Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

94. Urinary Tract Infections and Prostatitis

Elizabeth A. Coyle and Randall A. Prince


KEY CONCEPTS

 Images Urinary tract infections (UTIs) can be classified as uncomplicated and complicated. Uncomplicated refers to an infection in an otherwise healthy, premenopausal female who lacks structural or functional abnormalities of the urinary tract. Most often complicated infections are associated with a predisposing lesion of the urinary tract; however, the term may be used to refer to all other infections, except for those in the otherwise healthy, premenopausal adult female.

 Images Recurrent UTIs are considered either reinfections or relapses. Reinfection usually happens more than 2 weeks after the last UTI and is treated as a new uncomplicated UTI. Relapse usually happens within 2 weeks of the original infection, and is a relapse of the original infection either because of unsuccessful treatment of the original infection, a resistant organism, or anatomical abnormalities.

 Images Seventy-five to ninety-five percent of uncomplicated UTIs are caused by Escherichia coli and the remainder are caused primarily by Staphylococcus saprophyticusProteus spp., and Klebsiella spp. Complicated infections may be associated with other gram-negative organisms and Enterococcus faecalis.

 Images Symptoms of lower UTIs include dysuria, urgency, frequency, nocturia, and suprapubic heaviness, whereas upper UTIs involve more systemic symptoms such as fever, nausea, vomiting, and flank pain.

 Images Significant bacteriuria traditionally has been defined as bacterial counts of greater than 105 organisms (CFU)/mL (108/L) of a midstream clean catch urine. Many clinicians, however, have challenged this statement as too general. Indeed, significant bacteriuria in patients with symptoms of a UTI may be defined as greater than 102 organisms (CFU)/mL and go ahead and take out the 105/L.

 Images The goals of treatment of UTIs are to eradicate the invading organism(s), prevent or treat systemic consequences of infections, prevent the recurrence of infection, and prevent antimicrobial resistance.

 Images Uncomplicated UTIs can be managed most effectively with short-course (3 days) therapy with either trimethoprim–sulfamethoxazole, one dose of fosfomycin, or 5 days of nitrofurantoin. Due to the possibility of collateral damage, fluoroquinolones should be reserved for suspected pyelonephritis or complicated infections.

 Images In choosing appropriate antibiotic therapy, practitioners need to be cognizant of antibiotic resistance patterns, particularly to E. coli. Trimethoprim–sulfamethoxazole has diminished activity against E. coli in some areas of the country, with reported resistance in some areas greater than 20%.

 Images Acute bacterial prostatitis can be managed with many agents that have activity against the causative organism. Chronic prostatitis requires prolonged therapy with an agent that penetrates the prostatic tissue and secretions. Therapy with fluoroquinolone or trimethoprim–sulfamethoxazole is preferred for up to 6 weeks.


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.13 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.

Images 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.

Images 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 Chlamydiainfections.

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.46 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.

TABLE 94-1 Diagnostic Criteria for Significant Abacteriuria

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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

Images 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 saprophyticusKlebsiella pneumoniaeProteus 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. pneumoniaeEnterobacter spp., P. aeruginosa, staphylococci, and enterococci. Enterococci represent the second most frequently isolated organisms in hospitalized patients.1113 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 tuberculosisSalmonella 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

Images 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.

TABLE 94-2 Clinical Presentation of Urinary Tract Infections in Adults

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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.2225 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

Images 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 105bacteria/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 105bacteria/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

Images 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. colicolonization.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


Clinical Controversy…

The use of cranberry juice or lactobacilli in the prevention of UTIs has long been discussed. Lactobacillus potentially helps keep the vaginal pH in the normal range (pH 4 to 4.5), regulating genitourinary bacteria therefore aiding in the prevention of UTIs.32 Possible clinical benefits with cranberry juice in sexually active adult women with recurrent UTI by decreasing the adherence of bacteria to the bladder epithelial cells. However, a placebo controlled trial with cranberry juice in the prevention of recurrent UTIs in college age females showed no benefit with cranberry juice.32 Unfortunately, the consistency of study results has varied, as have the types of cranberry products tested, leading to overall inconclusive evidence.32,33 More reliable and thorough studies on the overall effectiveness of cranberry juice or lactobacilli need to be performed before a uniform opinion on the role of these agents in UTIs can be stated.

Urinary analgesics such as phenazopyridine hydrochloride are used frequently by many clinicians.3 If the pain or dysuria present in a UTI is a consequence of infection, then urinary analgesics have little clinical role because most patients’ symptoms respond quite rapidly to appropriate antibacterial therapy. Also, urinary analgesics may mask signs and symptoms of UTIs not responding to antimicrobial therapy.34,35,36


Clinical Controversy…

Phenazopyridine hydrochloride is an over the counter urinary anesthetic/analgesic that can be used for symptom relief in UTIs. Common brand names are Pyridium®, Azo-Standard®, and Uristat®. It is utilized frequently by patients as self-medication to alleviate the dysuria associated with UTIs. The use of phenazopyridine in the treatment of UTIs is controversial. It has no antimicrobial properties and has a number of adverse effects such as red-orange discoloration of body fluids, rash, anaphylaxis, and rare effects such as hemolytic anemia, methemoglobinemia, and acute renal failure. In addition, its use can mask the symptoms of an untreated or inappropriately treated UTI. Unfortunately, there are not any guidelines for its role in the treatment of UTIs; however, experts agree that if phenazopyridine is utilized, only use the recommended dose (maximum 200 mg three times a day) and it should be limited to 1 to 2 days for symptomatic relief of the dysuria with UTIs.34,35 In addition, it should be used with the combination of appropriate antibiotic therapy.

Pharmacologic Therapy

Ideally, the antimicrobial agent chosen should be well tolerated, well absorbed, achieve high urinary concentrations, and have a spectrum of activity limited to the known or suspected pathogen(s). Table 94–3lists the most common agents used in the treatment of UTIs along with comments concerning their general use. Table 94–4 presents an overview of various therapeutic options for outpatient therapy of UTI. Table 94–5 describes empirical treatment regimens for selected clinical situations.

TABLE 94-3 Commonly Used Antimicrobial Agents in the Treatment of Urinary Tract Infections

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TABLE 94-4 Overview of Outpatient Antimicrobial Therapy for Lower Tract Infections in Adults

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TABLE 94-5 Evidence-Based Empirical Treatment of Urinary Tract Infections and Prostatitis

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Images The therapeutic management of UTIs is best accomplished by first categorizing the type of infection: acute uncomplicated cystitis, symptomatic abacteriuria, asymptomatic bacteriuria, complicated UTIs, recurrent infections, or prostatitis. In choosing the appropriate antibiotic therapy, it is important to be aware of the increasing resistance of E. coli and other pathogens to many frequently prescribed antimicrobials. Resistance to E. coli is as high as 37% for amoxicillin and ampicillin.1,37 Overall, most E. coli remain susceptible to trimethoprim–sulfamethoxazole, although resistance is continuing to increase and has been reported as high as 27%.38 Although resistance to the fluoroquinolones remains low, these agents are being utilized more frequently and the incidence of fluoroquinolone-resistant E. coliis increasingly being reported and is of great concern.3743 Current or recent antibiotic exposure is the most significant risk factor associated with E. coli resistance and with the extensive use of the fluoroquinolones and trimethoprim–sulfamethoxazole for various infections, including UTIs, resistance will continue to increase.3742In addition, broad-spectrum antimicrobials such as fluoroquinolones and broad-spectrum cephalosporins have a high impact on GI flora, increasing the risk of collateral damage or the selection of resistant E. coli pathogens.3740,43,44In light of rising resistance and in order to decrease the overuse of broad-spectrum antimicrobials, agents such as nitrofurantoin and fosfomycin are now considered first-line treatments along with trimethoprim–sulfamethoxazole in acute uncomplicated cystitis. Both nitrofurantoin and fosfomycin have little effects on the gut flora and E. coli susceptibility still remains high.3,4448 Antibiotic therapy should be determined based on the geographic resistance patterns, as well as the patient’s recent history of antibiotic exposure.

Acute Uncomplicated Cystitis

Acute uncomplicated cystitis is the most common form of UTI. These infections typically occur in women of childbearing age and often are related to sexual activity. Although the presence of dysuria, frequency, urgency, and suprapubic discomfort frequently is associated with lower tract infection, a significant number of patients have upper tract involvement as well.3 Because these infections are predominantly caused by E. coli, antimicrobial therapy initially should be directed against this organism. Other common causes include S. saprophyticus and occasionally K. pneumoniae and Proteus mirabilis. Because the causative organisms and their susceptibility generally are known, many clinicians advocate a cost-effective approach to management. This approach includes a urinalysis and initiation of empirical therapy without a urine culture (Fig. 94–1).1 Therefore, the susceptibility patterns of the geographic area drive the choice of empiric therapy.

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FIGURE 94-1 Management of UTIs in females.

The goal of treatment for uncomplicated cystitis is to eradicate the causative organism and to reduce the incidence of recurrence caused by relapse or reinfection. The ability to reduce the chance of recurrence depends on the agent’s efficacy in eradicating the uropathogenic bacteria from the vaginal and GI reservoir. In the past, conventional therapy consisted of an effective oral antibiotic administered for 7 to 14 days. However, acute cystitis is a superficial mucosal infection that can be eradicated with much shorter courses of therapy (3 days). Advantages of short-course therapy include increased adherence, fewer side effects, decreased cost, and less potential for the development of resistance.

Images Three-day courses of trimethoprim–sulfamethoxazole or a fluoroquinolone (e.g., ciprofloxacin or levofloxacin, not moxifloxacin) are superior to single-dose therapies.47,4951 Although the fluoroquinolones have shown excellent efficacy in acute cystitis, the newest guidelines recommend reserving these agents for patients with suspected or possible pyelonephritis due to the collateral damage risk. Instead, a 3-day course of trimethoprim–sulfamethoxazole, a 5-day course of nitrofurantoin, or a one-time dose of fosfomycin should be considered as first-line therapy.1,45,46,50,52 In areas where there is >20% resistance of E. coli to trimethoprim–sulfamethoxazole, nitrofurantoin or fosfomycin should be utilized. Amoxicillin or ampicillin should not be utilized due to the high incidence of resistant E. coli. Instead, if a β-lactam must be utilized, amoxicillin/clavulanate, cefdinir, cefaclor, or cefpodoxime proxetil for 3 to 7 days are the preferred choices. For most adult females, short-course therapy is the treatment of choice for uncomplicated lower UTIs. Short-course therapy is inappropriate for patients who have had previous infections caused by resistant bacteria, for male patients, and for patients with complicated UTIs. If symptoms recur or do not respond to therapy, a urine culture should be obtained and conventional therapy with a suitable agent instituted.1

Symptomatic Abacteriuria

Symptomatic abacteriuria or acute urethral syndrome represents a clinical syndrome in which females present with dysuria and pyuria, but the urine culture reveals less than 105 bacteria/mL (108/L) of urine. Acute urethral syndrome accounts for more than half the complaints of dysuria seen in the community today. These women most likely are infected with small numbers of coliform bacteria, including E. coliStaphylococcus spp., or Chlamydia trachomatis. Additional causes include Neisseria gonorrhoeaeGardnerella vaginalis, and Ureaplasma urealyticum.

Most patients presenting with pyuria will, in fact, have infection that requires treatment. If antimicrobial therapy is ineffective, a culture should be obtained. If the patient reports recent sexual activity, therapy for C. trachomatisshould be considered. Chlamydial treatment should consist of 1 g azithromycin or doxycycline 100 mg twice daily for 7 days. Often, concomitant treatment of all sexual partners is required to cure chlamydial infections and prevent reacquisition (see Chap. 95).

Asymptomatic Bacteriuria

Asymptomatic bacteriuria is the finding of two consecutive urine cultures with >105 organisms/mL (>108/L) of the same organism in the absence of urinary symptoms. Most patients with asymptomatic bacteriuria are elderly and female. Also, pregnant women frequently present with asymptomatic bacteriuria. Although this group of patients typically responds to treatment, relapse and reinfection are very common and chronic asymptomatic bacteriuria is difficult to eradicate.

The management of asymptomatic bacteriuria depends on the age of the patient and whether or not the patient is pregnant. In children, because of a greater risk of developing renal scarring and long-standing renal damage, treatment should consist of the same conventional courses of therapy as used for symptomatic infection. The greatest risk of renal damage occurs during the first 5 years of life.53 In nonpregnant females, therapy is controversial; however, treatment has little effect on the natural course of infections. Two groups characterize asymptomatic bacteriuria in the elderly: those with persistent bacteriuria and those with intermittent bacteriuria.

Several studies in hospitalized elderly subjects, however, have not found antimicrobial therapy to be efficacious for abacteruria.5457 A number of questions remain unanswered. For example: What is the effect of eradication of bacteriuria on life expectancy? What are the cost-effectiveness and risk-to-benefit ratio of therapy? What is the effect on morbidity? Certainly with the information available and the high adverse reaction rate in the elderly, vigorous treatment and screening programs cannot be advocated.

Complicated Urinary Tract Infections

Acute Pyelonephritis

The presentation of high-grade fever (>38.3°C [100.9°F]) and severe flank pain should be treated as acute pyelonephritis and warrants aggressive management. Severely ill patients with pyelonephritis should be hospitalized and IV antimicrobials administered initially (see Table 94–5). However, milder cases may be managed with orally administered antibiotics in an outpatient setting. Signs and symptoms of nausea, vomiting, and dehydration may require hospitalization.

At the time of presentation, a Gram stain of the urine should be performed along with a urinalysis, culture, and sensitivity tests. The Gram stain should indicate the morphology of the infecting organism(s) and help to direct the selection of an appropriate antibiotic. However, the precise identity and susceptibility of the infecting organism(s) will be unknown initially, warranting empirical therapy. The goals of treatment include the achievement of therapeutic concentrations of an antimicrobial agent in the bloodstream and urinary tract to which the invading organism is susceptible and sufficient therapy to eradicate residual infection in the tissues of the urinary tract.

In the mildly to moderately symptomatic patient in whom oral therapy is considered, an effective agent should be administered for 7 to 14 days, depending on the agent used.1,5863 Oral antibiotics that are highly active against the probable pathogens and that are sufficiently bioavailable are preferred. Fluoroquinolones (ciprofloxacin or levofloxacin) orally for 7 to 10 days are the first-line choice in mild to moderate pyelonephritis. Other options include trimethoprim–sulfamethoxazole for 14 days. If amoxicillin/clavulanate or an oral cephalosporin is utilized, it is recommended to give an initial long-acting parenteral antimicrobial such as ceftriaxone first and continue the oral agent for 10 to 14 days. If a Gram stain reveals gram-positive cocci, Enterococcus faecalis should be considered and treatment directed against this potential pathogen (ampicillin). Close follow-up of outpatient treatment is mandatory to ensure success.

In the seriously ill patient, parenteral therapy should be administered initially. Therapy should provide a broad spectrum of coverage and should be directed toward bacteremia or sepsis, if present. A number of antibiotic regimens have been used as empirical therapy, including an IV fluoroquinolone, an aminoglycoside with or without ampicillin, and extended-spectrum cephalosporins with or without an aminoglycoside.1,64 Other options include aztreonam, the β-lactamase inhibitor combinations (e.g., ampicillin–sulbactam, ticarcillin–clavulanate, and piperacillin–tazobactam), carbapenems (e.g., imipenem, meropenem, doripenem, or ertapenem), or IV trimethoprim–sulfamethoxazole.65 If the patient has been hospitalized within the past 6 months, has a urinary catheter, or is a nursing home resident, the possibility of P. aeruginosa and enterococci, as well as multiple resistant organisms, should be considered. In this setting, ceftazidime, ticarcillin–clavulanate, piperacillin, aztreonam, meropenem, or imipenem in combination with an aminoglycoside is recommended. Ertapenem should not be used in this situation owing to its inactivity against enterococci and P. aeruginosa.64 The rationale for combination therapy is that in experimental animals 3 days of aminoglycoside combination therapy followed by nonaminoglycoside single-agent therapy for 7 days resulted in a 100% cure rate.58,63 If the patient responds to initial combination therapy, the aminoglycoside may be discontinued after 3 days. Although the aminoglycoside therapy is stopped, renal tissue concentrations of the aminoglycoside will persist for days. Based on antimicrobial sensitivity data, the patient then can be maintained or switched to a less expensive single agent and ultimately, an appropriate oral agent may be used.

Effective therapy should stabilize the patient within 12 to 24 hours. A significant reduction in urine bacterial concentrations should occur in 48 hours. If bacteriologic response has not occurred, an alternative agent should be considered based on susceptibility testing. If the patient fails to respond clinically within 3 to 4 days or has persistently positive blood or urine cultures, further investigation is needed to exclude bacterial resistance, possible obstruction, papillary necrosis, intrarenal or perinephric abscess, or some other disease process. Usually by the third day of therapy, the patient is afebrile and significantly less symptomatic. In general, after the patient has been afebrile for 24 hours, parenteral therapy may be discontinued and oral therapy instituted to complete a 2-week course. Follow-up urine cultures should be obtained 2 weeks after completion of therapy to ensure a satisfactory response and detect possible relapse.

Urinary Tract Infections in Males

The management of UTIs in males is distinctly different and often more difficult than in females. Infections in male patients are considered to be complicated because endogenous bacteria in the presence of functional and/or structural abnormalities that disrupt the normal defense mechanisms of the urinary tract cause them. The incidence of infections in males younger than 60 years of age is much less than the incidence in females. During the adult years, the occurrence of infection can be related directly to some manipulation of the urinary tract. The most common causes are instrumentation of the urinary tract, catheterization, and renal and urinary stones. Uncomplicated infections are rare, but they may occur in young males as a result of homosexual activity, noncircumcision, and having sex with partners who are colonized with uropathogenic bacteria. As the patient ages, the most common cause of infection is related to bladder outlet obstruction because of prostatic hypertrophy. In addition, the prostate gland may become infected and provide a nidus for recurrent infection in males.

The conventional view is that therapy in males requires prolonged treatment (Fig. 94–2). A urine culture should be obtained before treatment because the cause of infection in men is not as predictable as in women. Single-dose or short-course therapy is not recommended in males. Considerably fewer data are available comparing various antimicrobial agents in males as compared with females. If gram-negative bacteria are presumed, trimethoprim–sulfamethoxazole or the quinolone antimicrobials should be considered because these agents achieve high renal tissue, urine, and prostatic concentrations.66

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FIGURE 94-2 Management of UTIs in males.

Initial therapy should be for 10 to 14 days. Factors associated with treatment success are isolation of a single organism, the absence of significant obstruction or anatomic abnormalities, a normally functioning urinary tract, and the absence of prostatic involvement. Parenteral therapy may be required in certain situations, such as in severely ill patients, in the presence of acute prostatitis or epididymitis and in patients who cannot tolerate oral medications. A comparison of 2-week versus 6-week therapy in males with recurrent infections who were given trimethoprim–sulfamethoxazole had cure rates of 29% and 62%, respectively.67 Other investigators advocate longer treatment periods in males, as well.68 Follow-up cultures at 4 to 6 weeks after treatment are important in males to ensure bacteriologic cure. Many patients require longer periods of treatment and possible alterations in antibiotics, depending on culture and sensitivity results and clinical response.

Recurrent Infections

Recurrent episodes of UTI account for a significant portion of all UTIs. Of the patients suffering from recurrent infections, 80% can be considered reinfections, that is, the recurrence of infection by an organism different from the organism isolated from the preceding infection. These patients most commonly are female and recurrence develops in approximately 20% of females with cystitis. Reinfections can be divided into two groups: those with less than three episodes per year and those who develop more frequent infections.

Management strategies depend on predisposing factors, number of episodes per year, and the patient’s preference. Factors commonly associated with recurrent infections include sexual intercourse and diaphragm or spermicide use for birth control. Therapeutic options include self-administered therapy, postcoital therapy, and continuous low-dose prophylaxis. In patients with infrequent infections (less than three infections per year), each episode may be treated as a separately occurring infection. Short-course therapy is appropriate in this setting. Many women have been treated successfully with self-administered short-course therapy at the onset of symptoms.36,69

In patients with more frequent symptomatic infections and no apparent precipitating event, long-term prophylactic antimicrobial therapy may be instituted. Prophylactic therapy reduces the frequency of symptomatic infections in elderly men, women, and children. In women, most studies show a reinfection rate of 2 to 3 per patient-year reduced to 0.1 to 0.2 per patient-year with treatment.69 Before prophylaxis is initiated, patients should be treated conventionally with an appropriate agent. Trimethoprim–sulfamethoxazole (one-half of a single-strength tablet), trimethoprim (100 mg daily), a fluoroquinolone (levofloxacin 500 mg daily), and nitrofurantoin (50 or 100 mg daily) all reduce the rate of reinfection as single-agent therapy.69 Full-dose therapy with these agents is unnecessary and single daily doses can be used. Therapy generally is prescribed for a period of 6 months, during which time urine cultures are followed monthly. If symptomatic episodes develop, the patient should receive a full course of therapy with an effective agent and then resume prophylactic therapy.

In women who experience symptomatic reinfections in association with sexual activity, voiding after intercourse may help to prevent infection. Also, single-dose prophylactic therapy with trimethoprim–sulfamethoxazole taken after intercourse reduces the incidence of recurrent infection significantly.69

In postmenopausal women with recurrent infections, the lack of estrogen results in changes in the bacterial flora of the vagina, resulting in increased colonization with uropathogenic E. coli. Topically administered estrogen cream reduces the incidence of infections in this population.18,19

The remaining 20% of recurrent UTIs are relapses, that is, persistence of infection with the same organism after therapy for an isolated UTI. The recurrence of symptomatic or asymptomatic bacteriuria after therapy usually indicates that the patient has renal involvement, a structural abnormality of the urinary tract or chronic bacterial prostatitis. In the absence of structural abnormalities, relapse often is related to renal infection and requires a long duration of treatment. Women who relapse after short-course therapy should receive a 2-week course of therapy. In patients who relapse after 2 weeks of therapy, therapy should be continued for another 2 to 4 weeks. If relapse occurs after 6 weeks of therapy, urologic evaluation should be performed and any obstructive lesion should be corrected. If this is not possible, therapy for 6 months or longer may be considered. Asymptomatic adults who have no evidence of urinary obstruction should not receive long-term therapy.

In males, relapse usually indicates bacterial prostatitis, the most common cause of persistent bacteriuria. Although many agents have been used for long-term therapy of relapses, trimethoprim–sulfamethoxazole and the fluoroquinolones appear to be highly effective.

Special Conditions

UTIs in Pregnancy

During pregnancy, significant physiologic changes occur to the entire urinary tract that dramatically alter the prevalence of UTIs and pyelonephritis. Severe dilation of the renal pelvis and ureters, decreased ureteral peristalsis, and reduced bladder tone occur during pregnancy.70 These changes result in urinary stasis and reduced defenses against reflux of bacteria to the kidneys. In addition, increased urine content of amino acids, vitamins, and nutrients encourages bacterial growth. All of these factors increase the incidence of bacteriuria resulting in symptomatic infections, especially during the third trimester.

Asymptomatic bacteriuria occurs in 4% to 7% of pregnant patients. Of these, 20% to 40% will develop acute symptomatic pyelonephritis during pregnancy. If untreated, asymptomatic bacteriuria has the potential to cause significant adverse effects, including prematurity, low birth weight, and stillbirth.71,72 Because pyelonephritis is associated with significant adverse events during pregnancy, routine screening tests for bacteriuria should be performed at the initial prenatal visit and again at 28 weeks’ gestation. In patients with significant bacteriuria, symptomatic or asymptomatic, treatment is recommended so as to avoid possible complications. Organisms associated with bacteriuria are the same as those seen in uncomplicated UTIs with E. coli isolated most frequently.

Therapy should consist of an agent administered for 7 days that has a relatively low adverse effect potential and is safe for the mother and baby. The administration of amoxicillin, amoxicillin–clavulanate, or cephalexin is effective in 70% to 80% of patients. Nitrofurantoin has been utilized in pregnancy; however, it must be used with caution as occurrences of birth defects have been reported. 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. In addition, the available fluoroquinolones should not be given because of their potential to inhibit cartilage and bone development in the newborn. A follow-up urine culture 1 to 2 weeks after completing therapy and then monthly until gestation is complete is recommended.

Catheterized Patients

The use of an indwelling catheter frequently is associated with infection of the urinary tract and represents the most common cause of hospital-acquired infection. The incidence of catheter-associated infection is related to a variety of factors, including method and duration of catheterization, the catheter system (open or closed), the care of the system, the susceptibility of the patient, and the technique of the healthcare personnel inserting the catheter. Catheter-related infections are reasonably preventable infections and are now considered one of the hospital-acquired complications chosen by the Centers for Medicare and Medicaid Services (CMS) in which hospitals will no longer receive reimbursement for treatment.73,74

Bacteria may enter the bladder in a number of ways. During the catheterization, bacteria may be introduced directly into the bladder from the urethra. Once the catheter is in place, bacteria may pass up the lumen of the catheter via the movement of air bubbles, by motility of the bacteria, or by capillary action. In addition, bacteria may reach the bladder from around the exudative sheath that surrounds the catheter in the urethra. Cleaning the periurethral area thoroughly and applying an antiseptic (povidone-iodine) can minimize infection occurring during insertion of the catheter. The use of closed drainage systems has reduced significantly the ability of bacteria to pass up the lumen of the catheter and cause infection. Presently, a bacterium passing around the catheter sheath in the urethra is probably the most important pathway for infection. Avoiding manipulation of the catheter and trauma to the urethra and urethral meatus can minimize this path of acquisition.

Patients with indwelling catheters acquire UTIs at a rate of 5% per day.7375 The closed systems are capable of preventing bacteriuria in most patients for up to 10 days with appropriate care. After 30 days of catheterization, however, there is a 78% to 95% incidence of bacteriuria, despite use of a closed system.74,76 Unfortunately, UTI symptoms in catheterized patient are not clearly defined. Fever, peripheral leukocytosis, and urinary signs and symptoms may be of little predictive value.73,74 When bacteriuria occurs in the asymptomatic, short-term catheterized patient (<30 days), the use of systemic antibiotics should be withheld and the catheter removed as soon as possible. If the patient becomes symptomatic, the catheter should be removed and treatment as described for complicated infections started. The optimal duration of therapy is unknown. In the long-term catheterized patient (>30 days), bacteriuria is inevitable.73,74 The administration of systemic antibiotics active against the infecting organism will sterilize the urine; however, reinfection occurs rapidly in more than 50% of patients. In addition, resistant organisms recolonize the urine. Symptomatic patients must be treated because they are at risk of developing pyelonephritis and bacteremia. Bacteria adhere to the catheter and produce a biofilm consisting of bacterial glycocalyces, Tamm–Horsfall protein, as well as apatite and struvite salts, that act to protect the bacteria from antibiotics.75 Recatheterization with a new sterile unit should be performed in those symptomatic patients, if the existing catheter has been in place for more than 2 weeks.

Various methods have been proposed to prevent the development of bacteriuria and infection in the patient with an indwelling catheter (see Table 94–5). The success of these methods depends on the type of catheter and the length of time it is in place. The use of constant bladder irrigation with antiseptic or antibacterial solutions reduces the incidence of infection in those with open drainage systems, but this approach has no advantage in those with closed systems. The use of prophylactic systemic antibiotics in patients with short-term catheterization reduces the incidence of infection over the first 4 to 7 days.74,76In long-term catheterized patients, however, antibiotics only postpone the development of bacteriuria and lead to the emergence of resistant organisms. Therefore, antibiotic prophylaxis should not be utilized in short-term or long-term catheterized patients.

PROSTATITIS

Bacterial prostatitis is an inflammation of the prostate gland and surrounding tissue as a result of infection. It is classified as either acute or chronic. By definition, pathogenic bacteria and significant inflammatory cells must be present in prostatic secretions and urine to make the diagnosis of bacterial prostatitis. Prostatitis occurs rarely in young males, but it is commonly associated with recurrent infections in persons older than 30 years of age. As many as 50% of all males develop some form of prostatitis at some period in their life.7779 The acute form typically is an acute infectious disease characterized by a sudden onset of fever, tenderness, and urinary and constitutional symptoms. Chronic prostatitis presents with few symptoms related to the prostate but rather symptoms of urinating difficulty, low back pain, perineal pressure, or a combination of these. It represents a recurring infection with the same organism that results from incomplete eradication of bacteria from the prostate gland.

Pathogenesis and Etiology

The exact mechanism of bacterial infection of the prostate is not well understood. The possible routes of infection are the same as those for UTIs. Reflux of infected urine into the prostate gland is thought to play an important role in causing infection. Intraprostatic reflux of urine occurs commonly and results in direct inoculation of infected urine into the prostate.7779 In addition, intraprostatic reflux of sterile urine can result in a chemical prostatitis and may be the cause of nonbacterial prostatitis. Sexual intercourse may contribute to infection of the prostate gland because prostatic secretions from men with chronic prostatitis and vaginal cultures from their sexual partners grow identical organisms. Other known causes of bacterial prostatitis include indwelling urethral and condom catheterization, urethral instrumentation, and transurethral prostatectomy in patients with infected urine.

Physiologic factors are believed to contribute to the development of prostatitis. Functional abnormalities found in bacterial prostatitis include altered prostate secretory functions. Prostatic fluid obtained from normal males contains prostatic antibacterial factor. This heat-stable, low-molecular-weight cation is a zinc-complexed polypeptide that is bactericidal to most urinary tract pathogens.80 The antibacterial activity of prostatic antibacterial factor is related directly to the zinc content of prostatic fluid. Prostate fluid zinc levels and prostatic antibacterial factor activity also appear diminished in patients with prostatitis, as well as in the elderly.80 Whether these changes are a cause or effect of prostatitis remains to be determined.

The pH of prostatic secretions in patients with prostatitis is altered.81 Normal prostatic secretions have a pH in the range of 6.6 to 7.6. With increasing age, the pH tends to become more alkaline. In patients with inflammation of the prostate, prostatic secretions may have an alkaline pH in the range of 7 to 9. These changes suggest a generalized secretory dysfunction of the prostate that not only can affect the pathogenesis of prostatitis but also can influence the mode of therapy.

Gram-negative enteric organisms are the most frequent pathogens in acute bacterial prostatitis.7779 E. coli is the predominant organism, occurring in 75% of cases. Other gram-negative organisms frequently isolated include K. pneumoniaeP. mirabilis, and less frequently, P. aeruginosaEnterobacter spp., and Serratia spp. Infrequently, cases of gonococcal and staphylococcal prostatitis occur.

E. coli most commonly causes chronic bacterial prostatitis with other gram-negative organisms isolated less frequently. The importance of gram-positive organisms in chronic bacterial prostatitis remains controversial. S. epidermidisS. aureus, and diphtheroids have been isolated in some studies.

Clinical Presentation

Acute bacterial prostatitis presents as other acute infections (Table 94–6). Massage of the prostate will express a purulent discharge that will readily grow the pathogenic organism. Prostatic massage is contraindicated in acute bacterial prostatitis, however, because of the risk of inducing bacteremia and the associated local pain. The diagnosis of acute bacterial prostatitis can be made from the patient’s clinical presentation and the presence of significant bacteriuria. As with other UTIs, the infecting organism can be isolated from a midstream specimen.

TABLE 94-6 Clinical Presentation of Bacterial Prostatitis

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In contrast, chronic bacterial prostatitis is more difficult to diagnose and treat. Chronic bacterial prostatitis typically is characterized by recurrent UTIs with the same pathogen and is the most common cause of recurrent UTI in males. The patient’s clinical presentation can vary widely (see Table 94–6). Many adults, however, are asymptomatic.

Because physical examination of the prostate is often normal, urinary tract localization studies are critical to the diagnosis of chronic bacterial prostatitis. The method of quantitative localization culture, as described by Meares and Stamey,15,82 remains the diagnostic standard (Fig. 94–3). The method compares the bacterial growth in sequential urine and prostatic fluid cultures obtained during micturition. The first 10 mL of voided urine is collected (voiding bladder 1, or VB1) and constitutes urethral urine. After approximately 200 mL of urine has been voided, a 10-mL midstream sample is collected (VB2). This specimen represents bladder urine. After the patient voids, the prostate is massaged and expressed prostatic secretions (EPS) are collected. After prostatic massage, the patient voids again and 10 mL of urine is collected (VB3).

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FIGURE 94-3 Segmented cultures of the lower tract in men. (EPS, expressed prostatic secretions; VB1, voiding bladder 1; VB2, voiding bladder 2; VB3, voiding bladder 3.)

The diagnosis of bacterial prostatitis is made when the number of bacteria in EPS is 10 times that of the urethral sample (VB1) and midstream sample (VB2). If no EPS is available, the urine sample following massage (VB3) should contain a bacterial count 10-fold greater than that of VB1 or VB2. If significant bacteriuria is present, ampicillin, cephalexin, or nitrofurantoin should be given for 2 to 3 days to sterilize the urine prior to performing the localization study.

TREATMENT

Images In general, the goals in the management of bacterial prostatitis are the same as those for UTIs. Acute bacterial prostatitis responds well to appropriate antimicrobial therapy that is directed at the most commonly isolated organisms. Prostatic penetration of antimicrobials occurs because the acute inflammatory reaction alters the cellular membrane barrier between the bloodstream and the prostate. Most patients can be managed with oral antimicrobial agents, such as trimethoprim–sulfamethoxazole and the fluoroquinolones (e.g., ciprofloxacin, levofloxacin) (see Table 94–5). Other effective agents in this setting include cephalosporins and β-lactam–β-lactamase combinations. Although IV therapy is rarely necessary for total treatment, IV to oral sequential therapy with trimethoprim-sulfamethoxazole or the fluoroquinolones is appropriate. The conversion to an oral antibiotic can be considered after the patient is afebrile for 48 hours or after 3 to 5 days of IV therapy. The total course of antibiotic therapy should be 4 weeks in order to reduce the risk of development of chronic prostatitis, although in some cases 2 weeks may be sufficient. Therapy may be prolonged with chronic prostatitis (6 to 12 weeks). Long-term suppressive therapy also may be initiated for recurrent infections, such as three times weekly ciprofloxacin, trimethoprim–sulfamethoxazole regular-strength tablet daily, or nitrofurantoin 100 mg daily.82

Chronic bacterial prostatitis often presents a more vexing situation because cures are obtained rarely. Despite high serum concentrations of antibacterial drugs in excess of the minimal inhibitory concentrations of the infecting organisms, bacteria persist in prostatic fluid. Most likely the failure to eradicate sensitive bacteria is caused by the inability of antibiotics to reach sufficient concentrations in the prostatic fluid and cross the prostatic epithelium.

Several factors that determine antibiotic diffusion into prostatic secretions were delineated from the canine model. Lipid solubility is a major determinant in the ability of drugs to diffuse from plasma across epithelial membranes. The degree of ionization in plasma also affects the diffusion of drugs. Only unionized molecules can cross the lipid barrier of prostatic cells, and the drug’s pKa (negative logarithm of acid ionization constant) directly determines the fraction of unchanged drug.

The pH gradient across the membrane has an influence on tissue penetration, as well. A pH gradient of at least one pH unit between separate compartments allows for ion trapping. As the unionized drug crosses the epithelial barrier into prostatic fluid, it becomes ionized allowing less drug to diffuse back across the lipid barrier. In early studies with the canine model, the prostatic pH was reported to be acidic (6.4).81 In humans, however, the pH of prostatic secretions from an inflamed prostate is actually basic (8.1 to 8.3).81

The choice of antibiotics in chronic bacterial prostatitis should include agents that are capable of reaching therapeutic concentrations in the prostatic fluid and which possess the spectrum of activity to be effective. Agents that achieve therapeutic prostatic concentrations include trimethoprim and the fluoroquinolones. Sulfamethoxazole penetrates poorly and probably contributes very little to trimethoprim activity when used in combination. The fluoroquinolones appear to provide the best therapeutic options in the management of chronic bacterial prostatitis. Therapy should be continued for 4 to 6 weeks initially. Longer treatment periods may be necessary in some cases. If therapy fails with these regimens, chronic suppressive therapy may be used or surgery considered.

PERSONALIZED PHARMACOTHERAPY

Patient-centered pharmacotherapy and management of UTIs require knowledge of the pathogenesis and causative organisms associated with the various clinical syndromes described in this chapter. Individualizing the antimicrobial therapy will depend on many factors, first and foremost being the susceptibility of the offending pathogen. As was discussed in the chapter, E. coli resistance is continuing to increase, therefore it is imperative for the healthcare professional to be familiar with the resistance trends in their geographical area when prescribing therapy. In addition, the prevention of increasing resistance and collateral damage should be considered when selecting antimicrobial therapy.1 Other factors to consider in selecting therapy would be a patient’s allergies and recent antimicrobial exposure. Lastly, cost may factor into compliance enhancing the effectiveness of therapy. The costs include both direct and indirect costs associated with treatment.

Direct costs are those associated with diagnosis, treatment, and follow-up. The cost of pharmaceuticals varies according to the agents used and the duration of therapy. Trimethoprim–sulfamethoxazole and amoxicillin–clavulanate are rather inexpensive. However, when considering rates of resistance leading to therapeutic failure, overall costs increase dramatically. The fluoroquinolones also are highly effective agents, but generally are more expensive and a rise in their utilization is now being associated with increasing resistance.64,83 In general, the outcome and total cost depend on whether therapy is empirical or definitive (based on a culture diagnosis for acute infection) and if the individual patient is adherent with the regimen. As a healthcare professional, working with and counseling the individual patient in order to select an appropriate therapy is essential in achieving positive therapeutic outcomes.

ABBREVIATIONS

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REFERENCES

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    2. Naber KG, Cho YH, Matsumoto T, et al. Immunoactive prophylaxis of recurrent urinary tract infections: A meta-analysis. Int J Antimicrob Agents 2009;33:111–119.

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