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Diagnosis and clinical management of urinary tract infection
Ita Pfeferman Heilberg , M.D. PhD.
1. Introduction
Uncomplicated urinary tract infection (UTI) is a very common clinical entity affecting particularly women with normal genitourinary tract. It is estimated that nearly 50% of women will present at least one episode of acute UTI during life, accounting for annual costs around $1,6 billion in USA 1,2 .The frequency of UTI varies according to gender and age, being much higher in female (during childhood and adult life), with peaks of increased incidence following starting of sexual activity, during pregnancy and after menopause. The exception to this sex predilection may be observed in male children aged less than 1 year (due to urinary tract malformations such as posterior urethral valve or others) or in elderly male for the presence of prostate enlargement leading to urinary tract obstruction. The presence of a foreskin may elevate the risk of UTI as well. Since the route of infection is mostly ascending, the shorter female urethral length and close proximity of the anus to the urethra favors the infection in females. Migration of microorganisms to the periurethral region, colonization of the vaginal vestibule and distal urethra, which can be modified by hormones, specially estrogen, are pre-requisite steps for further migration into the bladder 3. Conversely, complicated UTI is often associated with underlying functional or structural urinary tract abnormalities (neurogenic bladder, vesicourethral reflux, medullary sponge kidneys, nephrocalcinosis, renal cysts, etc.), urinary tract obstruction (benign prostate hyperplasia, urolithiasis, tumors, uretero-pelvic junction stricture), foreign bodies such as indwelling catheterization or instrumentation, multidrug-resistant uropathogens, immunosuppression or prostatitis. 2. Spectrum of UTI There is a wide variation in clinical presentation of UTI. Cystitis or acute uncomplicated UTI comprise the lower tract (bladder) and Pyelonephritis the upper tract (kidney) symptomatic infection. Urethral syndrome is characterized by UTI symptoms (dysuria, urgency and frequent voiding) accompanied by sterile leucocyturia and a negative culture test (also known as pyuria-dysuria syndrome or symptomatic abacteriuria). It can be caused by unusual or fastidious bacteria such as Chlamydia trachomatis, Ureaplasma urealyticum, Neisseria gonorrhoeae, Mycoplasma spp., Mycobacteria spp., Trichomonas spp. or Candida spp. Other causes of symptomatic abacteriuria include renal abscess formation without drainage, complete ureteral obstruction, urinary tract tuberculosis, incorrectly obtained urine samples. The differential diagnosis with other symptomatic conditions like vaginitis, vulvitis, urethritis and chemical (cyclophosfamide, etc), tumoral, or interstitial cystitis 4 must be sought. The term "bacteriuria" refers to the finding of 105 or more colony-forming units of micro-organisms per mililiter of urine (cfu/mL). However, in symptomatic women and also in men, this microbiological criterion for UTI can be reduced to > 104 (10.000) or less, depending on the isolated germ. On the other hand, in the absence of symptoms, bacteriuria will be considered as significant (so-called significant asymptomatic bacteriuria) only if bacterial count > 105 cfu/mL (same microorganism and antibiogram profile) is found in two consecutive clean-catch urine. Low-count bacteriuria might be an early phase of UTI (if micro-organisms are typical for UTI), or be produced by slow growth of uropathogens such as S. saprophyticus. This condition must be distinguished from contamination usually characterized by several bacterial species growth or small number of urethral and vaginal contaminants (Lactobacilii, Corynebacteria species, Gardnerella, 3. Risk factors A history of previous recurrent UTI, reflecting a biological or behavioural predisposition for persistent colonization with a uropathogenic strain is a strong risk factor for having a subsequent UTI. Having a first UTI at an early age, a mother or a first-degree relative with UTI, show that genetic predisposition is also important 5. There is a correlation between the P1 blood group phenotype and susceptibility to UTI 6 especially pyelonephritis 7. Non-secretors of Lewis blood group antigens are more prone to develop UTI than secretors 8. Among behavioral factors, sexual intercourse and spermicides, especially in conjunction with diaphragm use have been pointed out as the most important risk factors for UTI 9. Pre- and post-coital voiding patterns, frequency of urination, wiping patterns, douching, etc., are still controversial 10. Other host related factors 11 that may increase the susceptibility to UTI include urinary tract obstruction, vesicoureteral reflux 12, pregnancy, diabetes mellitus, prostatism, indwelling catheters, menopause, advanced age and renal transplantation. Pathogenetic aspects concerning bacterial virulence and cytoadherence are important determinants of UTI as well 13. The acute infection may be initiated by microorganisms that are able to colonize the uroepithelium depending on the type of fimbriae/pili they possess. The production of hemolysin and the resultant cytotoxical damage further facilitates bacterial invasion. Properties such as serum resistance, iron sequestration, hydroxamate production and the presence of capsular (K) antigen are associated with bacterial strains that persist in the host without symptoms. The interaction of these virulence properties with the host immune response and local defense mechanisms will determine the development of acute or chronic infection. The most frequent uropathogens isolated in uncomplicated UTI are gram-negative bacilli, being Escherichia coli responsible for the majority (up to 90% of cases), followed by Klebsiella pneumoniae, Proteus Mirabilis, Enterobacter spp., Acinetobacter spp., among others. In some series, Staphylococcus saprophyticus, is considered as the second most common microorganism accounting for 5 to 15% of cases. 4. Clinical presentation Typical symptoms of acute lower UTI are dysuria, urinary frequency and urgency whereas the presence of vaginal irritation or discharge increase the likelihood of vaginitis. The differentiation between cystitis and pyelonephritis is important because renal involvement is associated with more severe complications. The clinical presentation in upper UTI gives important clues pointing to systemic involvement such as fever and flank pain that help to distinguish it from lower UTI. The diagnostic procedures to localize the site of infection are invasive and risky (catheterization). Suprapubic aspiration is obvioulsy not a tool for routine diagnosis. The presence of elevated inflammatory parameters such as C-reactive protein or leucocytosis may help but they are not specific. Non-invasive methods have been proposed like the "antibody-coated bacteria" (immunofluorescence) or nuclear medicine (scintigraphy with DMSA 99mTc) but the in clinical practice, for the purpose of management, a prompt diagnosis must be sought and signs and symptoms of upper tract involvement are the most important hints to suggest pyelonephritis. Monitoring the evolution of bacteriuria may help in case of a retrospective analysis. 5. Diagnostic tests Considering the need for a rapid diagnostic procedure in acute UTI, the urinary reagent strip test (dipstick) is a cheaper, faster and more convenient test 14. In the presence of symptoms, the detection of a positive leukocyte esterase or nitrate reductase activity highly suggests UTI. However, since not all uropathogens are capable to reduce nitrate to nitrite, the positivity for nitrite is specific for Enterobacteriaceae infections. A negative dipstick usually is sufficient to exclude UTI but if the pretest likelihood is high, it is advisable to obtain a culture. The presence of pyuria (> 10 leucocytes /high-power field) on a centrifuged urinary sediment analysis, obtained as a clean-catch specimen, has high sensitivity (95%) but low specificity (75%). False-negative results by microscopy can be ascribed to erythrocytes and leukocytes lysis in alkaline or low osmolality urine or to a delayed analysis. In the outpatient setting, most women presenting with typical symptoms of an acute cystitis and pyuria, characterizing an uncomplicated UTI, can be treated without obtaining a urine culture. On the other hand, empiric treatment can also be initiated soon after a clean-catch, midstream urine specimen is obtained for culture, and the treatment continued according to bacterial resistance or stopped if the result is negative. Urine cultures are important to identify unusual or resistant organisms in women whose symptoms do not resolve or recur after 2 to 4 weeks after completion of treatment. The traditional threshold of 105 bacteria/mL should be lowered for symptomatic women in order to raise the sensitivity. The specificity of urine culture is always high. Bacterial counts are higher in early morning urine samples but considering the frequent voiding and dysuria, it is almost impossible to obtain an overnight specimen. Bacterial growth pattern is characterized by an initial lag phase (lasting 2 hours) followed by a logarithmic phase when bacteria double every 30 minutes up to around 6 hours when a plateau is reached. Therefore, in order to avoid false-negative results, urine should be collected at least 2 hours after the last micturition. Imaging prodedures such as plain abdominal radiography, ultrasound, spiral computed tomography, are indicated in case of recurrent infections to rule out complicating factors such as urinary stones, obstruction, hydronephrosis, abscesses, renal cysts 15. Intravenous urography is justified to detect anatomical abnormalities like ureteropelvic junction stenosis, pielocalyceal duplicity, etc. only if not evidenced by other methods, but should not be performed during acute infection. Renal scintigraphy with DMSA 99mTc is indicated to assess cortical damage secondary to UTI (renal scars), particularly in reflux nephropathy, but voiding cystourethrogram is the method of choice to establish the diagnosis of vesicoureteral reflux. Urological evaluation is indicated for UTI affecting newborn and children, persistent infection after 72 hr of therapy, recurrent UTI in men, renal transplantation and eventually in women with frequent reinfection. 6. Treatment The selection of an appropriate antimicrobial therapy relies on the knowledge of its pharmacokinetics, spectrum of activity, resistance prevalence for the community, adverse effects and renal excretion routes in order to achieve high urinary levels. Appropriate strategies and specific therapeutic regimens may maximize the benefit while reducing costs and adverse reactions 16. The Infectious Diseases Society of America (IDSA) has issued evidence-based practice guidelines on the management of uncomplicated acute bacterial cystitis and acute pyelonephritis in women 17. Despite the need of a periodical reassessment of local susceptibility patterns of uropathogens by any given community, those were the latest recommendations according to the guidelines for healthy adult non-pregnant women: 6.1. Acute uncomplicated bacterial cystitis: Standard first-line therapy for centers in which resistance for Sulfonamides is lower than 20% is:
When TMP-SMX resistance > 20% :
Other traditional oral agents 18 can be used in uncomplicated UTI, although not contemplated in the guidelines due to the paucity of prospective, randomized, controlled trials of sufficient size suitable for meta-analysis 17. Amoxicillin and other
Comments: Most antimicrobials given for 3 days are as effective as the same antimicrobial given for a longer duration (5 or 7 days), with a better compliance, lower cost and rate of adverse effects. The single-dose therapy is generally less-effective (except for fosfomycin). Older women tend to have lower bacteriuria eradication rates so that cystitis in postmenopausal or when caused by Staphylococcus saprophyticus might be better managed by longer courses of antimicrobials (7 days). Nitrofurantoin presents low rates of resistance among common uropathogens, can be used during pregnancy and in pediatric population, but is associated with lower cure rates than other first-line agents, even at a 7 days dosage (its usual prescription). Nitrofurantoin and Fosfomycin are good options that require further studies, specially focusing on a 3-days course. Nevertheless, Fosfomycin is not active against Klebsiella spp., Enterobacter spp., Acinetobacter spp., Proteus spp. and Pseudomonas spp. Despite of the fact that fluoroquinolones are highly effective in treating cystitis, and considering their utility in treating complicated UTI and prostatitis, which would be compromised if widespread use led to increase resistance, and also because of their expense, they should not be recommended as first-line empirical therapy for uncomplicated cystitis. They should be rather used in areas with high prevalence of resistance to TMP-SMX. Clinicians should be aware of current antimicrobial susceptibility patterns for E.coli and other uropathogens in the local community. However, there is a trend toward treating episodes of acute cystitis without obtaining cultures of urine. Complicated UTI (or affecting men), patients with previous treatment or with high probability of infection caused by resistant bacteria should be always treated in a 7-days regimen. Tetracyclines (Doxycycline 100mg bid for 7 to 14 days) are indicated in women with urethral syndrome, caused mostly by Chlamydia Trachomatis 20 or by other fastidious bacteria as Ureaplasma urealyticum. Some protocols suggest the use of Azithromycin (500mg for 6 days) 20. Treatment of asymptomatic bacteriuria in pregnancy is mandatory because of the high likelihood of developing pyelonephritis later on and its association with preterm delivery. First line-agents for acute cystitis and also asymptomatic bacteriuria in pregnant women are (ref): Nitrofurantoin (50-100 mg q6hr, 7 days), Cephalexin (250 mg q6hr, 7days) , Amoxicillin-clavulanate (500 mg bid, 3 days) or Amoxicillin (500 mg tid, 7 days) in case of known susceptibility TMP-SMX should be avoided in first trimester and fluoroquinolones are contraindicated due to potential negative effects on the cartilage of developing fetus. Pyelonephritis in pregancy usually requires hospitalization for parenteral Aminoglycoside or Ceftriaxone 6.2. Acute uncomplicated pyelonephritis In cases of acute pyelonephritis, because of the potential severity of the infection, and the much higher rate of resistance to either TMP-SMX, fluoroquinolones or nitrofurantoin 21, culture of urine and susceptibility testing of isolated organisms must be obtained. According to the IDSA guidelines 17, not all and perhaps none of the therapy must be delivered IV, in case of mild or moderate symptoms in a compliant patient. Before the result of urine culture is available empirical treatment with oral Fluoroquinolone can be started. If uropathogen is known to be susceptible, TMP-SMX is also an alternative. In case of a gram-positive pathogen, Amoxicillin or Amoxicillin-clavulanate are recommended. Some centers advocate a single parenteral dose of antimicrobial (Ceftriaxone, Gentamicin or Fluorquinolone) before initiating oral therapy in an outpatient basis. Some patients may require 12 to 24 hours observation in ER to monitor the response to parenteral or oral Rx. In patients with severe systemic symptoms (high fever, evidence of sepsis, dehydration, high white blood cell count) hospitalization is indicated. Parenteral therapy options include Fluoroquinolone, Aminoglycoside with or without Ampicilin, extended-spectrum Cephalosporin with or without Aminoglycoside and for gram-positive, Ampicilin/sulbactam with or without Aminoglycoside. After clinical improvement (48-72 hr), patients may be switched to an oral regimen based on pretherapy urine culture and susceptibility. There must be concern about Aminoglycoside nephrotoxicity. 7. Prophylaxis Prophylaxis is generally considered for women with frequent recurrent infection (2 symptomatic episodes within 6 months, or 3 episodes within 1 year). A long-term (average 6 months) low dose prophylaxis can be recommended with either TMP-SMX (80/400 mg daily or 3 times/week) or Nitrofurantoin (50 mg/day) taken at bedtime (ref). Although Norfloxacin 200 mg 3 times/week could also be an option, it is more expensive and the need for postponement of resistance to this drug must be considered. For those women who associate episodes of infection with sexual activity, spermicidal contraceptives or diaphragms for contraception should be replaced by other methods and a postintercourse prophylaxis maybe an appropriate approach. Small doses of antimicrobials (TMP-SMX, Nitrofurantoin or others) can be taken immediately after voiding postintercourse. Postmenopausal women with recurrent UTI may benefit from either intravaginal use of topical estrogen preparations that restore the population of vaginal lactobacilli and reduce vaginal pH 22. In a very recent trial, Raz et al 23 have shown that Nitrofurantoin taken once daily for 9 months was more effective in the prevention of symptomatic or asymptomatic bacteriuria in postmenopausal women than estriol-containing pessaries. It seems that Nitrofurantoin does not predispose to the selection of resistant strains or to the presence of Candida vaginitis because it does not alter the bacterial flora in the vagina and colon References
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-hemolitic Streptococci). 
-lactam antimicrobials are indicated in 7-day regimens, but considering the increasing resistance to Amoxicillin in the United States its empiric use should be restricted. The oral cephalosporins including Cephalexin (250mg, q6hr, 7 days), Cefuroxime axetil and Cefixime are not considered as first-line agents since their broad spectrum of activity may lead to an increased frequency of vulvovaginal candidiasis. Cephalexin can be used during pregnancy.