1. Urinary Tract Infections (UTIs) and Prostatitis Pharm.D Balsam Alhasan

2. DEFINITION Infections of the urinary tract represent a wide variety of clinical syndromes, including urethritis, cystitis, prostatitis, and pyelonephritis. A urinary tract infection (UTI) is defined as the presence of microorganisms in the urine that cannot be accounted for by contamination. The organisms have the potential to invade the tissues of the urinary tract and adjacent structures.

3. DEFINITION Lower tract infections include cystitis (bladder), urethritis (urethra), prostatitis (prostate gland), and epididymitis. Upper tract infections (such as pyelonephritis) involve the kidney and are referred to as pyelonephritis.

4. DEFINITION Uncomplicated UTIs are not associated with structural or neurologic abnormalities that may interfere with the normal flow of urine or the voiding mechanism. Complicated UTIs are the result of a predisposing lesion of the urinary tract such as a congenital abnormality or distortion of the urinary tract, a stone, indwelling catheter, prostatic hypertrophy, obstruction, or neurologic deficit that interferes with the normal flow of urine and urinary tract defenses.

5. DEFINITION Recurrent UTIs are characterized by multiple symptomatic episodes with asymptomatic periods occurring between these episodes. These infections are either due to reinfection or to relapse. Reinfections are caused by a different organism and account for the majority of recurrent UTIs. Relapse represents the development of repeated infections caused by the same initial organism.

6. PATHOPHYSIOLOGY The bacteria causing UTIs usually originate from bowel flora of the host. UTIs can be acquired via three possible routes: the ascending, hematogenous, or lymphatic pathways.

7. PATHOPHYSIOLOGY In females, the short length of the urethra and proximity to the perirectal area make colonization of the urethra likely. Bacteria are then believed to enter the bladder from the urethra. Once in the bladder, the organisms multiply quickly and can ascend the ureters to the kidney.

8. PATHOPHYSIOLOGY Three factors determine the development of UTI: the size of the inoculum, virulence of the microorganism, and competency of the natural host defense mechanisms. Patients who are unable to void urine completely are at greater risk of developing UTIs and frequently have recurrent infections.

9. PATHOPHYSIOLOGY An important virulence factor of bacteria is their ability to adhere to urinary epithelial cells by fimbriae, resulting in colonization of the urinary tract, bladder infections, and pyelonephritis. Other virulence factors include hemolysin, a cytotoxic protein produced by bacteria that lyses a wide range of cells including erythrocytes, polymorphonuclear leukocytes, and monocytes; and aerobactin, which facilitates the binding and uptake of iron by Escherichia coli.

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

11. MICROBIOLOGY The urinary pathogens in complicated or nosocomial infections may include E. coli, which accounts for less than 50% of these infections, Proteus spp., Klebsiella pneumoniae, Enterobacter spp., Pseudomonas aeruginosa, staphylococci, and enterococci.

12. MICROBIOLOGY Candida spp. have become common causes of urinary infection in the critically ill and chronically catheterized patient. The majority of UTIs are caused by a single organism; however, in patients with stones, indwelling urinary catheters, or chronic renal abscesses, multiple organisms may be isolated.

13. CLINICAL PRESENTATION The typical symptoms of lower and upper UTIs are presented in Table 50-1.

15. CLINICAL PRESENTATION Symptoms alone are unreliable for the diagnosis of bacterial UTIs. The key to the diagnosis of a UTI is the ability to demonstrate significant numbers of microorganisms present in an appropriate urine specimen to distinguish contamination from infection.

16. CLINICAL PRESENTATION Elderly patients frequently do not experience specific urinary symptoms, but they will present with altered mental status, change in eating habits, or GI symptoms. A standard urinalysis should be obtained in the initial assessment of a patient.

17. DIAGNOSIS: Microscopic examination of the urine should be performed by preparation of a Gram stain of unspun or centrifuged urine. The presence of at least one organism per oil-immersion field in a properly collected uncentrifuged specimen correlates with more than 100,000 bacteria/mL of urine. Criteria for defining significant bacteriuria are listed in Table 50-2.

18. DIAGNOSIS:

19. The presence of pyuria (more than 10 white blood cells/mm 3) in a symptomatic patient correlates with significant bacteriuria. The nitrite test can be used to detect the presence of nitrate- reducing bacteria in the urine (such as E. coli). The leukocyte esterase test is a rapid dipstick test to detect pyuria.

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

21. TREATMENT

22. DESIRED OUTCOME The goals of treatment for UTIs are to prevent or treat systemic consequences of infection, eradicate the invading organism, and prevent recurrence of infection.

23. GENERAL PRINCIPLES 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 primarily based on the severity of the presenting signs and symptoms, the site of infection, and whether the infection is determined to be complicated or uncomplicated.

24. PHARMACOLOGIC TREATMENT The ability to eradicate bacteria from the urinary tract is directly related to the sensitivity of the organism and the achievable concentration of the antimicrobial agent in the urine. 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.

25. Table 50-3 lists the most common agents used in the treatment of UTIs, along with comments concerning their general use. PHARMACOLOGIC TREATMENT

29. THERAPEUTIC OPTIONS Table 50-4 presents an overview of various therapeutic options for outpatient therapy for UTI.

32. TREATMENT REGIMENS Table 50-5 describes empiric treatment regimens for selected clinical situations.

34. Acute Uncomplicated Cystitis These infections are predominantly caused by E. coli, and antimicrobial therapy should be directed against this organism initially. Other causes include S. saprophyticus and occasionally K. pneumoniae and Proteus mirabilis.

35. Acute Uncomplicated Cystitis Because the causative organisms and their susceptibilities are generally known, a cost-effective approach to management is recommended that includes a urinalysis and initiation of empiric therapy without a urine culture (Fig. 50-1).

37. Acute Uncomplicated Cystitis Short-course therapy (3-day therapy) with trimethoprim– sulfamethoxazole or a fluoroquinolone (e.g., ciprofloxacin, levofloxacin, or norfloxacin) is superior to single-dose therapy for uncomplicated infection and should be the treatment of choice. Amoxicillin or sulfonamides are not recommended because of the high incidence of resistant E. coli. Follow-up urine cultures are not necessary in patients who respond.

38. Symptomatic Abacteriuria Single-dose or short-course therapy with trimethoprim– sulfamethoxazole has been used effectively, and prolonged courses of therapy are not necessary for the majority of patients. If single-dose or short-course therapy is ineffective, a culture should be obtained. If the patient reports recent sexual activity, therapy for Chlamydia trachomatis should be considered (azithromycin 1 g as a single dose or doxycycline 100 mg twice daily for 7 days).

39. Asymptomatic Bacteriuria The management of asymptomatic bacteriuria depends on the age of the patient and, if female, whether she is pregnant. In children, treatment should consist of conventional courses of therapy, as described for symptomatic infections.

40. Asymptomatic Bacteriuria In the nonpregnant female, therapy is controversial; however, it appears that treatment has little effect on the natural course of infections. Most clinicians feel that asymptomatic bacteriuria in the elderly is a benign disease and may not warrant treatment. The presence of bacteriuria can be confirmed by culture if treatment is considered.

41. Complicated Urinary Tract Infections

42. Acute Pyelonephritis The presentation of high-grade fever (greater than 38.3°C [100.9°F]) and severe flank pain should be treated as acute pyelonephritis, and aggressive management is warranted. Severely ill patients with pyelonephritis should be hospitalized and IV drugs administered initially. Milder cases may be managed with oral antibiotics in an outpatient setting.

43. Acute Pyelonephritis At the time of presentation, a Gram stain of the urine should be performed, along with urinalysis, culture, and sensitivities. In the mild to moderately symptomatic patient for whom oral therapy is considered, an effective agent should be administered for at least a 2-week period, although use of highly active agents for 7 to 10 days may be sufficient.

44. Acute Pyelonephritis Oral antibiotics that have shown efficacy in this setting include trimethoprim–sulfamethoxazole or fluoroquinolones. If a Gram stain reveals gram-positive cocci, Streptococcus faecalis should be considered and treatment directed against this pathogen (ampicillin).

45. Acute Pyelonephritis In the seriously ill patient, the traditional initial therapy has included an IV fluoroquinolone, an aminoglycoside with or without ampicillin, or an extended-spectrum cephalosporin with or without an aminoglycoside. If the patient has been hospitalized in the last 6 months, has a urinary catheter, or is in a nursing home, the possibility of P. aeruginosa and enterococci infection, as well as multiply-resistant organisms, should be considered.

46. Acute Pyelonephritis In this setting, ceftazidime, ticarcillin-clavulanic acid, piperacillin, aztreonam, meropenem, or imipenem, in combination with an aminoglycoside, is recommended. If the patient responds to initial combination therapy, the aminoglycoside may be discontinued after 3 days. Follow-up urine cultures should be obtained 2 weeks after the completion of therapy to ensure a satisfactory response and to detect possible relapse.

47. Urinary Tract Infections in Males The conventional view is that therapy in males requires prolonged treatment (Fig. 50-2).

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

50. Recurrent Infections Recurrent episodes of UTI (reinfections and relapses) account for a significant portion of all UTIs. These patients are most commonly women and can be divided into two groups: those with fewer than two or three episodes per year and those who develop more frequent infections.

51. Recurrent Infections In patients with infrequent infections (i.e., fewer than three infections per year), each episode should be treated as a separately occurring infection. Short-course therapy should be used in symptomatic female patients with lower tract infection.

52. Recurrent Infections In patients who have frequent symptomatic infections, long- term prophylactic antimicrobial therapy may be instituted (see Table 50-4). Therapy is generally given for 6 months, with urine cultures followed periodically.

53. Recurrent Infections In women who experience symptomatic reinfections in association with sexual activity, voiding after intercourse may help prevent infection. Also, self-administered, single-dose prophylactic therapy with trimethoprim– sulfamethoxazole taken after intercourse has been found to significantly reduce the incidence of recurrent infection in these patients.

54. Recurrent Infections Women who relapse after short-course therapy should receive a 2-week course of therapy. In patients who relapse after 2 weeks, therapy should be continued for another 2 to 4 weeks. If relapse occurs after 6 weeks of treatment, urologic examination should be performed, and therapy for 6 months or even longer may be considered.

55. SPECIAL CONDITIONS

56. Urinary Tract Infection in Pregnancy In patients with significant bacteriuria, symptomatic or asymptomatic, treatment is recommended in order to avoid possible complications during the pregnancy. Therapy should consist of an agent with a relatively low adverse-effect potential (a sulfonamide, cephalexin, amoxicillin, amoxicillin/clavulanate, nitrofurantoin) administered for 7 days.

57. Urinary Tract Infection in Pregnancy Tetracyclines should be avoided because of teratogenic effects, and sulfonamides should not be administered during the third trimester because of the possible development of kernicterus and hyperbilirubinemia. Also, the fluoroquinolones should not be given because of their potential to inhibit cartilage and bone development in the newborn.

58. Catheterized Patients When bacteriuria occurs in the asymptomatic, short-term catheterized patient (less than 30 days), the use of systemic antibiotic therapy should be withheld and the catheter removed as soon as possible. If the patient becomes symptomatic, the catheter should again be removed, and treatment as described for complicated infections should be started.

59. Catheterized Patients The use of prophylactic systemic antibiotics in patients with short-term catheterization reduces the incidence of infection over the first 4 to 7 days. In long-term catheterized patients, however, antibiotics only postpone the development of bacteriuria and lead to emergence of resistant organisms.

60. PROSTATITIS

61. DIFINITION: Prostatitis is an inflammation of the prostate gland and surrounding tissue as a result of infection. It can be either acute or chronic. The acute form is characterized by a severe illness characterized by a sudden onset of fever and urinary and constitutional symptoms.

62. DIFINITION: Chronic bacterial prostatitis (CBP) represents a recurring infection with the same organism (relapse). Pathogenic bacteria and significant inflammatory cells must be present in prostatic secretions and urine to make the diagnosis of bacterial prostatitis.

63. PATHOGENESIS AND ETIOLOGY The exact mechanism of bacterial infection of the prostate is not well understood. The possible routes of infection include ascending infection of the urethra, reflux of infected urine into prostatic ducts, invasion by rectal bacteria through direct extension or lymphatic spread, and by hematogenous spread.

64. PATHOGENESIS AND ETIOLOGY Gram-negative enteric organisms are the most frequent pathogens in acute bacterial prostatitis. E. coli is the predominant organism, occurring in 75% of cases. CBP is most commonly caused by E. coli, with other gram- negative organisms isolated much less often.

65. CLINICAL PRESENTATION AND DIAGNOSIS The clinical presentation of bacterial prostatitis is presented in Table 50-6.

66. Digital palpation of the prostate via the rectum may reveal a swollen, tender, warm, tense, or indurated prostate. Massage of the prostate will express a purulent discharge, which will readily grow the pathogenic organism. However, prostatic massage is contraindicated in acute bacterial prostatitis because of a risk of inducing bacteremia and associated pain. CBP is characterized by recurrent UTIs with the same pathogen. Urinary tract localization studies are critical to the diagnosis of CBP. CLINICAL PRESENTATION AND DIAGNOSIS

67. TREATMENT The majority of patients can be managed with oral antimicrobial agents, such as trimethoprim–sulfamethoxazole or the fluoroquinolones (ciprofloxacin, levofloxacin). When IV treatment is necessary, IV to oral sequential therapy with trimethoprim– sulfamethoxazole or a fluoroquinolone, such as ciprofloxacin or ofloxacin, would be appropriate. The total course of therapy should be 4 weeks, which may be prolonged to 6 to 12 weeks with chronic prostatitis.

68. TREATMENT Parenteral therapy should be maintained until the patient is afebrile and less symptomatic. The conversion to an oral antibiotic can be considered if the patient has been afebrile for 48 hours or after 3 to 5 days of IV therapy.

69. TREATMENT The choice of antibiotics in CBP should include those agents that are capable of crossing the prostatic epithelium into the prostatic fluid in therapeutic concentrations and that also possess the spectrum of activity to be effective. Currently, the fluoroquinolones (given for 4 to 6 weeks) appear to provide the best therapeutic option in the management of CBP.

70. Questions?