Urinary Tract Infections and Prostatitis

Elizabeth A. Coyle and Randall A. Prince

Infections of the urinary tract represent a wide variety of syndromes, including urethritis, cystitis, prostatitis, and pyelonephritis. Urinary tract infections (UTIs) are the most commonly occurring bacterial infections and one of the most common reasons for antibiotic exposure, especially in females of childbearing age.^1–3 Approximately 60% of females will develop a UTI during their lifetime with about one fourth having a recurrence within a year.² Infections in men occur much less frequently until the age of 65 years at which point the incidence rates in men and women are similar.

A UTI is defined as the presence of microorganisms in the urinary tract that cannot be accounted for by contamination. The organisms present have the potential to invade the tissues of the urinary tract and adjacent structures. Infection may be limited to the growth of bacteria in the urine, which frequently may not produce symptoms. A UTI can present as several syndromes associated with an inflammatory response to microbial invasion and can range from asymptomatic bacteriuria to pyelonephritis with bacteremia or sepsis.

UTIs are classified by lower and upper UTIs. Typically, they have been described by anatomic site of involvement. Lower tract infections correspond to cystitis (bladder), and pyelonephritis (an infection involving the kidneys) represents upper tract infection.

Also, UTIs are designated as uncomplicated or complicated. Uncomplicated infections occur in individuals who lack structural or functional abnormalities of the urinary tract that interfere with the normal flow of urine or voiding mechanism. These infections occur in premenopausal females of childbearing age (15 to 45 years) who are otherwise normal, healthy individuals. Infections in males generally are not classified as uncomplicated because these infections are rare and most often represent a structural or neurologic abnormality.

Complicated UTIs are usually 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. Complicated infections occur in both genders and frequently involve the upper and lower urinary tract.

Recurrent UTIs in healthy nonpregnant women—two or more UTIs occurring within 6 months or three or more UTIs within 1 year—are a common problem. They are characterized by multiple symptomatic infections with asymptomatic periods occurring between each episode and may be either reinfections or relapses. Reinfections are caused by a different organism than originally isolated and account for the majority of recurrent UTIs. Relapses are the development of repeated infections with the same initial organism and usually indicate a persistent infectious source.²

Asymptomatic bacteriuria is a common finding, particularly among those 65 years of age and older when there is significant bacteriuria (>10⁵ bacteria/mL [>10⁸/L] of urine) in the absence of symptoms. Symptomatic abacteriuria or acute urethral syndrome consists of symptoms of frequency and dysuria in the absence of significant bacteriuria. This syndrome is commonly associated with Chlamydia infections.

Significant abacteriuria is a term used to distinguish the presence of microorganisms that represent true infection versus contamination of the urine as it passes through the distal urethra prior to collection. Historically, bacterial counts equal to or greater than 100,000 organisms/mL (10⁸/L) of urine in a “clean-catch” specimen were judged to indicate true infection.^4–6 Counts less than 100,000 organisms/mL (10⁸/L) of urine, however, may represent true infection in certain situations. For example, with concurrent antibacterial drug administration, rapid urine flow, low urinary pH, or upper tract obstruction.⁶ Table 94–1 lists the clinical definitions of significant bacteriuria, which are dependent on the clinical setting and the method of specimen collection.⁶ These criteria allow for more appropriate specificity and sensitivity in documenting infection under differing clinical circumstances.

EPIDEMIOLOGY

The prevalence of UTIs varies with age and gender. In newborns and infants up to 6 months of age, the prevalence of abacteriuria is approximately 1% and is more common in boys. Most of these infections are associated with structural or functional abnormalities of the urinary tract and also have been correlated with noncircumcision.⁷ Between the ages of 1 and 6 years, UTIs occur more frequently in females. The prevalence of abacteriuria in females and males of this age group is 3% to 7% and 1% to 2%, respectively.^7,8 Infections occurring in preschool boys usually are associated with congenital abnormalities of the urinary tract. These infections are difficult to recognize because of the age of the patient, but they often are symptomatic. In addition, the majority of renal damage associated with UTI develops at this age.^7,8

Through grade school and before puberty, the prevalence of UTI is approximately 1%, with 5% of females reported to have significant bacteriuria prior to leaving high school. This percentage increases dramatically to 1% to 4% after puberty in nonpregnant females primarily as a result of sexual activity. Approximately 1 in 5 women will suffer a symptomatic UTI at some point in their lives. Many women have recurrent infections with a significant proportion of these women having a history of childhood infections. In contrast, the prevalence of bacteriuria in adult men is very low (<0.1%).⁹

In the elderly, the ratio of bacteriuria in women and men is dramatically altered and is approximately equal in persons older than age 65 years.¹⁰ The overall incidence of UTI increases substantially in this population with the majority of infections being asymptomatic. The rate of infection increases further for elderly persons who are residing in nursing homes, particularly those who are hospitalized frequently. The increase is probably the result of factors such as obstruction from prostatic hypertrophy in males, poor bladder emptying as a result of prolapse in females, fecal incontinence in demented patients, and neuromuscular disease including strokes and increased urinary instrumentation (catheterization).

ETIOLOGY

The bacteria causing UTIs usually originate from bowel flora of the host. Although virtually every organism is associated with UTIs, certain organisms predominate as a result of specific virulence factors. The most common cause of uncomplicated UTIs is Escherichia coli, which accounts for 80% to 90% of community-acquired infections. Additional causative organisms in uncomplicated infections include Staphylococcus saprophyticus, Klebsiella pneumoniae, Proteus spp., Pseudomonas aeruginosa, and Enterococcus spp.¹¹ Because Staphylococcus epidermidis is frequently isolated from the urinary tract, it should be considered initially a contaminant. Repeat cultures should be performed to help confirm the organism as a real pathogen.

Organisms isolated from individuals with complicated infections are more varied and generally are more resistant than those found in uncomplicated infections. E. coli is a frequently isolated pathogen, but it accounts for less than 50% of infections. Other frequently isolated organisms include Proteus spp., K. pneumoniae, Enterobacter spp., P. aeruginosa, staphylococci, and enterococci. Enterococci represent the second most frequently isolated organisms in hospitalized patients.^11–13 In part, this finding may be related to the extensive use of third-generation cephalosporin antibiotics, which are not active against the enterococci. Vancomycin-resistant Enterococcus faecalis and Enterococcus faecium (vancomycin-resistant enterococci) have become more widespread, especially in patients with long-term hospitalizations or underlying malignancies. Vancomycin-resistant enterococci are major therapeutic and infection control issues because these organisms are susceptible to few antimicrobials.^12,13

Staphylococcus aureus infections may arise from the urinary tract, but they are more commonly a result of bacteremia producing metastatic abscesses in the kidney. Candida spp. are common causes of UTI in the critically ill and chronically catheterized patient.

Most UTIs are caused by a single organism; however, in patients with stones, indwelling urinary catheters, or chronic renal abscesses, multiple organisms may be isolated. Depending on the clinical situation, the recovery of multiple organisms may represent contamination and a repeat evaluation should be done.

PATHOPHYSIOLOGY

Route of Infection

Organisms typically gain entry into the urinary tract via three routes: the ascending, hematogenous (descending), and lymphatic pathways. The female urethra usually is colonized by bacteria believed to originate from the fecal flora. The short length of the female urethra and its proximity to the perirectal area make colonization of the urethra likely. Other factors that promote urethral colonization include the use of spermicides and diaphragms as methods of contraception.^2,3 Although there is evidence in females that bladder infections follow colonization of the urethra, the mode of ascent of the microorganisms is incompletely understood. Massage of the female urethra and sexual intercourse allow bacteria to reach the bladder.¹⁴ Once bacteria have reached the bladder, the organisms quickly multiply and can ascend the ureters to the kidneys. This sequence of events is more likely to occur if vesicoureteral reflux (reflux of urine into the ureters and kidneys while voiding) is present. UTIs are more common in females than in males because the anatomic differences in location and length of the urethra tend to support the ascending route of infections as the primary acquisition route.

Infection of the kidney by hematogenous spread of microorganisms usually occurs as the result of dissemination of organisms from a distant primary infection in the body. Infections via the descending route are uncommon and involve a relatively small number of invasive pathogens. Bacteremia caused by S. aureus may produce renal abscesses. Additional organisms include Candida spp., Mycobacterium tuberculosis, Salmonella spp., and enterococci. Of particular interest, it is difficult to produce experimental pyelonephritis by IV administering common gram-negative organisms such as E. coli and P. aeruginosa. Overall, less than 5% of documented UTIs result from hematogenous spread of microorganisms.

There appears to be little evidence supporting a significant role for renal lymphatics in the pathogenesis of UTIs. There are lymphatic communications between the bowel and kidney, as well as between the bladder and kidney. There is no evidence, however, that microorganisms are transferred to the kidney via this route.

After bacteria reach the urinary tract, three factors determine the development of infection: the size of the inoculum, the virulence of the microorganism, and the competency of the natural host defense mechanisms. Most UTIs reflect a failure in host defense mechanisms.

Host Defense Mechanisms

The normal urinary tract generally is resistant to invasion by bacteria and is efficient in rapidly eliminating microorganisms that reach the bladder. The urine under normal circumstances is capable of inhibiting and killing microorganisms. The factors thought to be responsible include a low pH, extremes in osmolality, high urea concentration, and high organic acid concentration. Bacterial growth is further inhibited in males by the addition of prostatic secretions.^14,15

The introduction of bacteria into the bladder stimulates micturition with increased diuresis and efficient emptying of the bladder. These factors are critical in preventing the initiation and maintenance of bladder infections. Patients who are unable to void urine completely are at greater risk of developing UTIs and frequently have recurrent infections. Also, patients with even small residual amounts of urine in their bladder respond less favorably to treatment than patients who are able to empty their bladders completely.¹⁶

An important virulence factor of bacteria is their ability to adhere to urinary epithelial cells resulting in colonization of the urinary tract, bladder infections, and pyelonephritis. Various factors that act as antiadherence mechanisms are present in the bladder preventing bacterial colonization and infection. The epithelial cells of the bladder are coated with a urinary mucus or slime called glycosaminoglycan. This thin layer of surface mucopolysaccharide is hydrophilic and strongly negatively charged. When bound to the uroepithelium, it attracts water molecules and forms a layer between the bladder and urine. The antiadherence characteristics of the glycosaminoglycan layer are nonspecific and when the layer is removed by dilute acid solutions, rapid bacterial adherence results.¹⁷

In addition, the Tamm–Horsfall protein is a glycoprotein produced by the ascending limb of Henle and distal tubule that is secreted into the urine and contains mannose residues. These mannose residues bind E. coli that contain small surface-projecting organellae on their surfaces called pili or fimbriae. Type 1 fimbriae are mannose-sensitive and this interaction prevents the bacteria from binding to similar receptors present on the mucosal surface of the bladder. Other factors that possibly prevent adherence of bacteria include immunoglobulins (Ig) G and A. Investigators have documented both systemic and local kidney immunoglobulin synthesis in upper tract infections. The role of immunoglobulins in preventing bladder infection is less clear. Patients with reduced urinary levels of secretory IgA are, however, at increased risk of infections of the urinary tract.

After bacteria have invaded the bladder mucosa, an inflammatory response is stimulated with the mobilization of polymorphonuclear leukocytes (PMNs) and resulting phagocytosis. PMNs are primarily responsible for limiting the tissue invasion and controlling the spread of infection in the bladder and kidney. They do not play a role in preventing bladder colonization or infections and actually contribute to renal tissue damage.

Other host factors that may play a role in the prevention of UTIs are the presence of Lactobacillus in the vaginal flora and circulating estrogen levels. In premenopausal women, circulating estrogen supports the vaginal tract growth of lactobacilli, which produce lactic acid to help maintain a low vaginal pH, thereby preventing E. coli vaginal colonization.¹⁸ Topical estrogens are used for the prevention of UTI in postmenopausal women who have more than 3 recurrent UTI episodes per year and are not on oral estrogens.¹⁹

Bacterial Virulence Factors

Pathogenic organisms have differing degrees of pathogenicity (virulence), which play a role in the development and severity of infection. Bacteria that adhere to the epithelium of the urinary tract are associated with colonization and infection. The mechanism of adhesion of gram-negative bacteria, particularly E. coli, is related to bacterial fimbriae that are rigid, hair-like appendages of the cell wall.⁹ These fimbriae adhere to specific glycolipid components on epithelial cells. The most common type of fimbriae is type 1, which binds to mannose residues present in glycoproteins. Glycosaminoglycan and Tamm–Horsfall protein are rich in mannose residues that readily trap those organisms that contain type 1 fimbriae, which are then washed out of the bladder.²⁰ Other fimbriae are mannose resistant and are associated more frequently with pyelonephritis, such as P fimbriae, which bind avidly to specific glycolipid receptors on uroepithelial cells. These bacteria are resistant to washout or removal by glycosaminoglycan and are able to multiply and invade tissue, especially the kidney. In addition, PMNs, as well as secretory IgA antibodies, contain receptors for type 1 fimbriae, which facilitate phagocytosis, but are lacking receptors for P fimbriae.

Other virulence factors include the production of hemolysin and aerobactin.²¹ Hemolysin is a cytotoxic protein produced by bacteria that lyses a wide range of cells, including erythrocytes, PMNs, and monocytes. E. coli and other gram-negative bacteria require iron for aerobic metabolism and multiplication. Aerobactin facilitates the binding and uptake of iron by E. coli; however, the significance of this property in the pathogenesis of UTIs remains unknown.

PREDISPOSING FACTORS TO INFECTION

The normal urinary tract typically is resistant to infection and colonization by pathogenic bacteria. In patients with underlying structural abnormalities of the urinary tract, the typical host defenses previously discussed usually are lacking or compromised. There are several known abnormalities of the urinary tract system that interfere with its natural defense mechanisms, the most important of which is obstruction. Obstruction can inhibit the normal flow of urine disrupting the natural flushing and voiding effect in removing bacteria from the bladder and resulting in incomplete emptying. Common conditions that result in residual urine volumes include prostatic hypertrophy, urethral strictures, calculi, tumors, bladder diverticula, and drugs such as anticholinergic agents. Additional causes of incomplete bladder emptying include neurologic malfunctions associated with stroke, diabetes, spinal cord injuries, tabes dorsalis, and other neuropathies. Vesicoureteral reflux represents a condition in which urine is forced up the ureters to the kidneys. Urinary reflux is associated not only with an increased incidence of UTIs and pyelonephritis, but also with renal damage.^8,16 Reflux may be the result of a congenital abnormality or, more commonly, bladder overdistension from obstruction.

Other risk factors include urinary catheterization, mechanical instrumentation, pregnancy, and the use of spermicides and diaphragms.

CLINICAL PRESENTATION

The presenting signs and symptoms of UTIs in adults are recognized easily (Table 94–2). Women frequently will report gross hematuria. Systemic symptoms, including fever, typically are absent in this setting. Unfortunately, large numbers of patients with significant bacteriuria are asymptomatic. These patients may be normal, healthy patients, elderly patients, children, pregnant patients, and patients with indwelling catheters. It is important to note that attempts at differentiating upper tract from lower tract infections on the basis of symptoms alone are not reliable.

Elderly patients frequently do not experience specific urinary symptoms, but they will present with altered mental status, change in eating habits, or GI symptoms. In addition, patients with indwelling catheters or neurologic disorders commonly will not have lower tract symptoms. Instead, they may present with flank pain and fever. Many of the aforementioned patients, however, frequently will develop upper tract infections with bacteremia and no or minimal urinary tract symptoms.

Symptoms alone are unreliable for the diagnosis of bacterial UTIs. The key to the diagnosis of UTI is the ability to demonstrate significant numbers of microorganisms in an appropriate urine specimen to distinguish contamination from infection. The type and extent of laboratory examination required depends on the clinical situation.

Urine Collection

Examination of the urine is the cornerstone of laboratory evaluation for UTIs. There are three acceptable methods of urine collection. The first is the midstream clean-catch method. After cleaning the urethral opening area in both men and women, 20 to 30 mL of urine is voided and discarded. The next part of the urine flow is collected and should be processed immediately (refrigerated as soon as possible). Specimens that are allowed to sit at room temperature for several hours may result in falsely elevated bacterial counts. The midstream clean-catch is the preferred method for the routine collection of urine for culture. When a routine urine specimen cannot be collected or contamination occurs, alternative collection techniques must be used.

The two acceptable alternative methods include catheterization and suprapubic bladder aspiration. Catheterization may be necessary for patients who are uncooperative or who are unable to void urine. If catheterization is performed carefully with aseptic technique, the method yields reliable results. Note, however, that introduction of bacteria into the bladder may result and the procedure is associated with infection in 1% to 2% of patients. Suprapubic bladder aspiration involves inserting a needle directly into the bladder and aspirating the urine. This procedure bypasses the contaminating organisms present in the urethra and any bacteria found using this technique generally are considered to represent significant bacteriuria.^22–25 Suprapubic aspiration is a safe and painless procedure that is most useful in newborns, infants, paraplegics, seriously ill patients, and others in whom infection is suspected and routine procedures have provided confusing or equivocal results.

Bacterial Count

The diagnosis of UTI is based on the isolation of significant numbers of bacteria from a urine specimen. Microscopic examination of a urine sample is an easy-to-perform and reliable method for the presumptive diagnosis of bacteriuria. The examination may be performed by preparing 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 well with more than 100,000 colony-forming units (CFU)/mL (10⁵ CFU/mL or 10⁸ CFU/L) of urine. For detecting smaller numbers of organisms, a centrifuged specimen is more sensitive. Such examinations detect more than 10⁵ bacteria/mL (10⁸ CFU/L) with a sensitivity of greater than 90% and a specificity of greater than 70%.^22,23 A quantitative count of greater than or equal to 10⁵ CFU/mL (10⁸ CFU/L) is considered indicative of a UTI; however, up to 50% of women will present with clinical symptoms of a UTI with lower counts (10³ CFU/mL [10⁶ CFU/L]).⁴

Pyuria, Hematuria, and Proteinuria

Microscopic examination of the urine for leukocytes is used to determine the presence of pyuria. The presence of pyuria in a symptomatic patient correlates with significant bacteriuria.²⁴ Pyuria is defined as a white blood cell (WBC) count of greater than 10 WBC/mm³ (10 × 10⁶/L) of urine. A count of 5 to 10 WBC/mm³ (5 × 10⁶ to 10 × 10⁶/L) is accepted as the upper limit of normal. It should be emphasized that pyuria is nonspecific and signifies only the presence of inflammation and not necessarily infection. Thus patients with pyuria may or may not have infection. Sterile pyuria has long been associated with urinary tuberculosis, as well as chlamydial and fungal urinary infections.

Hematuria, microscopic or gross, is frequently present in patients with UTI, but is nonspecific. Hematuria may indicate the presence of other disorders, such as renal calculi, tumors, or glomerulonephritis. Proteinuria is found commonly in the presence of infection.

Chemistry

Several biochemical tests have been developed for screening urine for the presence of bacteria. A common dipstick test detects the presence of nitrite in the urine, which is formed by bacteria that reduce nitrate normally present in the urine. False-positive tests are uncommon. False-negative tests are more common and frequently are caused by the presence of gram-positive organisms or P. aeruginosa that do not reduce nitrate.²⁵ Other causes of false tests include low urinary pH, frequent voiding, and dilute urine.

The leukocyte esterase dipstick test is a rapid screening test for detecting the presence of pyuria. Leukocytes esterase is found in primary neutrophil granules and indicates the presence of WBCs. The leukocyte esterase test is a sensitive and highly specific test for detecting more than 10 WBC/mm³ (10 × 10⁶/L) of urine. When the leukocyte esterase test is used with the nitrite test, the reported positive predictive value and specificity is 79% and 82%, respectively, for the detection of bacteriuria.^26,27 These tests can be useful in the outpatient evaluation of uncomplicated UTIs. However, urine culture is still the “gold standard” test in determining the presence of UTIs.

Culture

The most reliable method of diagnosing UTI is by quantitative urine culture. Urine in the bladder is normally sterile making it statistically possible to differentiate contamination of the urine from infection by quantifying the number of bacteria present in a urine sample. This criterion is based on a properly collected midstream clean-catch urine specimen. Patients with infection usually have greater than 10⁵ bacteria/mL (10⁸/L) of urine. It should be emphasized that as many as one third of women with symptomatic infection have less than 10⁵ bacteria/mL (10⁸/L). Also, a significant portion of patients with UTIs, either symptomatic or asymptomatic, have less than 10⁵ bacteria/mL (10⁸/L) of urine.

Several laboratory methods are used to quantify bacteria present in the urine. The most accurate method is the pour-plate technique. This method is unsuitable for a high-volume laboratory because it is expensive and time-consuming. The streak-plate method is an alternative that involves using a calibrated-loop technique to streak a fixed amount of urine on an agar plate. This method is used most commonly in diagnostic laboratories because it is simple to perform and less costly.

After identification and quantification are complete, the next step is to determine the susceptibility of the organism. There are several methods by which bacterial susceptibility testing may be performed. Knowledge of bacterial susceptibility and achievable urine concentration of the antibiotics puts the clinician in a better position to select an appropriate agent for treatment.

Infection Site

Several methods have been evaluated to determine the location of infection within the urinary system and differentiate upper tract from lower tract involvement. The most direct method is a ureteral catheterization procedure as described by Stamey and colleagues.²⁸ The method involves the passage of a catheter into the bladder and then into each ureter, where quantitative cultures are obtained. History and physical examination were of little value in predicting the site of infection. Although this method provides direct quantitative evidence for UTI, it is invasive, technically difficult, and expensive. The Fairley bladder washout technique is a modification of the Stamey procedure that involves Foley catheterization only.²⁹ After the catheter is passed into the bladder, bladder samples are obtained and the bladder is washed out with culture samples taken at 10, 20, and 30 minutes. The procedure shows that up to 50% of patients have renal involvement, regardless of signs and symptoms. Other investigators found 10% to 20% of tests to be equivocal.²⁹

Noninvasive methods of localization may be more acceptable for routine use; however, they have limited clinical value. Patients with pyelonephritis can have abnormalities in urinary concentrating ability. The use of concentrating ability for localization of UTIs, however, is associated with high false-positive and false-negative responses and is not useful clinically.²⁵ The antibody-coated bacteria test is an immunofluorescent method that detects bacteria coated with Ig in freshly voided urine indicating upper UTI. The sensitivity and specificity of this test to localize the site of infection are reported to average 88% and 76%, respectively.³⁰ Because of the high incidence of false-positive and false-negative results, antibody-coated bacteria testing is not used routinely in the management of UTIs.

Virtually all patients with uncomplicated lower tract infections can be cured with a short course of antibiotic therapy and this assumption sometimes can be used to distinguish between patients with lower and upper tract infections. Patients who do not respond or who relapse may do so because of upper tract involvement. It is rarely necessary to localize the site of infection to direct the clinical management of such patients.

TREATMENT

Desired Outcomes

The goals of UTI treatments are (a) to eradicate the invading organism(s), (b) to prevent or to treat systemic consequences of infection, (c) to prevent the recurrence of infection, and (d) to decrease the potential for collateral damage with too broad of antimicrobial therapy.

Management

The management of a patient with a UTI 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 UTI is based primarily on the severity of the presenting signs and symptoms, the site of infection and whether the infection is determined to be uncomplicated or complicated. Other considerations include antibiotic susceptibility, side-effect potential, cost, current antimicrobial exposure, and the comparative inconvenience of different therapies.¹

Various pharmacologic factors may affect the action of antibacterial agents. Certainly, the ability of the agent to achieve appropriate concentrations in the urine is of utmost importance. Factors that affect the rate and extent of excretion through the kidney include the patient’s glomerular filtration rate and whether or not the agent is actively secreted. Filtration depends on the molecular size and degree of protein binding of the agent. Agents such as sulfonamides, tetracyclines, and aminoglycosides enter the urine via filtration. As the glomerular filtration rate is reduced, the amount of drug that enters the urine is reduced. Most β-lactam agents and quinolones are filtered and are actively secreted into the urine. For this reason, most of these agents achieve high urinary concentrations despite unfavorable protein-binding characteristics or the presence of renal dysfunction.

The ability to eradicate bacteria from the urine is related directly to the sensitivity of the microorganism and the achievable concentrations of the antimicrobial agent in the urine. Unfortunately, most susceptibility testing is directed at achievable concentrations in the blood. There is a poor correlation between achievable blood concentrations of antimicrobial agents and the eradication of bacteria from the urine.³¹ In the treatment of lower tract infections, plasma concentrations of antibacterial agents may not be important, but achieving appropriate plasma concentrations appears critical in patients with bacteremia and renal abscesses.

Nonspecific therapies have been advocated in the treatment and prevention of UTIs. Fluid hydration has been used to produce rapid dilution of bacteria and removal of infected urine by increased voiding. A critical factor appears to be the amount of residual volume remaining after voiding. As little as 10 mL of residual urine can alter the eradication of infection significantly.¹⁶ Paradoxically, increased diuresis also may promote susceptibility to infection by diluting the normal antibacterial properties of the urine. Often in clinical practice the concentrations of antimicrobial agents in the urine are so high that dilution has little effect on efficacy.

The antibacterial activity of the urine is related to the low pH, which is the result of high concentrations of various organic acids. Large volumes of cranberry juice increase the antibacterial activity of the urine and prevent the development of UTIs.^3,32,33 Apparently, the fructose and other unknown substances (condensed tannins, proanthocyanidin) in cranberry juice act to interfere with adherence mechanisms of some pathogens, thereby preventing infection or reinfection. Acidification of the urine by cranberry juice does not appear to play a significant role. The use of other agents (ascorbic acid) to acidify the urine to hinder bacterial growth does not achieve significant acidification. Consequently, attempts to acidify urine with systemic agents are not recommended. Lactobacillus probiotics also may aid in the prevention of female UTIs by decreasing the vaginal pH, thereby decreasing E. coli colonization.^19,33 In postmenopausal women, estrogen replacement may be of help in the prevention of recurrent UTIs. After 1 month of topical estrogen replacement, decreases in vaginal Lactobacillus, as well as decreases in vaginal pH and E. coli colonization, have been found.^18,33