Urinary Tract Infections and Prostatitis

Definition

Infections of the urinary tract represent a wide variety of clinical syndromes including urethritis, cystitis, prostatitis, and pyelonephritis.
A urinary tract infection is defined as the presence of microorganisms in the urine that cannot be accounted for by contamination. The organisms have the potential to invade the tissues of the urinary tract and adjacent structures.
Lower tract infections include cystitis (bladder), urethritis (urethra), prostatitis (prostate gland), and epididymitis. Upper tract infections involve the kidney and are referred to as pyelonephritis.
Uncomplicated urinary tract infections are not associated with structural or neurologic abnormalities that may interfere with the normal flow of urine or the voiding mechanism. Complicated urinary tract infections are the result of a predisposing lesion of the urinary tract such as a congenital abnormality or distortion of the urinary tract, a stone, indwelling catheter, prostatic hypertrophy, obstruction, or neurologic deficit that interferes with the normal flow of urine and urinary tract defenses.
Recurrent urinary tract infections are characterized by multiple symptomatic episodes with asymptomatic periods occurring between these episodes. These infections are either due to reinfection or to relapse.
Reinfections are caused by a new organism and account for the majority of recurrent urinary tract infections.
Relapse represents the development of repeated infections caused by the same initial organism.

Pathophysiology

The bacteria causing urinary tract infections usually originate from bowel flora of the host.
Urinary tract infections can be acquired via three possible routes: the ascending, hematogenous, or lymphatic pathways.
In females, the short length of the urethra and proximity to the perirectal area make colonization of the urethra likely. Bacteria are then believed to enter the bladder from the urethra. Once in the bladder, the organisms multiply quickly and can ascend the ureters to the kidney.
Three factors determine the development of urinary tract infection: the size of the inoculum, virulence of the microorganism, and competency of the natural host defense mechanisms.
Patients who are unable to void urine completely are at greater risk of developing urinary tract infections and frequently have recurrent infections.
An important virulence factor of bacteria is their ability to adhere to urinary epithelial cells by fimbriae. Other virulence factors include hemolysin, a cytotoxic protein produced by bacteria that lyses a wide range of cells including erythrocytes, polymorphonuclear leukocytes, and monocytes; and aerobactin, which facilitates the binding and uptake of iron by Escherichia coli.

Microbiology

The most common cause of uncomplicated urinary tract infections is E. coli, accounting for more than 85% of community-acquired infections, followed by Staphylococcus saprophyticus (coagulase-negative staphylococcus), accounting for 5% to 15%.

TABLE. Clinical Presentation of Urinary Tract Infections in Adults

Signs and Symptoms Lower Urinary tract infection: Dysuria, urgency, frequency, nocturia, suprapublic heaviness Gross heamturia Upper Urinary tract infection: Flank pain, fever, nausea, vomiting malaise Physical Examination Upper Urinary tract infection – costovertebral tenderness Laboratory Tests Bacteriuria Pyuria (white blood cell count >10/mm³ Nitrite-positive urine (with nitrite reducers) Leukocyte esterase-positive urine Antibody-coated bacteria (upper Urinary tract infection)

The urinary pathogens in complicated or nosocomial infections may include E. coli, which accounts for less than 50% of these infections, Proteus spp., Klebsiella pneumoniae, Enterobacter spp., Pseudomonas aeruginosa, staphylococci, and enterococci. Candida spp. have become common causes of urinary infection in the critically ill and chronically catheterized patient.
The majority of urinary tract infections are caused by a single organism; however, in patients with stones, indwelling urinary catheters, or chronic renal abscesses, multiple organisms may be isolated.

Clinical presentation

The typical symptoms of lower ad upper urinary tract infections are presented in Table. Clinical Presentation of Urinary Tract Infections in Adults.
Symptoms alone are unreliable for the diagnosis of bacterial urinary tract infections. The key to the diagnosis of Urinary tract infection is the ability to demonstrate significant numbers of microorganisms present in an appropriate urine specimen to distinguish contamination from infection.
A standard urinalysis should be obtained in the initial assessment of a patient. Microscopic examination of the urine should be performed by preparation of a Gram stain of unspun or centrifuged urine. The presence of at least one organism per oil-immersion field in a properly collected uncentrifuged specimen correlates with more than 100,000 bacteria/mL of urine.
Criteria for defining significant bacteriuria are listed in Table Diagnostic Criteria for Significant Bacteriuria.
The presence of pyuria (more than 10 WBCs/mm³ in a symptomatic patient correlates with significant bacteriuria.
The nitrite test can be used to detect the presence of nitrate-reducing bacteria in the urine (such as E. coli). The leukocyte esterase test is a rapid dipstick test to detect pyuria.

TABLE. Diagnostic Criteria for Significant Bacteriuria

10²CFU coliforms/mL or 10⁵ CFU noncoliforms/mL in a symptomatic female 10³ CFU bacteria/mL in a symptomatic male 10⁵ CFU bacteria/mL in asymptomatic individuals on two consecutive specimens Any growth of bacteria on suprapubic catheterization in a symptomatic patient 10² CFU bacteria/mL in a catheterized patient

The most reliable method of diagnosing urinary tract infections is by quantitative urine culture. Patients with infection usually have more than 10⁵ bacteria/mL of urine, although as many as one-third of women with symptomatic infection have less than 10⁵ bacteria/mL.
A method to detect upper Urinary tract infection is the antibody-coated bacteria test, an immunofluorescent method that detects bacteria coated with immunoglobulin in freshly voided urine.

Desired outcome

The goals of treatment for urinary tract infections are to prevent or to treat systemic consequences of infection, eradicate the invading organism, and prevent recurrence of infection.

Treatment

General principles

The management of a patient with a Urinary tract infection includes initial evaluation, selection of an antibacterial agent and duration of therapy, and follow-up evaluation.
The initial selection of an antimicrobial agent for the treatment of Urinary tract infection is primarily based on the severity of the presenting signs and symptoms, the site of infection, and whether the infection is determined to be complicated or uncomplicated.

Pharmacologic treatment

The ability to eradicate bacteria from the urinary tract is directly related to the sensitivity of the organism and the achievable concentration of the antimicrobial agent in the urine.
Table Commonly Used Antimicrobial Agents in the Treatment of Urinary Tract Infections lists the most common agents used in the treatment of urinary tract infections, along with comments concerning their general use.
Table Overview of Outpatient Antimicrobial Therapy for Lower Tract Infections in Adults presents an overview of various therapeutic options for outpatient therapy for Urinary tract infection.

Acute Uncomplicated Cystitis

These infections are predominantly caused by E. coli, and antimicrobial therapy should be directed against this organism initially. Other causes include S. saprophyticus and occasionally K. pneumoniae and Proteus mirabilis.
Because the causative organisms and their susceptibilities are generally known, a cost-effective approach to management is recommended that includes a urinalysis and initiation of empiric therapy without a urine culture.
Short-course therapy (3-day therapy) with trimethoprim-sulfamethoxazole or a fluoroquinolone (e.g., ciprofloxacin, levofloxacin, norfloxacin, or gatifloxacin) is superior to single-dose therapy for uncomplicated infection and should be the treatment of choice. Amoxicillin or sulfonamides are not recommended because of the high incidence of resistant E. coli. Follow-up urine cultures are not necessary in patients who respond.

Symptomatic Abacteriuria

Single-dose or short-course therapy with trimethoprim-sulfamethoxazole has been used effectively, and prolonged courses of therapy are not necessary for the majority of patients.

TABLE. Commonly Used Antimicrobial Agents in the Treatment of Urinary Tract Infections

Agent	Comments
Oral Therapy
Sulfonamides	These agents generally have been replaced by more agents due to resistance.
Trimethoprim-sulfamethoxazole (TMP-SMX)	This combination is highly effective against most aerobic enteric bacteria except Pseudomonas aeruginosa. High urinary tract tissue levels and urine levels are achieved, which may be important in complicated infection treatment. Also effective as prophylaxis for recurrent infections.
Penicillins Ampicillin Amoxicillin-clavulanic acid Carbenicillin indanyl	Ampicillin is the standard penicillin that has broad-spectrum activity. Increasing E. coli resistance has limited amoxicillin use in acute cystitis. Drug of choice for enterococci sensitive to penicillin. Amoxicillin-clavulanate is preferred for resistance problems. Carbenicillin indanyl is only indicated for the treatment of urinary tract infections.
Cephalosporins Cephalexin Cephradine Cefaclor Cefadroxil Cefuroxime Cefixime Cefzil Cefpodoxime	There are no major advantages of these agents over other agents in the treatment of urinary tract infections, and they are more expensive. They may be useful in cases of resistance to amoxicillin and trimethoprim-sulfamethoxazole. These agents are not active against enterococci.
Tetracyclines Tetracycline Doxycycline Minocycline	These agents have been effective for initial episodes of urinary tract infections; however, resistance develops rapidly, and their use is limited. These agents also lead to candidal overgrowth. The are useful primarily for chlamydial infections.
Fluoroquinolones Ciprofloxacin Norfloxacin Levofloxacin	The newer quinolones have a greater spectrum of activity, including Pseudomonas aeruginosa. These agents are effective for pyelonephritis and prostatitis. Avoid in pregnancy and children. Moxifloxacin should not be used owing to inadequate urinary concentrations.
Nitrofurantoin	This agent is effective as both a therapeutic and prophylactic agent in patients with recurrent urinary tract infections. Main advantage is the lack of resistance even after long courses of therapy. Adverse effects may limit use (Gl intolerance, neuropathies, pulmonary reactions).
Azithromycin	Single-dose therapy for chlamydial infections.
Methanamine hippurate-mandalate	These agents are reserved for prophylactic therapy or suppressive use between episodes of infection.
Fosfomycin	Single-dose therapy for uncomplicated infections.
Parenteral Therapy
Aminoglycosides Centamicin Tobramycin Amikacin Netilmicin	Gentamicin and tobramycin are equally effective; gentamicin is less expensive. Tobramycin has better pseudomonal activity, which may be important in serious systemic infections. Amikacin generally is reserved for multiresistant bacteria.
Penicillins Ampicillin Ampicillin-sulbactam Ticarcillin-clavulanate Piperacillin Piperacillin-tazobactam	These agents generally are equally effective for susceptible bacteria. The extended-spectrum penicillins are more active against P. aeruginosa and enterococci and often are preferred over cephalosporins. They are very useful in renally impaired patients or when an aminoglycoside is to be avoided.
Cephalosporins, first-, second-, and third-generation	Second- and third-generation cephalosporins have a broad spectrum of activity against gram-negative bacteria but are not active against enterococci and have limited activity against P. aeruginosa. Ceftazidime and cefepime are active against P. aeruginosa. They are useful for nosocomial infections and urosepsis due to susceptible pathogens.
Carbapenems Imipenem-cilastatin	These agents have broad spectrum of activity, including gram-positive, gram-negative, and anaerobic bacteria.
Meropenem Ertapenem	Imipenem and meropenem are active against P. aeruginosa and enterococci, but ertapenem is not. All may be associated with candidal superinfections.
Aztreonam	A monobactam that is only active against gram-negative bacteria, including some strains of P. aeruginosa. Generally useful for nosocomial infections when aminoglycosides are to be avoided and in penicillin-sensitive patients.
Quinolones Ciprofloxacin Levofloxacin Gatifloxacin	These agents have broad-spectrum activity against both gram-negative and gram-positive bacteria. They provide urine and high-tissue concentrations and are actively secreted in reduced renal function

If single-dose or short-course therapy is ineffective, a culture should be obtained.
If the patient reports recent sexual activity, therapy for Chlamydia trachomatis should be considered (azithromycin 1 g as a single dose or doxycycline 100mg twice daily).

Asymptomatic Bacteriuria

The management of asymptomatic bacteriuria depends on the age of the patient and, if female, whether she is pregnant. In children, treatment should consist of conventional courses of therapy, as described for symptomatic infections.
In the nonpregnant female, therapy is controversial; however, it appears that treatment has little effect on the natural course of infections.
Most clinicians feel that asymptomatic bacteriuria in the elderly is a benign disease and may not warrant treatment. The presence of bacteriuria can be confirmed by culture if treatment is considered.

Complicated Urinary Tract Infections

Acute Pyelonephritis

The presentation of high-grade fever (greater than 38.3В°C) and severe flank pain should be treated as acute pyelonephritis, and aggressive management is warranted. Severely ill patients with pyelonephritis should be hospitalized and intravenous drugs administered initially.
At the time of presentation, a Gram stain of the urine should be performed, along with urinalysis, culture, and sensitivities.
In the mild to moderately symptomatic patient for whom oral therapy is considered, an effective agent should be administered for at least a 2-week period, although use of highly active agents for 7 to 10 days may be sufficient. Oral antibiotics that have shown efficacy in this setting include trimethoprim-sulfamethoxazole or fluoroquinolones. If a Gram stain reveals gram-positive cocci, S. faecalis should be considered and treatment directed against this pathogen (ampicillin).

TABLE. Overview of Outpatient Antimicrobial Therapy for Lower Tract Infections in Adults

Indications	Antibiotic	Dose^a	Interval	Duration
Lower tract Infections		2 DS tablets	Single dose	1 day
Uncomplicated	Trimethoprim-sulfamethoxazole	1 DS tablet	Twice a day	3 days
	Ciprofloxacin	250 mg	Twice a day	3 days
	Norfloxacin	400 mg	Twice a day	3 days
	Gatifloxacin	200-400 mg	Once a day	3 days
	Levofloxacin	250 mg	Once a day	3 days
	Lomefloxacin	400 mg	Once a day	3 days
	Enoxacin	200 mg	Once a day	3 days
	Amoxicillin	6 x 500 mg	Single dose	1 day
	Amoxicillin	500 mg	Twice a day	3 days
	Amoxicillin-clavulanate	500 mg	Every 8 h	3 days
	Trimethoprim	100 mg	Twice a day	3 days
	Nitrofurantoin	100 mg	Every 6 h	3 days
	Fosfomycin	3 g	Single dose	1 day
Complicated	Trimethoprim-sulfamethoxazole	1 DS tablet	Twice a day	7-10 days
	Trimethoprim	100 mg	Twice a day	7-10 days
	Norfloxacin	400 mg	Twice a day	7-10 days
	Ciprofloxacin	250-500 mg	Twice a day	7-10 days
	Gatifloxacin	400 mg	Once a day	7-10 days
	Moxifloxacin (PO only)	400 mg	Once a day	7-10 days
	Lomefloxacin	400 mg	Once a day	7-10 days
	Levofloxacin	250 mg	Once a day	7-10 days
	Amoxicillin-clavulanate	500 mg	Every 8 h	7-10 days
Recurrent Infections	Nitrofurantion	50 mg	Once a day	6 months
	Trimethoprim	100 mg	Once a day	6 months
	Trimethoprim-sulfamethoxazole	1/2 ss tablet	Once a day	6 months
Acute urethral syndrome	Trimethoprim-sulfamethoxazole	1 DS	Twice a day	3 days
Failure of TMP-SMX	Azithromycin	1 g	Single dose
Failure of TMP-SMX	Doxycycline	100 mg	Twice a day	7 days
Acute pyelonephritis	Trimethoprim-sulfamethoxazole	1 DS tablet	Twice a day	14 days
	Ciprofloxacin	500 mg	Twice a day	14 days
	Gatifloxacin	400 mg	Once a day	14 days
	Norfloxacin	400 mg	Twice a day	14 days
	Levofloxacin	250 mg	Once a day	14 days
	Lomefloxacin	400 mg	Once a day	14 days
	Enoxacin	400 mg	Twice a day	14 days
	Amoxicillin-clavulanate	500 mg	Every 8 h	14 days
^aDosing intervals for normal renal function.

In the seriously ill patient, the traditional initial therapy has included an intravenous fluoroquinolone, an aminoglycoside with or without ampicillin, or an extended-spectrum cephalosporin with or without an aminoglycoside.
If the patient has been hospitalized in the last 6 months, has a urinary catheter, or is in a nursing home, the possibility of P. aeruginosa and enterococci infection, as well as multiply resistant organisms, should be considered. In this setting, ceftazidime, ticarcillin-clavulanic acid, piperacillin, aztreonam, meropenem, or imipenem, in combination with an aminoglycoside, is recommended. If the patient responds to initial combination therapy, the aminoglycoside may be discontinued after 3 days.
Follow-up urine cultures should be obtained 2 weeks after the completion of therapy to ensure a satisfactory response and to detect possible relapse.

TABLE. Empirical Treatment of Urinary Tract Infections and Prostatitis

Diagnosis	Pathogens	Treatment	Comments
Acute uncomplicated	E. coli	1. Trimethoprim-sulfamethoxazole x 3 days	Short-course therapy more effective than
cystitis	S. saprophyticus	2. Quinolone x 3 days
Pregnancy	As above	1. Amoxicillin-clavulanate x 7 days 2. Cephalosporin x 7 days 3. Trimethoprim-sulfamethoxazole x 7 days	Avoid trimethoprim-sulfamethoxazole durig third trimester
Acute pyelonephritis
Uncomplicated	E. coli	1. Trimethoprim-sulfamethoxazole x 14 days 2. Quinolone x 14 days	Can be managed as outpatient
Complicated	E. coli, P. mirabilis Pseudomonas aeruginosa, E. fecalis	1. Quinolone x 14 days 2. Extended-spectrum penicillin Plus aminoglycoside	Severity of illness will determine duration of intravenous therapy; culture results should direct therapy Oral therapy may complete 14 days of therapy
Postatitis	E. coli, K. pneumoniae Pseudomonas aeruginosa	1. Trimethoprim-sulfamethoxazole x 4-6 weeks 2. Quinolone x 4-6 weeks	Acute prostatitis may require intravenous therapy initially Chronic prostatitis may require longer treatment periods or surgery

Urinary Tract Infections in Males

The conventional view is that therapy in males requires prolonged treatment.
A urine culture should be obtained before treatment, because the cause of infection in men is not as predictable as in women.
If gram-negative bacteria are presumed, trimethoprim-sulfamethoxazole or a fluoroquinolone is a preferred agent. Initial therapy is for 10 to 14 days. For recurrent infections in males, cure rates are much higher with a 6-week regimen of trimethoprim-sulfamethoxazole.

Recurrent Infections

Recurrent episodes of urinary tract infection (reinfections and relapses) account for a significant portion of all urinary tract infections.
These patients are most commonly women and can be divided into two groups: those with fewer than two or three episodes per year and those who develop more frequent infections.
In patients with infrequent infections (i.e., fewer than three infections per year), each episode should be treated as a separately occurring infection. Short-course therapy should be used in symptomatic female patients with lower tract infection.
In patients who have frequent symptomatic infections, long-term prophylactic antimicrobial therapy may be instituted. Therapy is generally given for 6 months, with urine cultures followed periodically.
Special conditions
In women who experience symptomatic reinfections in association with sexual activity, voiding after intercourse may help prevent infection. Also, self-administered, single-dose prophylactic therapy with trimethoprim-sulfamethoxazole taken after intercourse has been found to significantly reduce the incidence of recurrent infection in these patients.
Women who relapse after short-course therapy should receive a 2-week course of therapy. In patients who relapse after 2 weeks, therapy should be continued for another 2 to 4 weeks. If relapse occurs after 6 weeks of treatment, therapy for 6 months or even longer may be considered.

Urinary Tract Infection in Pregnancy

In patients with significant bacteriuria, symptomatic or asymptomatic, treatment is recommended in order to avoid possible complications during the pregnancy. Therapy should consist of an agent with a relatively low adverse-effect potential (a sulfonamide, cephalexin, amoxicillin, amoxicillin/clavulanate, nitrofurantoin) administered for 7 days.
Tetracyclines should be avoided because of teratogenic effects, and sulfonamides should not be administered during the third trimester because of the possible development of kernicterus and hyperbilirubinemia. Also, the quinolones should not be given because of their potential to inhibit cartilage and bone development in the newborn.

Catheterized Patients

When bacteriuria occurs in the asymptomatic, short-term catheterized patient (less than 30 days), the use of systemic antibiotic therapy should be withheld and the catheter removed as soon as possible. If the patient becomes symptomatic, the catheter should again be removed and treatment as described for complicated infections should be started.
The use of prophylactic systemic antibiotics in patients with short-term catheterization reduces the incidence of infection over the first 4 to 7 days. In long-term catheterized patients, however, antibiotics only postpone the development of bacteriuria and lead to emergence of resistant organisms.

Prostatitis

Prostatitis is an inflammation of the prostate gland and surrounding tissue as a result of infection. It can be either acute or chronic. The acute form is characterized by a severe illness characterized by a sudden onset of fever and urinary and constitutional symptoms. Chronic bacterial prostatitis represents a recurring infection with the same organism (relapse). Pathogenic bacteria and significant inflammatory cells must be present in prostatic secretions and urine to make the diagnosis of bacterial prostatitis.

Pathogenesis and etiology

The exact mechanism of bacterial infection of the prostate is not well understood. The possible routes of infection include ascending infection of the urethra, reflux of infected urine into prostatic ducts, invasion by rectal bacteria through direct extension or lymphatic spread, and by hematogenous spread.
Gram-negative enteric organisms are the most frequent pathogens in acute bacterial prostatitis. E. coli is the predominant organism, occurring in 75% of cases.
Chronic bacterial prostatitis is most commonly caused by E. coli, with other gram-negative organisms isolated much less often.

Clinical presentation and diagnosis

The clinical presentation of bacterial prostatitis is presented in Table Clinical Presentation of Bacterial Prostatitis.
Digital palpation of the prostate via the rectum may reveal a swollen, tender, warm, tense, or indurated prostate. Massage of the prostate will express a purulent discharge, which will readily grow the pathogenic organism. However, prostatic massage is contraindicated in acute bacterial prostatitis because of a risk of inducing bacteremia and associated pain.
Chronic bacterial prostatitis is characterized by recurrent urinary tract infections with the same pathogen.
Urinary tract localization studies are critical to the diagnosis of Chronic bacterial prostatitis.
Both acute bacterial prostatitis and Chronic bacterial prostatitis are characterized by the presence of numerous white blood cells and lipid-containing macrophages (oval fat bodies) on microscopic examination of expressed prostatic secretions.

TABLE. Clinical Presentation of Bacterial Prostatitis

Signs and Symptoms Acute bacterial prostatitis: High fever, chills, malaise, myalgia, localized pain (perineal, rectal, sacrococcygeal), frequency, urgency, dysuria, nocturia, and retention Chronic bacterial prostatitis: Voiding difficulties (frequency, urgency, dysuria), low back pain, and perineal and suprapubic discomfort Physical Examination Acute bacterial prostatitis: Swollen, tender, tense, or indurated gland Chronic bacterial prostatitis: Boggy, indurated (enlarged) prostate in most patients Laboratory Tests Bacteriuria Bacteria in expressed prostatic secretions

Treatment

The majority of patients can be managed with oral antimicrobial agents, such as trimethoprim-sulfamethoxazole or the fluoroquinolones (ciprofloxacin, levofloxacin, gatifloxacin). When intravenous treatment is necessary, intravenous to oral sequential therapy with trimethoprim-sulfamethoxazole or a fluoroquinolone, such as ciprofloxacin or ofloxacin, would be appropriate.
The total course of therapy should be 4 weeks, which may be prolonged to 6 to 12 weeks with chronic prostatitis.
Parenteral therapy should be maintained until the patient is afebrile and less symptomatic. The conversion to an oral antibiotic can be considered if the patient has been afebrile for 48 hours or after 3 to 5 days of intravenous therapy.
The choice of antibiotics in Chronic bacterial prostatitis should include those agents that are capable of crossing the prostatic epithelium into the prostatic fluid in therapeutic concentrations and which also possess the spectrum of activity to be effective.
Currently, the fluoroquinolones (given for 4 to 6 weeks) appear to provide the best therapeutic option in the management of Chronic bacterial prostatitis.