterase sticks (establishes pyuria)

5. Automated technology to detect bacteriuria:

• BacT Screen based upon amount of safranin dye absorbed by bacteria present in a specified volume of urine.
• LUMAC based upon amount of bacterial ATP present in a urine sample.

There are a number of tests to establish the site of infection.

1. Antibody-coated bacteria 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.
2. Presence of white blood cell casts indicates the patient has pyelonephritis.
3. Ureteral catheterization under cystoscopic visualization to culture urine directly obtained from each kidney.

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

Asymptomatic bacteriuria is defined as the presence of more than 100,000 CFU per mL of voided urine in persons with no symptoms of urinary tract infection. The largest patient population at risk for asymptomatic bacteriuria is the elderly. Up to 40 percent of elderly men and women may have bacteriuria without symptoms. Aggressively screening elderly persons for asymptomatic bacteriuria and subsequent treatment of the infection has not been found to reduce either infectious complications or mortality. Consequently, this approach currently is not recommended.

Three groups of patients with asymptomatic bacteriuria have been shown to benefit from treatment:

1. pregnant women,
2. patients with renal transplants and
3. patients who are about to undergo genitourinary tract procedures.

A diagnostic approach to urinary tract infection in adults.

A. The clinical manifestations determine the initial step in therapy.

• 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, are usually hospitalized.

1. Uncomplicated symptomatic acute cystitis and/or urethritis are usually treated for three days with trimethoprim-sulfamethoxazole (TMP-SMX), norfloxacin, or ciprofloxacin.

2. Pyelonephritis is more difficult to cure than urethritis-cystitis and reoccurrence due to relapse (i.e. treatment failure) or reinfection is more common.

• Three day therapy is inappropriate.
• Give IV antibiotics until 24 hrs. after fever breaks, then remaining time give oral antibiotic for a total treatment time of 14 days.
• Oral 14 day therapy can be considered in women with mild to moderate symptoms who 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.

4. Single-dose antibiotic therapy fell into disfavor when it was observed that women had a high risk of recurrence within six weeks of the initial treatment. The risk was attributed to the failure of single-dose antibiotics to eradicate gram-negative bacteria from the rectum, the source or reservoir for ascending uropathogens.

5. Women who have more than three 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.

6. 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 percent 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.

If the patient has a urinary tract infection urge them to:

• Maintain a high fluid intake to be sure you have a good urine output-at least one to two quarts of fluid in 24 hours.
• Drink cranberry juice. It may be helpful. Tannins in the juice appear to prevent binding of the bacteria to the uroepithelial cell surfaces.
• 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 your infection do not subside after two or three days, .

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, or it may be a marker for low socioeconomic status and thus, low birthweight. Drug treatment of asymptomatic bacteriuria in pregnant women substantially decreases the risk of pyelonephritis. Urine samples should be obtained periodically from pregnant women to determine if they have bacteriuria.

1.  Good personal hygiene is important. Blot or wipe gently from front to back after urinating or having a bowel movement. This will avoid spreading bacteria from your rectum to the vagina or urethra.
2. Try not to use colored toilet paper, bubble bath, perfumed soaps, douches, feminine hygiene deodorants, and deodorant tampons and napkins.
3. Wear cotton underwear. Avoid wearing tight clothing, such as bodysuits, tight pants and nylon panty hose without cotton liners.
4. Avoid using strong soaps and bleaches when washing underclothes.
5. Avoid prolonged activities that can aggravate bladder infections, such as bicycling, horseback riding, motorcycling and traveling.
6. Drink six to eight glasses of water or fluids a day.
7. Drinking cranberry juice may be helpful, but check with your doctor first. It should not be used with some medications.
8. Urinate when you feel the urge - do not hold urine for long periods of time.
9. Urinate before and after having intercourse.
10. During menses, if you wear pads, change them at least twice a day.

Vaginal Vaccine Curbs Urinary Tract Infections (Urovac)

Repeated immunization with a vaginal mucosal vaccine increases the time to re-infection in women susceptible to urinary tract infections (UTIs), researchers report in the September issue of the Journal of Urology. In fact, as lead investigator Dr. David T. Uehling told Reuters Health, "women receiving 6 doses of the vaccine remained infection-free significantly longer than patients receiving 3 doses or placebo only."

The researchers conducted a double-blind phase 2 trial of suppositories containing Urovac, a vaginal vaccine containing 10 heat-killed uropathogens. There were significantly fewer uti’s in women given the vaccine than in the control groups.

Dr. Uehling said that the findings "set the stage for a phase 3 clinical trial involving other medical centers and we are currently seeking a pharmaceutical sponsor."

MAJOR COMPLICATIONS OF UTI

1. Bacteremia
2. Chronic pyelonephritis
3. Renal abscess
4. Death