From the Department of Obstetrics and Gynecology, Section of Infectious Diseases, Baylor College of Medicine, Houston. Texas

Urinary tract infections are among the oldest and most frequently described conditions seen in community and hospital practice. Acute urinary tract infections are most common among women, affecting an estimated 10 percent to 20 percent of women at some time and accounting for more than 5 million physician visits annually in the United States.’ More than 100,000 of these patients are hospitalized annually in the United States for an average of seven days because of renal infections.” Changing Demographics of Urinary Tract Infections Despite the increasing awareness of the prevalence and clinical importance of urinary tract infections, their diagnosis remains a complex issue. In one prospective study of female patients in a large family practice, an appropriate diagnosis could be made in only 34 percent of the women with genitourinary symptoms evaluated using common office and laboratory procedures; when selected nonroutine laboratory procedures and clinical criteria were employed, a diagnosis could be suggested in 66 percent of the patients.3 For the clinician, a challenging aspect of managing urinary tract infections is the recognition of these infections in a diverse patient population. These infections are widespread among sexually active women and are now clinically important problems among sexually active males and the elderly. Community-acquired urinary tract infections are increasing, with sexual promiscuity often being implicated as a major factor. An association between these infections and the frequency of sexual intercourse has been observed.4 The use of a diaphragm significantly increases the risk of a urinary tract infection de-







veloping,4,s whereas this association has been inconsistent for oral contraceptive or tampon use. Most important is the change in etiology of urinary tract infections observed over the past several decades. While coliform bacteria continue to account for the majority of communityacquired infections, the pathogens implicated in many infections are now associated with sexually transmitted diseases. Infections caused by Neisseria gonorrhoeae, Trichomonas vaginalis, Chlamydia trachomatis, and Ureaplasma are now commonplace. Urinary tract infections in males and epididymitis have also been associated with Escherichia coli, Pseudomonas aeruginosa, HIV, and Staphylococcus saprophyticus, particularly among homosexuals.“msIn general, urinarvi tract infections in older boys and young men are rare and are usually due to bacteria introduced by instrumentation. However, after middle age, the incidence of these infections increases progressively in men, and by age sixty-five, it is similar to that in women.’ These are often associated with an underlying prostatic infection”‘: furthermore, these infections play a major role in the development of community-acquired bacteremia in the elderly of both sexes.” Urinary tract infections remain a significant health problem; with the emergence of new pathogens, the availability of new chemotherapeutic treatment options, and the controversy regarding optimum duration of therapy, their treatment will be subject to continual reassessment. Sites of Urinary Tract Infections Urinary tract infections are most accurately characterized bv their site. Each has its own



unique epidemiology, diagnostic considerations, requirements for therapy, and prognosisn2The determination of the exact site of infection is perhaps the most important factor in the correct management of the infected patient.12 In one survey of women with bacteriuria, the infections were confined to the bladder in half the women and to the kidney in the other half. Symptoms usually regarded as evidence of bladder infection (frequency, burning, suprapubic pain) often were observed only in renal infections. I2 Consequently, determining the site of infection is often difficult. The following provides a brief description of the major clinical svndromes associated with urinary tract infections. Asymptomatic


Asymptomatic urinary tract infections in adults are generally diagnosed following the recovery of >lO” colony-forming units (cfu)/mL of a single bacterial species in at least two consecutive clean voided urine specimens. These infections are often difficult to diagnose and have been associated with serious sequelae. During pregnancy, these infections cause pyelonephritis and low-birth-weight deliveries and increase the risk of perinatal fetal death. Asymptomatic urinary tract infections have been associated with increased mortality rates among adult women in the community and among patients of both sexes in nursing homes. I:{ Asymptomatic bacteriuria due to Streptococcus agalactiae (GBS) in pregnancy is significant. Approximate rates of genital GBS colonization vary and may be as high as 25 percent to 30 percent. 14.15Attack rates in term newborn infants born to colonized mothers is about 1 percent, whereas in the premature, it is 7 percent. However, in the premature infant born to a woman with GBS asymptomatic bacteriuria, the attack rate is 16 percent. rfiIs In addition, the patient who is colonized and delivered by cesarean section is at significant risk to develop postpartum endometritis.2”.“’ The gynecologic patient who is colonized and has a pelvic procedure is also at risk for a postoperative infection. Louxr urinary tract infwtions Most commonly diagnosed as acute cystitis, these infections result from superficial bacterial infection of the bladder, urethra, or both. Dysuria is a primary symptom often accompanied by urinary frequency, nocturia, incontinence, and suprapubic or pelvic pain. The patient, es-


pecially the pregnant patient, in whom sudden onset of urinary frequency develops should also be suspected of having a urinary tract infection. Patients with acute hematuria should also be evaluated for a urinary tract infection. Bacterial infection is responsible for most of these symptoms,22 and bacterial vaginosis and diaphragm use have been further implicated in the development of acute cystitis.“” Many women experience “acute urethral syndrome,” a problematic entity with no clear etiology. About 25 percent of sexually active women have “low-count” bacteriuria and about one half of these are infected with C. trachomatis, N. gonorrhoeae, or E. coli. The syndrome may resolve spontaneously or may require antibiotic therapy.24m2fi Upper urinary tract infections Patients present with the classic symptoms of acute pyelonephritis (localized flank or lowback pain, fever, sweats, headache, nausea, vomiting, prostration) .27 Concomitant symptoms of cystitis may not be present. Among the hospitalized elderly, acute pyelonephritis has been identified as the most common cause of gram-negative bacteremia,28 but appropriate antibacterial therapy confers a 97 percent survival rate to these patients. Adults with pyelonephritis may have mild symptoms permitting the continuation of normal activity, whereas in others significant pain, debility, and complications (i.e., intrarenal abscesses, gram-negative sepsis) may develop. Urinary tract infections are often described as “complicated” or “uncomplicated,” depending on the presence or absence of conditions known to promote infection, account for the persistence of infection, or which promote recurrence.2 Uncomplicated infections primarily affect women and usually respond to conservative therapy. Complicated infections imply a predisposing lesion, such as a stone, stricture, neurogenic bladder, or prostatic involvement. A thorough urologic evaluation is generally required for these infections.2” These distinctions often are made during the evaluation of new antimicrobial agents and carry important prognostic implications. The presence of complicating host factors may contribute to antimicrobial resistance, a reduced response to therapy, or complications of the primary infection. A description of the complicating factors should be provided to adequately assess their effects on therapy.









Finally. rt should be recognized that tract infections are often characterized chronic. recurrent nature. Treatment should consider whether an infection is chronic,. hlicrobiologic Confirming

urinar!. by their options acute or

Criteria for Infection

The cluantitative analysis of urinary bacteria has emerged as a reproducible criteria for the assessment of urinary tract infections. As earl! as 19ri’;. Kas?’ had established that patients \\ith more than 100,000 bacteria/mL of urine could be considered to have true bacteriuria. Further analyses have indicated that this traditional diagnostic criterion was insufficient& sensiti\ce for clinical applications because more than half of the women with acute symptomatic coliform infection had bacterial counts below this level. In one stud]; bacterial counts of > 10’ bacteria/mL of midstream urine identified only Fil percent of women whose bladder lu-ine contained coliforms. The best diagnostic criterion was determined to be > lo* bacteria/ a value which provides good sensitivity, llll,, specificity. and predictabilit!::‘” Various rapid methods arc available to detect bacteriuria using either photometry or bioluminescence. \YhiIe these provide generally sensitive measures of bacterial counts, their sensitivity is unsatisfactor!. in detecting levels of 10” to lo4 bacteria/mL.’ In practice, phvsicians commonl~~ treat patients with dysuria empiricall! based on symptoms.:” and the value of pretreatment Ilrinalysis in symptomatic patients remains debatable. Pathogenesis and Etiolog. Lirinary Tract Infections


The Enterobacteriaceae are responsible for about HO percent of bacterial urinary tract infections. II:. coli. other Enterobacteiiaceae, S. or Enterococcus together acsaprophyticus, count for more than 90 percent of cases of acute lower urinaqr tract infections in uncompromised lmsts.” The Enterococcus is more likely to be found in patients who have received cephalosporin prophylaxis preoperatively. Classically, the pathogenesis of these infections in women has described the colonization of the vaginal introitus and urethra by fecal flora. Sexual interc’oI1rse facilitates migration of the organisms from the urethra into the bladder initiating the infection: ceontinuing ascending spread is be-

lieved to result in pyelonephritis? Although this scheme is believed to describt: the pathogenesis of the majority of community-acquired infections, questions remain regarding its widespread applicability. Additional Factors must be clmsidered including the relative role of bacterj al virulence factors versus host s~lsceptibilit); and the importance of factors that facilitate the progression from introital colonization to actual infection. :I2 S. saprophyticus is the second most common pathogen, being isolated from more than 10 percent of cases of acute cystitis. Both men and women ma>. present with sexually transmitted pathogens including T. vaginalis. N. gonorr:loeae, C. trachomatis, and Lrreaplasma. Klebsiella sp, Enterobacter sp, and Proteus sp account for a small percentage of communitysquired urinary tract infections’. Serratia marcescens, Staphylococcus epidermidis, and P. azruginosa are primarily nosocomial infections which are associated with poor infection-control practices following catheterization or manipulation. Other gram-positive organisms, inc.uding groups B and D streptococci, are responsible for 1 percent to 2 percent of urinaq tract infections.“” Urinary tract infections, particularly in imnlunocompromised hosts. have recently been associated with viral agents such as HIV or herpes virus. Although these agents account for only a small fraction-of urinary infections, the) will undoubtedly contribute to the changing c laracter of these infections. Determining




In the outpatient setting, 80 percent of first infections that are caused by IF:. coli can be treated effectively with a brief course of antibiotic therapy; resistance is generall!. not a significant problem, and only about 25 percent of patients experience a recurrence over the, next of more eighteen months. XJ Hospital treatnlent severe infections may require a three-step approach: stage one typicallv lasts two or three days. In stage one, uncertainty t:xists abollt the nature of the infection and combination therap!. is often given empirically to maximize c:)verage for suspected pathogens: the second stage begins about the third day n-hen sufficient microbiologic and clinical data are available to select a more directed, cost-effective single agent; the third stage begins arollncl the seventh day when the patient is clinicall!. stable and afebrile, at which time parentclral antibiotics

are switched to oral forms.33 This approach to therapy permits the “streamlining” of antibiotic selection (converting from a more complex to a less complex regimen) which in one study resulted in projected annual savings exceeding $107,000.33 Perhaps the most perplexing questions center on the most appropriate duration of therapy for urinary tract infections. Lower urinary tract infections often clear spontaneously, and small doses of an antibacterial, which produce subincan further enhance the hibitory levels, clearing.34 The development of single-dose therapy has contributed significantly to the understanding of these infections. Typically, more than 90 percent of women with documented lower urinary tract infections are cured by single-dose therapy if the organism is susceptible.34 Best studied single-dose regimens include amoxicillin or a combination of trimethoprim/ sulfamethoxazole (TMP/SMZ). Single-dose therapy is considered the treatment of choice in female patients with acute uncomplicated urinary tract infections because of its effectiveness, tolerability, compliance, and low cost.3s Despite this consensus, there is still considerable use of longer therapy regimens (including 3-, 7-, and lo-day treatments), and the relative merit of these regimens has been the subject of intense investigation. For example, in women with lower urinary tract infections, a three-day course of TMPlSMZ therapy was as effective as a seven-day course . 36Even among patients with upper tract infections, single-dose therapy with ofloxacin has been effective in eradicating susceptible organisms, and its efficacy has been found to be comparable to that of a three-day course. 37 Because of the general effectiveness of these short-term regimens, a therapeutic failure is often considered diagnostic for the presence of a more deep-seated or complicated renal infection. Upper urinary tract disease is characterized by an entrenched infection of the renal medulla, an area particularly susceptible to infection because of decreased flow and hypertonicity that inhibit exudation of leukocytes, prevent killing of bacteria by antibody complement, and allow the survival of damaged bacterial variants.34 These factors may contribute to the failure of some single-dose regimens. Consequently, controversy surrounds the optimal duration of treatment of upper and lower urinary tract infections. In general, these upper urinary tract and resistant lower urinary tract


infections can be managed effectively with the short-term administration of parenteral or oral agents including the aminoglycosides, widespectrum penicillin derivatives, third-generation cephalosporins, or one of the new fluoroquinolones. Three major factors determine the microbiologic activity of an antibiotic. First, the drug must bind at an effective level to some region on the microorganism; to effectively interfere with the growth cycle of the microorganism, the drug must remain bound to the cell for a critical period of time; and the drug must reach and selecting a penetrate the cell wall .38 Therefore, drug whose pharmacokinetic parameters enhance microbiologic activity contributes to a cost-effective treatment regimen. 38 When comparing drugs within a class, generally those that are most completely absorbed, achieve higher peak serum concentrations, and have longer terminal elimination half-lives may be of most clinical value.3g Newer agents such as the fluoroquinolones and the oral third-generation cephalosporins offer good oral bioavailability providing suitable alternatives to parenteral treatment. The broad spectrum of these agents also contributes to their clinical effectiveness. Many antimicrobial agents may cause major changes in fecal bacterial flora resulting in bacterial overgrowth or gastrointestinal disturbances, and a drug’s propensity to affect fecal flora also should be considered when selecting an antibiotic regimen.40 New agents in treatment of urinary tract infections The selection of the most appropriate drug and regimen should be based on a number of factors, including the site of infection, etiologic agent, age of the patient, complicating host factors, and history of the infection.32 A number of effective antibiotics from several diverse classes are available for the treatment of urinary tract infections, the most frequently used being TMP/SMZ combinations, amoxicillin (alone or in combination with clavulanic acid), the cephalosporins (particularly the third-generation members), and the quinolones.41 While the erythromycins, penems, and monobactams are of clinical value in certain clinical situations, the majority of urinary tract infections can be controlled effectively with one of the following antibiotics. Trimethoprim/sulfamethoxaxole. TMPiSMZ has become a widely used agent for urinary




tract infections because of its long duration of antimicrobial activity and its broad spectrum of activiti. against most coliform bacteria, S. saprophf.ticus, and C. trachomatis.“’ Single-dose therapy \+.ith this product has been found to be less effecti\~e than a ten-day course.“’ Among 136 women treated for uncomplicated urinary infections. 10 of 68 who received single-dose therap!. had a relapse of infection compared with 2 of 68 who received the drug for ten days iP symptom in women in a family practice, J AM.4 251: 620 (19841. 4. Strom RI,, catal: Sexual activity. cwntrwt~ptiw t~se. and



other risk factors for symptomatic and asymptomatic bactcriuria: a cast controlled study, Ann Intern Med 107: 816 (1987). 5. Fihn SD, et (11: Association hetween diaphragm use and urinary tract infection, JAMA 254: 240 (1985). 6. Curran JW: Gonorrhea and the urethral syndrome, Sex Transm Dis 4: 119 (1977). 7. Berger RE, Kessler D, and Holmes KK: Etiology and manifestations of epididymitis in young men: correlations with sexual orientation, J Infect Dis 155: 1341 (1987). 8. Barnes RC, Daifuku R, Roddy RE. and Stamm WE: Urinary tract infection in sexually active homosexual men, Lancet 2: 171 (1986). 9. Lipsky BA: Urinary tract infections in men: cpidemiolog): pathophysiology, diagnosis, and treatment, Ann Intern Med 110: 138 (1989). 10. Clarke M, Pead L, and Maskell R: Urinary infection in adult men: a laboratory perspective, Br J Ural 57: 222 (1985). bacteremia in the 11. Esposito AI,, ct al: Community-acquired elderly: analysis of 100 consecutive episodes, J Am Ceriatr Sot 28: ,315 (1980). 12. Fairly KF, d al: Site of infection in acute urinary-tract irrfectian in general practice, Lancet 1: 615 (1971). 13. Platt R: Adverse consequences of asymptomatic urinaq tract infections in adults, Am J Med (Suppl 6B) 82: 47 (1987). 14. Baker CJ, and Barrett FF: Transmission of group B streptococci among parturient women and their neonates, J Pediatrics 83: 919 (1973). 15. Wood EG, and Dillion MC: .4 prospective study of group B streptococcal hacteriuria in pregnancy, Am J Obstet Cynccol 140: 515 (1981). 16. Moller M, ct al: Rupture of fetal membranes and prcmature delivery associated with group B streptococci in urine of pregnant women. Lancet 2: 69 (1984). 17. Baker CJ: Summary of the workshop on pcrinatal infection due to Group B streptococcus, J Infect Dis 136: 137 (1977). 18. Persson K, ct al: Group B streptococci at delivery. High count in urine increases risk for neonatal colonization, Stand J Infect Dis 18: 525 (1986). 19. Persson K, ct al: Asymptomatic bactcriuria during prcx:nancy with special reference to group B streptococcus. Scand J Infect Dis 17: 195 (1985). 20. Faro S: Group B streptococcus and puerperal sepsis. Am J Ohstet Gynecol 138: 1219 (1980). 21. Faro S: Group B, beta-hemolytic streptococci and puerperal infections, Am J Ohstct Gyecol 139: 686 (1981). 22. Wathne B, Hovelius B, and Mardh PA: Causes of frequcnq and dysuria in lvomcn, Stand J Infect Dis 19: 223 (1987). 23. IIooten TM, cf al: Association between bacterial vaginoais and acute cystitis in women using diaphragms, Arch Intern Med 149: 1932 (1989). 24. Stamm WE, et al: Causes of the acute urethral syndrome in lvomen, N Engl J Med 303: 409 (1980). 25. Ronald AR: Current concepts in the management ol urinary tract infections in adults, Med Clin North Am 68: 335 (1984). 26. Gallagher JA, Montgorneric JZ, and North JDK: Acute infectiom of the urinary tract and the urethral syndrome in general practice. Br Med J 1: 622 (1965). 27. Kass EH: Bacteriuria and the diagnosis of infections of the urinary tract, Arch Intern Med 100: 709 (1957). 28. Gleckman R, ct al: Acute g&nephritis in the elderly South Med J 75: 551 (1982). 29. Childs SJ: Management of urinary tract infections, Am J Med (Suppl 3A) 85: 14 (1988). 30. Stamm WE, ct al: Diagnosis of coliform infection in acutely dyuric women, N Engl J Med 307: 463 (1982). 31. Schultz IIJ, and McCaffrey LA: Acute cystitis: a prospective study of laboratory tests and duration of therapy, Mayo Clin Proc 59: 391 (1984). 32. Stamm WE, c’tal: Urinary tract infections: from pathogenesis to treatment, J Infect Dis 159: 400 (1989). 33. Briceland 1.1,. et al: Antibiotic streamlining from con,bination therapy to monotherapy utilizing an interdisciplinar!


approach, Arch Intern Med 148: 2019 (198X). 34. Sheehan 6. Harding GKM, and Ronald AR: Advances in the treatment of urinary tract infections, Am J Med 76: I41 (1984). 35. N&r KG: Single-dose therapy of uncomplicated urinar) tract infections in females, treatment of choice?, Infection 17: 119 (1989). 36. Tricnekens TAM. c’l crl: Different lengths of trcatmrnt with co-trimoxazole for acute uncomplicated urinary tract infections in women, Rr Md J 299: 1319 (1989). 37. Ludwig G, and Oauthner H: Clinical expericncc \vith ofloxacin in upper and lower urinary tract infections, Drugs (Suppl 1) 34: 95 (19ls7). 38. Nightingale CII: Interaction of microbiology and pharmacokinetics in the seltTtion of appropriate antibiotic therapy Drug Intcll Clin Pharm 23: Sl6 (1989). 39. Wolfson JS, and 1Iooper DC: Cornparativc pharmacokinetics of ofloxacin and ciprofloxacin, Am J Med (Suppl 6C) 87: 31s (1989). 40. Leigh DA, ct al: Pharmacokinctics of oflosacin and the cffeet on the fecal flora of healthy volunteers, J Antimicrob Chemother (Suppl C) 22: 115 (1988). 41, Bergeron MG: The future of new oral antibiotics including the quinoloncs. Can Med Assoc J 138: 35 (1988). 42. Fihn SD, el 01: ‘liimethoI)rim-s~llfanrethoxazole for acutr dysuria in Lvomcn: a single-dose or IO-day course, Ann Intern Med 108: 350 (1988). 43. IIooten TM, cf al: Ofloxacin vs trimcthoprinl-sulfanlethosazole for treatment of acute cystitis, Antimicrob Agents Chcmother 33: 1.308 (1989). 44. Porpaczy P: Comparison of ofloxacin \vith co-trirnoua7.ole and nitrofurantoin in urinary tract infections, Proceedings of 14th International Congress of Chrmotherap!; 1985. Kynto, Japan. in Recent Advances in Chemotherapy, Antimicrobials, Section 2. Tokyo, University of Tokyo Press, 198.5. 45. Joffe MA, ct (11:Trimethoprim-sulfamctho\;azole-associated aseptic meningitis: case reports and revie\v of the litcrature, Am J Med 87: 332 (1989). 46. Amoxicillin-clavulanic acid (Augmentin). Mtd I&t Drllt(\ Ther 26: 99 (1984). 47. Karachalios GN: Randomized comparative stud!, 01 amoxicillin-clavulanic acid and co-trimoxazole in the treatment of acute urinarv tract infections in adults, Antimicrob Agent\ Chrmother 28: 693 (1985). 48. Knothe 1-I. Shah I’M. and Schafer V: Efficacy and safety of ofloxacin in the treatment of urinary tract infections in comparison with cotrimoxazole and amoxicillin + clavulanic acid. Proceedings of 14th International Congress of Chemothcrap); 198.5, Kyoto, Japan, in Recent Advances in Chemotherapy, Antimicrobials. Section 2, Tokyo, University of Tokyo Press. 1985. pp. 18071808. 49. Brogden RN, and Ward A: Ccftriaxonc: a reappraisal of its antibacterial activity and pharmacokinetic properties. and an up date on its therapeutic use with particular reference to oncts-dail! administration, Drugs 35: 604 (1988). 50. Iravani A. and Richard GA: Single-dose ccfuroximc axetil verslls multiple-dose cefaclor in the treatment of acute urinq tract infections. Antimicrob Agents Chemother 33: 1212 (1989). 51, Cone I,A, and Woodard DR: Aztrconam therapy for sarious gram-negative bacillary infections, Rev Infect Dis (S1lppl 4) 7: s794 (1985). 52. Stein GE: The 4.quinolone antibiotics: past. present, and future, Pharmacotherapy 8: 301 (1988). 53. Phillips I, and King A: Comparative activit!, of the 4. quinoltrnes, Rev Infect Dis (Suppl 1) 10: S70 (1988). 54. IIoopcr DC, and Wolfson JS: The fllltrrocIrlinolone\: pharmacology clinical uses. and toxicitiea in humans, Antimicrob Agents Chemother 28: 716 (198.5). 55. Nix DE, and Schrntag JJ: The quinoloncs: an overview and comparative appraisal of their pharnracokinetics and pharmacodynamics, J Clin Pharmacol 28: 169 (1988). 56. Wolfson JS. and Hooper DC: Treatment of genitourinq tract infections with fluorocluinolones: activity in vitro. pharma-


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cokinc+ic\, prostatitis.

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efficac! in urinary tract inlcvtions and .4gents Chemother 33: 1655 (1989). .57. Shah f’I1 (Ed): Inflwncc of quinolones on hlunlan nlic~rtrfl

New considerations in treatment of urinary tract infections in adults.

Urinary tract infections remain some of the most common infections observed in community- and hospital-based practices. Although most infections conti...
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