REVIEW ARTICLE
CURRENTDIAGNOSISANDTREATMENTOF URINARY TRACT INFECTIONS STACY CHILD&
M.D.
From the Department of Urology, University of Alabama, Community Health Sciences, Tuscaloosa, Alabama
Urinary tract infections (UTIs) continue to be a major source of morbidity in the United States, and a major contributor to health care costs. In 1989 they were listed as the prime factor in 284,000 hospitalizations (62.3-37.3 % femalemale), and in 1,562,OOO hospitalizations overall (69-31%).’ UTIs accounted for an estimated 4.89 million physician office visits, up slightly over the previous survey in 1985. Among women of childbearing age, the incidence of UTIs is about 5 to 6 percent.” The annual cost nationally of evaluation and treatment of ambulatory cases alone among women has been estimated at $1 billion3 The high incidence and continued persistence of UTIs call for continued assessment and development of therapies. Short-course therapies, though attractive, deserve ongoing study in particular. Conventional treatment with seven to ten days of oral antibiotics is more likely to bring about side effects, adverse reactions, bacterial resistance, poor compliance, and higher costs4 Because short-course treatment is likely to be variable in its effectiveness, however, physicians need to be aware of patient-related factors influencing outcomes. Newer more potent antibiotics may prove useful for patients receiving short-course therapy, or for those at high risk for infections caused by unusual or resistant pathogens. They have intensified antimicrobial activity and pharmacokinetic profiles, and they concentrate in urine and renal tissues. The newer fluoroquinolones, for example, are effective against a broad spectrum of pathogens and are rarely subject to resistance. Common
Pathogens
While Escherichia coli, the most common pathogen in uncomplicated cases of acute cys-
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titis, is the infecting agent 80 percent to 95 percent of the time,5 microbiologic flora vary with presentation. Staphylococcus saprophyticus, a coagulase-negative nonhemolytic cocci accounting for 5 to 10 percent of uncomplicated cases, is common especially in young women who are sexually active.6z7 Less commonly found are other Enterobacteriaceae, for example Proteus mirabilis or Klebsiella pneumoniae, or other enterococci. Gram-positive cocci may account for 5 to 10 percent of cases8 Negative cultures, which may occur in up to 15 percent of uncomplicated ~ases,~ suggest other pathogens. In a study of women with acute urethral syndrome, Chlamydia trachomatis was isolated in one quarter of women with pyuria whose cultures were negative. lo The preponderance of E. coli as agent in initial infections does not extend to chronic or complicated cases, where more resistant organisms are likely-especially among patients with obstructions or structural abnormalities from whose urine multiple organisms may be isolated.” Infecting agents such as Pseudomonas, Klebsiella, Proteus, Enterobacter, and other Enterobacteriaceae that transform urea into ammonia are harder to eliminate because the increase in urine alkalinity promotes bacterial growth. Toxic by-products of pseudomonal infections can also degrade a clinical picture.8 Cocci are common sources, also, of nosocomial infections, though E. coli is the most commonly isolated organism, Among debilitated patients with indwelling urinary catheters who have been exposed to broad-spectrum antimicrobial therapy, Candida albicans is also a significant pathogen. The incidence of urinary tract infection by resistant organisms is higher among elderly patients, whose susceptibility is often greater
295
TABLE I.
Congenital and metabolic factors undermining host defenses (adapted from Child-s Sl.‘“) Altered Metabolic States
Congenital Factor
Gout Diabetes mellitus Hyperparathyroidism Pregnancy
Vesicoureteral reflux Ureteropelvic junction obstruction Horseshoe kidney Medullary-sponge kidney Polycystic kidney Urethral valves Urethral stenosis Bladder neck obstruction because of underlying disease. Likelihood of bacteriuria is higher among elderly women,re and higher among institutionalized elderly in general. l3 Though the predominant pathogens among women are Enterobacteriaceae,13 grampositive bacteria such as coagulase-negative staphylococci and enterococci are the more common agents among elderly men.‘* Among the elderly, UTIs often involve multiple organisms. 153
Normal Defenses Without therapy, many simple bladder infections disappear on their own because of inherent protections against them. The lower urinary tract normally inhibits growth of organisms of the normal urethral flora and of invading coliform bacteria through its physiologic acid pH, high or very low osmolality, and its urea and organic acid content. Anti-adherent qualities of the bladder’s mucin layer also help resist infection.” “Washout” action of urine eradicates or dilutes microbes even after they have become established in bladder urine, and polymorphonuclear leukocytes eliminate bacteria trapped in the bladder mucosal lining. The rarity of active infections in undamaged kidneys attest to the strength of their defenses8 The medulla, however, is much more susceptible to infection than the kidney cortex, requiring concentrations as small as 10 organisms as compared with the 100,000 needed for an infection of the cortex.r8 In the medulla, eradication of gram-negative bacteria through leukocyte mobilization, phagocytosis, and complement activity are inhibited by high osmolality and ammonia content. Similarly, the high osmolality in the medulla favors cell wall-deficient bacterial variants resistant to antimicrobials. While the long urethra of the male urinary tract situated far from the coliform-laden anus 296
offers protection from bacterial colonization, defenses can be lowered by numerous urinary tract abnormalities. These may include the presence of calculi, immunosuppression resulting from illness or drug therapy, or either the congenital defects or altered metabolic states listed in Table I. Organisms that succeed in colonizing the urinary tract appear to have a greater ability to adhere to the mucosal surfaces than those occurring elsewhere, apparently because their pili (fimbria) resist “washout” by the urinary stream .4 Pathogenesis Usually UTIs begin in the urethra and spread to the bladder. Among women, sexual intercourse-induced urethral trauma and bacterial inoculation are the most common causes. Enteric bacteria transit retrograde from the rectum to the perineum, vulva, and urethra. Though coliform bacteria are not usually harbored in the vaginal introitus or urethra among premenopausal women, when these areas do become colonized, patients can become intermittently symptomatic. le Single organisms are generally responsible; when multiple organisms are isolated from urine with such bladder infections, contamination is usually responsible. Sexual contact is the usual cause of UT1 among men as well, and young adults with multiple partners are especially vulnerable.20 Compromised host defenses may permit spread of infection to the kidney via the ureter. Factors allowing ascent of infection include ureteral reflux induced by the infection itself, or abnormal ureterovesical valve function, and interference with normal ureteral peristalsis, also caused by the initial infection. Bacteria can ultimately reach the parenchyma and spread to the collecting tubules, if infected urine penetrates the renal pelvis through Bellini’s ducts at
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the tip of the papillae.* UT1 arises occasionally from the blood stream in conjunction with focal gastrointestinal infection, ulceration or colitis, or infected teeth or tonsils.
Diagnostic guidelines Though the danger of catheter-induced infection has been reported to be as high as 20 percent in hospital settings,21 urine collection through urethral catheterization is accurate and safe in office settings.22 For men, a midstream sample suffices, while for women falsepositive results caused by fecal and vaginal contamination make clean-catch urine samples inadequate. However, a trained nurse should be able to collect a single mid-stream voided specimen that will yield more accurate results. The method of choice when culture results are in question is suprapubic bladder aspiration. Though patient resistance makes it an unlikely choice for routine office use, it is safe and relatively painless, and appropriate for newborns, paraplegics, and seriously ill patients. Classifying Patients
Starting Treatment
Approaches to classifying UT1 patients have been evolving gradually. The traditional descriptors for anatomic location and duration of infection (e.g., acute prostatitis or chronic cystitis) have been augmented with etiologic ones with both diagnostic and therapeutic imUncomplicated infections in feplications. males, for example, usually call for minimal therapy and evaluation. Complicated infections usually suggest a predisposing lesion of the urinary tract and require a thorough urologic workup. With recurrent infections, either complicated or uncomplicated, there are symptomatic episodes separated by quiescent periods. They often involve Klebsiella sp, Proteus sp, and Pseudomonas sp, organisms more resistant than those found in initial infections. The infections are often unresponsive to antibiotic therapy, or they reappear after treatment has stopped. When E. coli is responsible for recurrent bacteriuria, it is a more resistant strain than that found in simple, uncomplicated cases. The need for further clarification of recurrent infections brought about the addition of more terms: relapse, reinfection, and superinfection. A relapse is a reinfection with an organism of the same species and strain as that causing the initially treated infection-usually following within a week after therapy has ended. Reinfec-
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tion occurs when recurring infections are caused by different organisms, usually some weeks after completion of treatment. Superinfection is infection by a new and different organism arising during antibiotic therapy. Stamey23 recognized that classifications could provide information indicating disease stage and prognosis and categorized initial infections as either first infections, or unresolved bacteriuria, and recurrent infections as bacterial persistence, or reinfections. The terms were relevant to therapeutic approach, and significant, in particular, because UT1 may vary continually in individual patients over years. I proposed further modifications for added practicality and clarity.‘* The terms bacteriuria and bacterial do not allow for the possibility of other organisms that cause UT1 and are better replaced with infections. Furthermore, terms indicating location are relevant to patient status. Thus classifications such as unresolved cystitis, reinfection prostatitis, and initial pyelonephritis supply a maximum of pertinent information.
40, NUMBER 4
Although Stamey23 and Stamm24 showed that correctly collected urine samples with counts as low as lo2 bacteria per mL may indicate significant infection, the long-established acceptance of counts of lo5 bacteria per mL as the threshold of UT1 persists. As a consequence, when physicians hold to that standard, about one in five UTIs among patients seen in office practice are not diagnosed.22 Presenting signs and symptoms, and colony counts in urine affect the decision to treat UTI. While patients frequently present with dysuria and frequency, some may have asymptomatic bacteriuria. Symptomatic females with 2 lo2 CFU coliforms or ~10~ CFU of noncoliforms per mL of urine should be treated. Males should be treated if they are symptomatic with counts of ~10~ CFU. Asymptomatic patients with consecutive specimens showing 2 lo5 should be treated, as should catheterized patients with counts 2 lo2 CFU. Low counts obtained via suprapubic aspiration also should be considered significant.25 While acute uncomplicated infections are usually responsive to antimicrobial therapy, chronic and/or complicated infections need more aggressive and/or longer treatment. Clinicians should be alert to factors suggesting occult or complicated infections in their evaluations.
297
TABLE II. Parameter
Characteristics of antimicrobiakr commonly wed for treating uncomplicated UTI * Sulfamethoxazole
Frequency of resistance Urine concentration Half-life in urine Intestinal/vaginal effect coliformes Side effects cost
NitroAmoxicillin furantoin
Amoxicillinl Clavulanate
Cotrimoxazole 5-15 % High +++
25% High +++
30% High ++
5-15% High +
5% High ++
+
+
-
L+Oi
LfOi
L+OG
+ +++ High
Fluoroquinolones Cephalosporin (2%) High +++
+++
+++
L+Oi
Hiih
2-20 % High i-i + Modk+high
KEY: - = no apparent effect, + = short or minimal effect, + + = moderate effect, + + + = long, strong or frequent effect. *Adamed with nermissionfrom Childs ST: Current conceots in the treatment of urinary tract infectionsand prostatitis, Am J Med (Suppl6A) 91: 12G-122 (1991). -
These include: male sex, pregnancy, hospitalization, indwelling urinary catheter, recent instrumentation, urinary tract structural abnormality, history of childhood infections, recent antimicrobials, diabetes, symptoms lasting seven days or more, and immunosuppression.5 Choosing Antimicrobial
Agents
Patient characteristics, and severity of UT1 affect selection of antibiotics. The ideal choice balances the need for antimicrobial activity to cover the spectrum of common strains found in the clinical setting while avoiding nonpathogenie colonizers such as anaerobic flora and lactobacilli. Safety profiles and cost, as well as attainability of sufficient urine/tissue concentrations over minimum inhibitory concentrations of pathogens enter into choices of antimicrobials. Characteristics of several drug classes commonly used for UT1 are listed in Table II. Duration of treatment In establishing treatment duration within the usual range of one to ten days, several factors need to be considered. The attractiveness of the shorter range is based generally on convenience and lack of adverse reactions (both of which affect compliance) and cost, while the longer term usually offers greater effectiveness. For acute cystitis, the single dose regimens are popular, but have been shown to produce results inferior to multidose regimens.ge When there are also occult upper urinary tract infections, response rates may be unacceptably 10~2’ (acute pyelonephritis may occur in one third of acute cystitis patients2g). Some researchers have concluded that three to five-day regimens balance the need for effectiveness against the likelihood of adverse reactions.27*2g The risk of single-
298
dose therapies failing is increased by recent histories of UTI, use of diaphragm/spermicide, and >105 CFU/mL.2g Fluoroquinolones, as a drug class, have desirable characteristics: they are absorbed orally; they are active against a broad spectrum of microbes; and they have favorable pharmacologic properties. Bacterial resistance tends to occur infrequently and at low levels.2e A multicentered trial (n = 162 evaluable patients) compared the efficacy of oral ofloxacin (200 mg q 12 h) given for three or seven days with that of trimethoprimlsulfamethoxazole (MO:800 b.i.d. for 7 days) in women with uncomplicated urinary tract infections. Cure rates were similar among treatment groups, with an 88 percent cure rate in the ofloxacin three-day group, 86 percent in the ofloxacin seven-day group, and 88 percent in the trimethoprim/sulfamethoxazole group. 3o In another series of trials,31 ofloxacin tablets were administered every twelve hours for ten days to patients with complicated urinary tract infections. In one study, ofloxacin was compared with trimethoprim/sulfamethoxazole given b.i.d. for ten days, and in the other to oral carbenicillin administered q.i.d. for ten days. In the first study, 96 percent of patients had a clinical response following treatment with ofloxacin compared with 92 percent treated with trimethoprim/sulfamethoxazole. In the second study, 100 percent of the ofloxacin-treated patients and 75 percent of those treated with carbenicillin had a clinical response . The results of these studies indicate that ofloxacin, a novel fluoroquinolone antibiotic, is as effective as trimethoprim/sulfamethoxazole and oral carbenicillin when given for three or seven days for uncomplicated UTIs and for ten days for complicated infections.
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Consideration of previously identified pathogens and their susceptibilities affects therapy selection with complicated or recurrent infections. Where longer regimens are required, as in severe infections, antimicrobials with low resistance potential and good tissue concentrations are desirable. Pathogens causing acute cystitis in men have the same susceptibility as those occurring in cystitis among women5 and can be treated similarly (with the exclusion of administration of nitrofurantoin, which has poor tissue concentrations) . Because of the greater likelihood of an occult complicating factor in men,5 a regimen of seven to ten days is recommended, however. Relapse or reinfection should arouse suspicion of prostatitis or upper urinary tract infection and call for treatment for four to six weeks31 Such a course should suffice for acute bacterial prostatitis. However, chronic cases call for treatment with proved agents such as cotrimoxazole or a fluoroquinolone for up to twentyfour weeks. Chlamydia or Ureaplasma may be the causative agent when no bacterial pathogen is identified. Although many quinolones are not useful against nongonococcal urethritis, ofloxacin has been shown to be as effective as doxycycline against Chlamydia trachomatis.33
tions, J Clin Microbial 17: 267 (1983). 7. Hovelius B, and March P: Staphylococcus saprophyticus as a common cause of urinary tract infections, Rev Infect Dis 6: 328 (1984). 8. Seneca H: Urinary tract infections: etiology, microbiology, pathophysiology, diagnosis and management, J Am Geriatr Sot 29: 359 (1981). 9. Ronald AR, and Conway B: An approach to urinary tract infections in ambulatory women, Curr Clin Top Infect Dis 9: 76 (1988). 10. Stamm WE, et al: Causes of the acute urethral syndrome in women, N Enel I Med 303: 408 (1980). 11. Sobel JD, &d Kaye D: Urinary tract infections, in Mandell CL, Douglas RG Jr, and Bennett JE (Eds): Principles and Practice of Infectious Diseases, ed 3, New York, Churchill Livingstone, 1990, pp 582-611. 12. Boscia JA, et al: Epidemiology of bacteriuria in an elderly ambulatory population, Am J Med 80: 208 (1986). 13. Kaye D: Urinary tract infections in the elderly, Bull NY Acad Med 56: 209 (1980). 14. Lipsky BA, et al: Diagnosis of bacteriuria in men: specimen collection and culture interpretation, J Infect Dis 155: 847 (1987). 15. Nicolle LE, Mayhew WJ, and Bryan L: Prospective, randomized comparison of therapy and no therapy for asymptomatic bacteriuria in an institutionalized elderly woman, Am J Med 83: 27 (1987). 16. Nicolle LE, et al: Localization of UT1 in elderly institutionalized women with asymptomatic bacteriuria, J Infect Dis 157: 65 (1988). 17. Parsons LC: Lower urinary tract infections in females, Hosp Med 27: 28 (1991). 18. Childs SJ: The diagnosis and classification of urinary tract infections, Clin Ther (Suppl B) 7: 1 (1985). 19. Stamey TA, d al: Recurrent urinary infections in adult women: the role of introital enterobacteria, Calif Med 115: 1 (1971). 20. Fowler JE Jr; Urethritis in men, Semin Ural 9: 15 (1991). 21. Thiel G, and Spiihler 0: Urinary tract infection by catheter and the so-called infections (episoma) resistance, Schweix Med Wochenschr 95: 1155 (1965). 22. Turck M, Groffe B, and Petersdorf R: The urethral catheter and urinary tract infection, J Urol 88: 834 (1962). 23. Stamey T: Pathogenesis and Treatment of Urinary Tract Infections, Baltimore, Williams & Wilkins, 1980, p 1. 24. Stamm W: Diagnosis of c&form infection in acutely dysuric women, N Engl J Med 307: 463 (1982). 25. Johnson CC: Definitions, classification, and clinical presentation of urinary tract infection, Med Clin North Am 75: 241 (1991). 26. Hooper DC, and Wolfson JS: Fluoroquinolone antimicrobial agents, N Engl J Med 24: 384 (1991). 27. Norrby SR: Short-term treatment of uncomplicated urinary tract infections in women, Rev Infect Dis 12: 458 (1990). 28. Johnson JR, and Stamm WE: Urinary tract infections in women; diagnosis and treatment, Ann Intern Med 111: 906 (1989). 29. Fihn SD, et al: Trimethoprim-sulfamethoxazole for acute dysuria in women: a single-dose or lo-day course, Ann Intern Med 108: 350 (1988). 30. Hooton TM, et a2: Ofloxacin versus trimethoprim/sulfamethoxazole for treatment of acute cystitis, Antimicrob Agents Chemother 33: 1308 (1989). 31. Cox CE: Ofloxacin in the management of complicated urinary tract infections, including prostatitis, Am J Med (Suppl 6C) 87: 61s (1989). 32. Meares EM Jr: Prostatitis, Med Clin North Am 75: 405 (1991). 33. Batteiger BE, Jones RB, and White A: Efficacy and safety of ofloxacin in the treatment of nongonococcal sexually transmitted disease, Am J Med (Suppl6C) 87: 75s (1989).
Conclusion Careful diagnosis of UT1 and identification of likely pathogens will guide an appropriate choice of antimicrobials. While UT1 persists as a widespread problem in many patient groups, newer agents are helpful-though longer courses of therapy are still required for some infections. 1006 First North Street, Suite 203 Post Office Box 985 Alabaster, Alabama 35007 References 1. National Hospital Discharge Survey, National Center for Health Statistics, 1989. 2. Mulholland SC: Controversies in management of urinary tract infection, Urology 27: 3 (1986). 3. Johnson JR, and Stamm WE: Diagnosis and treatment of acute urinarv tract infections, Infect Dis Clin North Am 1: 773 (1987). ’ 4. Iravani A: Advances in the understanding and treatment of urinary tract infections in young women, Urology 37: 506 (1991). 5. Hooton TM. and Stamm WE: Management of acute uncomplicated urinary tract infection in adults;Med Clin North Am 75: 339 (1991). . 6. Nicolle LE, Hoban SA, and Harding GKM: Characterixation of coagulase-negative staphylococci from urinary tract infec-
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299
CURRENTDIAGNOSISANDTREATMENTOF URINARY TRACT INFECTIONS STACY CHILD&
M.D.
From the Department of Urology, University of Alabama, Community Health Sciences, Tuscaloosa, Alabama
Urinary tract infections (UTIs) continue to be a major source of morbidity in the United States, and a major contributor to health care costs. In 1989 they were listed as the prime factor in 284,000 hospitalizations (62.3-37.3 % femalemale), and in 1,562,OOO hospitalizations overall (69-31%).’ UTIs accounted for an estimated 4.89 million physician office visits, up slightly over the previous survey in 1985. Among women of childbearing age, the incidence of UTIs is about 5 to 6 percent.” The annual cost nationally of evaluation and treatment of ambulatory cases alone among women has been estimated at $1 billion3 The high incidence and continued persistence of UTIs call for continued assessment and development of therapies. Short-course therapies, though attractive, deserve ongoing study in particular. Conventional treatment with seven to ten days of oral antibiotics is more likely to bring about side effects, adverse reactions, bacterial resistance, poor compliance, and higher costs4 Because short-course treatment is likely to be variable in its effectiveness, however, physicians need to be aware of patient-related factors influencing outcomes. Newer more potent antibiotics may prove useful for patients receiving short-course therapy, or for those at high risk for infections caused by unusual or resistant pathogens. They have intensified antimicrobial activity and pharmacokinetic profiles, and they concentrate in urine and renal tissues. The newer fluoroquinolones, for example, are effective against a broad spectrum of pathogens and are rarely subject to resistance. Common
Pathogens
While Escherichia coli, the most common pathogen in uncomplicated cases of acute cys-
UROLOGY
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/ VOLUME
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titis, is the infecting agent 80 percent to 95 percent of the time,5 microbiologic flora vary with presentation. Staphylococcus saprophyticus, a coagulase-negative nonhemolytic cocci accounting for 5 to 10 percent of uncomplicated cases, is common especially in young women who are sexually active.6z7 Less commonly found are other Enterobacteriaceae, for example Proteus mirabilis or Klebsiella pneumoniae, or other enterococci. Gram-positive cocci may account for 5 to 10 percent of cases8 Negative cultures, which may occur in up to 15 percent of uncomplicated ~ases,~ suggest other pathogens. In a study of women with acute urethral syndrome, Chlamydia trachomatis was isolated in one quarter of women with pyuria whose cultures were negative. lo The preponderance of E. coli as agent in initial infections does not extend to chronic or complicated cases, where more resistant organisms are likely-especially among patients with obstructions or structural abnormalities from whose urine multiple organisms may be isolated.” Infecting agents such as Pseudomonas, Klebsiella, Proteus, Enterobacter, and other Enterobacteriaceae that transform urea into ammonia are harder to eliminate because the increase in urine alkalinity promotes bacterial growth. Toxic by-products of pseudomonal infections can also degrade a clinical picture.8 Cocci are common sources, also, of nosocomial infections, though E. coli is the most commonly isolated organism, Among debilitated patients with indwelling urinary catheters who have been exposed to broad-spectrum antimicrobial therapy, Candida albicans is also a significant pathogen. The incidence of urinary tract infection by resistant organisms is higher among elderly patients, whose susceptibility is often greater
295
TABLE I.
Congenital and metabolic factors undermining host defenses (adapted from Child-s Sl.‘“) Altered Metabolic States
Congenital Factor
Gout Diabetes mellitus Hyperparathyroidism Pregnancy
Vesicoureteral reflux Ureteropelvic junction obstruction Horseshoe kidney Medullary-sponge kidney Polycystic kidney Urethral valves Urethral stenosis Bladder neck obstruction because of underlying disease. Likelihood of bacteriuria is higher among elderly women,re and higher among institutionalized elderly in general. l3 Though the predominant pathogens among women are Enterobacteriaceae,13 grampositive bacteria such as coagulase-negative staphylococci and enterococci are the more common agents among elderly men.‘* Among the elderly, UTIs often involve multiple organisms. 153
Normal Defenses Without therapy, many simple bladder infections disappear on their own because of inherent protections against them. The lower urinary tract normally inhibits growth of organisms of the normal urethral flora and of invading coliform bacteria through its physiologic acid pH, high or very low osmolality, and its urea and organic acid content. Anti-adherent qualities of the bladder’s mucin layer also help resist infection.” “Washout” action of urine eradicates or dilutes microbes even after they have become established in bladder urine, and polymorphonuclear leukocytes eliminate bacteria trapped in the bladder mucosal lining. The rarity of active infections in undamaged kidneys attest to the strength of their defenses8 The medulla, however, is much more susceptible to infection than the kidney cortex, requiring concentrations as small as 10 organisms as compared with the 100,000 needed for an infection of the cortex.r8 In the medulla, eradication of gram-negative bacteria through leukocyte mobilization, phagocytosis, and complement activity are inhibited by high osmolality and ammonia content. Similarly, the high osmolality in the medulla favors cell wall-deficient bacterial variants resistant to antimicrobials. While the long urethra of the male urinary tract situated far from the coliform-laden anus 296
offers protection from bacterial colonization, defenses can be lowered by numerous urinary tract abnormalities. These may include the presence of calculi, immunosuppression resulting from illness or drug therapy, or either the congenital defects or altered metabolic states listed in Table I. Organisms that succeed in colonizing the urinary tract appear to have a greater ability to adhere to the mucosal surfaces than those occurring elsewhere, apparently because their pili (fimbria) resist “washout” by the urinary stream .4 Pathogenesis Usually UTIs begin in the urethra and spread to the bladder. Among women, sexual intercourse-induced urethral trauma and bacterial inoculation are the most common causes. Enteric bacteria transit retrograde from the rectum to the perineum, vulva, and urethra. Though coliform bacteria are not usually harbored in the vaginal introitus or urethra among premenopausal women, when these areas do become colonized, patients can become intermittently symptomatic. le Single organisms are generally responsible; when multiple organisms are isolated from urine with such bladder infections, contamination is usually responsible. Sexual contact is the usual cause of UT1 among men as well, and young adults with multiple partners are especially vulnerable.20 Compromised host defenses may permit spread of infection to the kidney via the ureter. Factors allowing ascent of infection include ureteral reflux induced by the infection itself, or abnormal ureterovesical valve function, and interference with normal ureteral peristalsis, also caused by the initial infection. Bacteria can ultimately reach the parenchyma and spread to the collecting tubules, if infected urine penetrates the renal pelvis through Bellini’s ducts at
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/ VOLUME40,NUMBER4
the tip of the papillae.* UT1 arises occasionally from the blood stream in conjunction with focal gastrointestinal infection, ulceration or colitis, or infected teeth or tonsils.
Diagnostic guidelines Though the danger of catheter-induced infection has been reported to be as high as 20 percent in hospital settings,21 urine collection through urethral catheterization is accurate and safe in office settings.22 For men, a midstream sample suffices, while for women falsepositive results caused by fecal and vaginal contamination make clean-catch urine samples inadequate. However, a trained nurse should be able to collect a single mid-stream voided specimen that will yield more accurate results. The method of choice when culture results are in question is suprapubic bladder aspiration. Though patient resistance makes it an unlikely choice for routine office use, it is safe and relatively painless, and appropriate for newborns, paraplegics, and seriously ill patients. Classifying Patients
Starting Treatment
Approaches to classifying UT1 patients have been evolving gradually. The traditional descriptors for anatomic location and duration of infection (e.g., acute prostatitis or chronic cystitis) have been augmented with etiologic ones with both diagnostic and therapeutic imUncomplicated infections in feplications. males, for example, usually call for minimal therapy and evaluation. Complicated infections usually suggest a predisposing lesion of the urinary tract and require a thorough urologic workup. With recurrent infections, either complicated or uncomplicated, there are symptomatic episodes separated by quiescent periods. They often involve Klebsiella sp, Proteus sp, and Pseudomonas sp, organisms more resistant than those found in initial infections. The infections are often unresponsive to antibiotic therapy, or they reappear after treatment has stopped. When E. coli is responsible for recurrent bacteriuria, it is a more resistant strain than that found in simple, uncomplicated cases. The need for further clarification of recurrent infections brought about the addition of more terms: relapse, reinfection, and superinfection. A relapse is a reinfection with an organism of the same species and strain as that causing the initially treated infection-usually following within a week after therapy has ended. Reinfec-
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tion occurs when recurring infections are caused by different organisms, usually some weeks after completion of treatment. Superinfection is infection by a new and different organism arising during antibiotic therapy. Stamey23 recognized that classifications could provide information indicating disease stage and prognosis and categorized initial infections as either first infections, or unresolved bacteriuria, and recurrent infections as bacterial persistence, or reinfections. The terms were relevant to therapeutic approach, and significant, in particular, because UT1 may vary continually in individual patients over years. I proposed further modifications for added practicality and clarity.‘* The terms bacteriuria and bacterial do not allow for the possibility of other organisms that cause UT1 and are better replaced with infections. Furthermore, terms indicating location are relevant to patient status. Thus classifications such as unresolved cystitis, reinfection prostatitis, and initial pyelonephritis supply a maximum of pertinent information.
40, NUMBER 4
Although Stamey23 and Stamm24 showed that correctly collected urine samples with counts as low as lo2 bacteria per mL may indicate significant infection, the long-established acceptance of counts of lo5 bacteria per mL as the threshold of UT1 persists. As a consequence, when physicians hold to that standard, about one in five UTIs among patients seen in office practice are not diagnosed.22 Presenting signs and symptoms, and colony counts in urine affect the decision to treat UTI. While patients frequently present with dysuria and frequency, some may have asymptomatic bacteriuria. Symptomatic females with 2 lo2 CFU coliforms or ~10~ CFU of noncoliforms per mL of urine should be treated. Males should be treated if they are symptomatic with counts of ~10~ CFU. Asymptomatic patients with consecutive specimens showing 2 lo5 should be treated, as should catheterized patients with counts 2 lo2 CFU. Low counts obtained via suprapubic aspiration also should be considered significant.25 While acute uncomplicated infections are usually responsive to antimicrobial therapy, chronic and/or complicated infections need more aggressive and/or longer treatment. Clinicians should be alert to factors suggesting occult or complicated infections in their evaluations.
297
TABLE II. Parameter
Characteristics of antimicrobiakr commonly wed for treating uncomplicated UTI * Sulfamethoxazole
Frequency of resistance Urine concentration Half-life in urine Intestinal/vaginal effect coliformes Side effects cost
NitroAmoxicillin furantoin
Amoxicillinl Clavulanate
Cotrimoxazole 5-15 % High +++
25% High +++
30% High ++
5-15% High +
5% High ++
+
+
-
L+Oi
LfOi
L+OG
+ +++ High
Fluoroquinolones Cephalosporin (2%) High +++
+++
+++
L+Oi
Hiih
2-20 % High i-i + Modk+high
KEY: - = no apparent effect, + = short or minimal effect, + + = moderate effect, + + + = long, strong or frequent effect. *Adamed with nermissionfrom Childs ST: Current conceots in the treatment of urinary tract infectionsand prostatitis, Am J Med (Suppl6A) 91: 12G-122 (1991). -
These include: male sex, pregnancy, hospitalization, indwelling urinary catheter, recent instrumentation, urinary tract structural abnormality, history of childhood infections, recent antimicrobials, diabetes, symptoms lasting seven days or more, and immunosuppression.5 Choosing Antimicrobial
Agents
Patient characteristics, and severity of UT1 affect selection of antibiotics. The ideal choice balances the need for antimicrobial activity to cover the spectrum of common strains found in the clinical setting while avoiding nonpathogenie colonizers such as anaerobic flora and lactobacilli. Safety profiles and cost, as well as attainability of sufficient urine/tissue concentrations over minimum inhibitory concentrations of pathogens enter into choices of antimicrobials. Characteristics of several drug classes commonly used for UT1 are listed in Table II. Duration of treatment In establishing treatment duration within the usual range of one to ten days, several factors need to be considered. The attractiveness of the shorter range is based generally on convenience and lack of adverse reactions (both of which affect compliance) and cost, while the longer term usually offers greater effectiveness. For acute cystitis, the single dose regimens are popular, but have been shown to produce results inferior to multidose regimens.ge When there are also occult upper urinary tract infections, response rates may be unacceptably 10~2’ (acute pyelonephritis may occur in one third of acute cystitis patients2g). Some researchers have concluded that three to five-day regimens balance the need for effectiveness against the likelihood of adverse reactions.27*2g The risk of single-
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dose therapies failing is increased by recent histories of UTI, use of diaphragm/spermicide, and >105 CFU/mL.2g Fluoroquinolones, as a drug class, have desirable characteristics: they are absorbed orally; they are active against a broad spectrum of microbes; and they have favorable pharmacologic properties. Bacterial resistance tends to occur infrequently and at low levels.2e A multicentered trial (n = 162 evaluable patients) compared the efficacy of oral ofloxacin (200 mg q 12 h) given for three or seven days with that of trimethoprimlsulfamethoxazole (MO:800 b.i.d. for 7 days) in women with uncomplicated urinary tract infections. Cure rates were similar among treatment groups, with an 88 percent cure rate in the ofloxacin three-day group, 86 percent in the ofloxacin seven-day group, and 88 percent in the trimethoprim/sulfamethoxazole group. 3o In another series of trials,31 ofloxacin tablets were administered every twelve hours for ten days to patients with complicated urinary tract infections. In one study, ofloxacin was compared with trimethoprim/sulfamethoxazole given b.i.d. for ten days, and in the other to oral carbenicillin administered q.i.d. for ten days. In the first study, 96 percent of patients had a clinical response following treatment with ofloxacin compared with 92 percent treated with trimethoprim/sulfamethoxazole. In the second study, 100 percent of the ofloxacin-treated patients and 75 percent of those treated with carbenicillin had a clinical response . The results of these studies indicate that ofloxacin, a novel fluoroquinolone antibiotic, is as effective as trimethoprim/sulfamethoxazole and oral carbenicillin when given for three or seven days for uncomplicated UTIs and for ten days for complicated infections.
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Consideration of previously identified pathogens and their susceptibilities affects therapy selection with complicated or recurrent infections. Where longer regimens are required, as in severe infections, antimicrobials with low resistance potential and good tissue concentrations are desirable. Pathogens causing acute cystitis in men have the same susceptibility as those occurring in cystitis among women5 and can be treated similarly (with the exclusion of administration of nitrofurantoin, which has poor tissue concentrations) . Because of the greater likelihood of an occult complicating factor in men,5 a regimen of seven to ten days is recommended, however. Relapse or reinfection should arouse suspicion of prostatitis or upper urinary tract infection and call for treatment for four to six weeks31 Such a course should suffice for acute bacterial prostatitis. However, chronic cases call for treatment with proved agents such as cotrimoxazole or a fluoroquinolone for up to twentyfour weeks. Chlamydia or Ureaplasma may be the causative agent when no bacterial pathogen is identified. Although many quinolones are not useful against nongonococcal urethritis, ofloxacin has been shown to be as effective as doxycycline against Chlamydia trachomatis.33
tions, J Clin Microbial 17: 267 (1983). 7. Hovelius B, and March P: Staphylococcus saprophyticus as a common cause of urinary tract infections, Rev Infect Dis 6: 328 (1984). 8. Seneca H: Urinary tract infections: etiology, microbiology, pathophysiology, diagnosis and management, J Am Geriatr Sot 29: 359 (1981). 9. Ronald AR, and Conway B: An approach to urinary tract infections in ambulatory women, Curr Clin Top Infect Dis 9: 76 (1988). 10. Stamm WE, et al: Causes of the acute urethral syndrome in women, N Enel I Med 303: 408 (1980). 11. Sobel JD, &d Kaye D: Urinary tract infections, in Mandell CL, Douglas RG Jr, and Bennett JE (Eds): Principles and Practice of Infectious Diseases, ed 3, New York, Churchill Livingstone, 1990, pp 582-611. 12. Boscia JA, et al: Epidemiology of bacteriuria in an elderly ambulatory population, Am J Med 80: 208 (1986). 13. Kaye D: Urinary tract infections in the elderly, Bull NY Acad Med 56: 209 (1980). 14. Lipsky BA, et al: Diagnosis of bacteriuria in men: specimen collection and culture interpretation, J Infect Dis 155: 847 (1987). 15. Nicolle LE, Mayhew WJ, and Bryan L: Prospective, randomized comparison of therapy and no therapy for asymptomatic bacteriuria in an institutionalized elderly woman, Am J Med 83: 27 (1987). 16. Nicolle LE, et al: Localization of UT1 in elderly institutionalized women with asymptomatic bacteriuria, J Infect Dis 157: 65 (1988). 17. Parsons LC: Lower urinary tract infections in females, Hosp Med 27: 28 (1991). 18. Childs SJ: The diagnosis and classification of urinary tract infections, Clin Ther (Suppl B) 7: 1 (1985). 19. Stamey TA, d al: Recurrent urinary infections in adult women: the role of introital enterobacteria, Calif Med 115: 1 (1971). 20. Fowler JE Jr; Urethritis in men, Semin Ural 9: 15 (1991). 21. Thiel G, and Spiihler 0: Urinary tract infection by catheter and the so-called infections (episoma) resistance, Schweix Med Wochenschr 95: 1155 (1965). 22. Turck M, Groffe B, and Petersdorf R: The urethral catheter and urinary tract infection, J Urol 88: 834 (1962). 23. Stamey T: Pathogenesis and Treatment of Urinary Tract Infections, Baltimore, Williams & Wilkins, 1980, p 1. 24. Stamm W: Diagnosis of c&form infection in acutely dysuric women, N Engl J Med 307: 463 (1982). 25. Johnson CC: Definitions, classification, and clinical presentation of urinary tract infection, Med Clin North Am 75: 241 (1991). 26. Hooper DC, and Wolfson JS: Fluoroquinolone antimicrobial agents, N Engl J Med 24: 384 (1991). 27. Norrby SR: Short-term treatment of uncomplicated urinary tract infections in women, Rev Infect Dis 12: 458 (1990). 28. Johnson JR, and Stamm WE: Urinary tract infections in women; diagnosis and treatment, Ann Intern Med 111: 906 (1989). 29. Fihn SD, et al: Trimethoprim-sulfamethoxazole for acute dysuria in women: a single-dose or lo-day course, Ann Intern Med 108: 350 (1988). 30. Hooton TM, et a2: Ofloxacin versus trimethoprim/sulfamethoxazole for treatment of acute cystitis, Antimicrob Agents Chemother 33: 1308 (1989). 31. Cox CE: Ofloxacin in the management of complicated urinary tract infections, including prostatitis, Am J Med (Suppl 6C) 87: 61s (1989). 32. Meares EM Jr: Prostatitis, Med Clin North Am 75: 405 (1991). 33. Batteiger BE, Jones RB, and White A: Efficacy and safety of ofloxacin in the treatment of nongonococcal sexually transmitted disease, Am J Med (Suppl6C) 87: 75s (1989).
Conclusion Careful diagnosis of UT1 and identification of likely pathogens will guide an appropriate choice of antimicrobials. While UT1 persists as a widespread problem in many patient groups, newer agents are helpful-though longer courses of therapy are still required for some infections. 1006 First North Street, Suite 203 Post Office Box 985 Alabaster, Alabama 35007 References 1. National Hospital Discharge Survey, National Center for Health Statistics, 1989. 2. Mulholland SC: Controversies in management of urinary tract infection, Urology 27: 3 (1986). 3. Johnson JR, and Stamm WE: Diagnosis and treatment of acute urinarv tract infections, Infect Dis Clin North Am 1: 773 (1987). ’ 4. Iravani A: Advances in the understanding and treatment of urinary tract infections in young women, Urology 37: 506 (1991). 5. Hooton TM. and Stamm WE: Management of acute uncomplicated urinary tract infection in adults;Med Clin North Am 75: 339 (1991). . 6. Nicolle LE, Hoban SA, and Harding GKM: Characterixation of coagulase-negative staphylococci from urinary tract infec-
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