Asymptomatic bacteriuria When to screen and when to treat

Infect Dis Clin N Am 17 (2003) 367 394 Asymptomatic bacteriuria When to screen and when to treat Lindsay E. Nicolle, MD Departments of Internal Medicine and Medical Microbiology, University of Manitoba, Health Sciences Centre, 820 Sherbrook Street, Room GG443, Winnipeg, MB R3A 1R9 Canada Asymptomatic bacteriuria, or asymptomatic urinary infection, is bacteria present in urine in the absence of clinical signs or symptoms of urinary infection in the host. The microbiologic definition is usually greater than or equal to 10 5 colony-forming units per milliliter of the same organism or organisms in two consecutive urine specimens [1]. The frequency and natural history of asymptomatic bacteriuria vary for different populations. The prevalence of bacteriuria in several different groups, including well men and women, diabetic men and women, women with cystoceles, pregnant women, and individuals with chronic indwelling catheters was reported in Kass s [2] initial description of the application of the quantitative urine culture to differentiate urinary infection from contamination. The clinical importance of asymptomatic bacteriuria has been controversial since the widespread use of the quantitative urine culture provided a reliable means for identification [3]. The principle question is whether bacteriuria, in the absence of symptoms, leads to complications of urinary infection [4 6]. Adverse outcomes of concern have included the short-term complications of symptomatic lower tract infection or pyelonephritis [7,8], and longer-term complications, such as urolithiasis, genitourinary cancer [9], renal failure [10], hypertension [11,12], and death [13,14]. Alternately, asymptomatic bacteriuria may be beneficial. Colonization of the genitourinary tract by an avirulent organism could prevent infection with more virulent organisms, through competition for nutrients or receptor sites, by eliciting a cross-protective host immune or inflammatory response, or by other mechanisms [15]. Early in the antimicrobial era, it was recognized that pyelonephritis and premature labor in later pregnancy were prevented by antimicrobial treatment of asymptomatic bacteriuria identified in early pregnancy [3]. This E-mail address: lnicolle@hsc.mb.ca 0891-5520/03/$ - see front matter Ó 2003, Elsevier Inc. All rights reserved. doi:10.1016/s0891-5520(03)00008-4

368 L.E. Nicolle / Infect Dis Clin N Am 17 (2003) 367 394 observation reinforced the view that asymptomatic bacteriuria was harmful, and that screening for and treatment of asymptomatic bacteriuria was appropriate. Subsequent studies in other groups, however, have generally not supported antimicrobial intervention [5,7]. Potential risks or benefits of treatment must be evaluated in each distinct population. Recommendations for screening for and treatment of asymptomatic bacteriuria for selected populations are as follows: Screening and treatment beneficial Pregnant women Before traumatic genitourinary procedure Screening and treatment may be beneficial Renal transplant recipient, first 6 months posttransplant Women with persistent catheter-acquired bacteriuria after catheter removal Screening and treatment not beneficial Healthy infants Healthy girls Healthy women or men Elderly men and women in the community Elderly men and women resident in long-term care facilities Women with diabetes Patients with HIV infection Patients with short-term indwelling urethral catheters (not recommended for patient care; may be appropriate to screen for bacteriuria for nosocomial infection surveillance or outbreak control) Patients with chronic-indwelling urethral catheters (not recommended for patient care; may be appropriate to screen for bacteriuria for nosocomial infection surveillance or outbreak control) Patients using intermittent catheterization Patients with neurologic impairment of bladder emptying Patients with chronic urologic devices Pathogenesis of bacteriuria The normal genitourinary tract is sterile, apart from the distal urethra. Asymptomatic bacteriuria occurs following ascension of bacteria up the urethra into the bladder, sometimes with subsequent ascension to the kidneys. Bacteria isolated from the urine of patients with asymptomatic bacteriuria usually originate as colonizing flora of the gut, vagina, or periurethral area. For patients subjected to urinary tract instrumentation, bacteria that contaminate urologic instruments or fluids may be introduced into the genitourinary tract without prior host colonization. Organisms then persist in the urinary tract without eliciting a host response sufficient to

L.E. Nicolle / Infect Dis Clin N Am 17 (2003) 367 394 369 produce symptoms or cause eradication. Variables, such as host genetic predisposition, incomplete bladder emptying, or the presence of a foreign body, may all facilitate persistence. Escherichia coli is the most frequent organism isolated from subjects with asymptomatic bacteriuria (Table 1) [16 22]. A wide range of other bacteria, however, may be isolated. For elderly subjects and patients managed with intermittent catheterization, E coli are isolated less frequently in men than women [21,23,24]. Patients with structural or functional abnormalities of the urinary tract, often with foreign material in situ and repeated antimicrobial exposure, frequently have other Enterobacteriaceae and gram-negative organisms, such as Pseudomonas aeruginosa isolated. Gram-positive organisms including Enterococcus spp and coagulase-negative staphylococcus other than Staphylococcus saprophyticus may be isolated more frequently from patients with asymptomatic compared with symptomatic infection. Escherichia coli urinary strains from patients with asymptomatic bacteriuria display a lower frequency of genetic markers or phenotypic expression of potential virulence factors compared with strains isolated from acute uncomplicated urinary infection or acute nonobstructive pyelonephritis [25 27]. In one small series, patients with indwelling catheters had bladder instillation of an E coli strain. Persistent asymptomatic bacteriuria was observed with the parent strain that had neither pap nor type 1 fimbriae. Transformants with either of these virulence factors precipitated an inflammatory response with early elimination [28]. Expression of organism virulence factors is, then, one variable that determines symptoms or persistence. A local urinary host response is often present despite the absence of symptoms. Pyuria is reported with asymptomatic bacteriuria in 43% of schoolgirls [16], 32% of young healthy women [17], 78% of diabetic women [22], 25% to 80% of pregnant women [29,30], and 90% of elderly men and women [23]. The absolute urinary leukocyte level varies, but patients may have high levels of pyuria accompanying persistent asymptomatic bacteriuria for years [31]. Bacteriuria with gram-positive organisms is associated with lower levels of pyuria [32]. Other local inflammatory or immune markers, such as cytokines and urinary immunoglobulins, may also be present [23,25]. The determinants and clinical significance of this local response are not yet fully described. Screening for bacteriuria Indications for screening Case finding of bacteriuria through screening, and treatment for risk reduction, is appropriate if adverse clinical outcomes are attributable to bacteriuria and prevented with treatment. The costs and potential adverse effects of screening and treatment programs must also be considered. If bacteriuria is benign, or treatment cannot prevent adverse outcomes,

370 L.E. Nicolle / Infect Dis Clin N Am 17 (2003) 367 394 Table 1 Distribution of bacterial species isolated from different populations with asymptomatic bacteriuria % School girls [16] % Young, healthy women [17] % Pregnant women [18] % Elderly institutionalized % Spinal cord/intermittent catheter [21] Women [19] Men [20] Women Men % Diabetic women [22] E coli 84 77 80 62 47 11 53 19 53 K pneumoniae 10 8.8 6.8 5.9 24 26 Citrobacter spp 2.6 2.5 5 P mirabilis 0.8 3.5 27 30 Providencia spp 6.8 16 P aeruginosa 0.8 0.9 5.1 19 9 Other gram-negative 0.8 9.7 2.6 4.2 20 Enterococcus spp 0.8 6 5 5 Streptococcus spp 9.7 1.7 18 22 1.4 S aureus 3.3 11.4 Coagulase-negative 0.9 4.2 4 5.9 staphylococcus Other gram-positive 4.3 Other 20 23 15

L.E. Nicolle / Infect Dis Clin N Am 17 (2003) 367 394 371 screening for bacteriuria has little use. Identification of bacteriuria may, in fact, promote unnecessary antimicrobial use with subsequent increased adverse drug effects and antimicrobial resistance. The relative risks and benefits of screening and treatment interventions are best evaluated through appropriate prospective, randomized clinical trials in well-defined populations. The optimal screening frequency must be also be evaluated, and varies in different populations. If asymptomatic bacteriuria is a risk for only a limited time period, such as during pregnancy or the perioperative period, defining a screening frequency may be straightforward. If there is a continuing risk over a long term, as in persistently bacteriuric elderly or catheterized subjects, developing a screening program is more problematic. In addition, bacteriuria in many subjects is dynamic, with spontaneous resolution and reinfection, and early posttreatment recurrence common [6,17,23,33]. Identification of all bacteriuria episodes requires repeated screening at relative short intervals if the goal is to maintain a sterile urine. Urine culture for screening A urine specimen for culture is necessary to screen for bacteriuria. Quantitative bacteriology of a single voided urine specimen is reliable for identification of bacteriuria in men [34,35]. A single voided specimen has been reported to be 80% specific, and two specimens 95% specific, for identification of bacteriuria in women [1,16]. Two consecutive specimens with isolation of the same organism has been the standard for identification of bacteriuria in women [6], although some studies have designated women as bacteriuric on the basis of a single specimen [17,33]. In a group of diabetic women, only 66% of those with an initial positive urine culture remained bacteriuric when a second specimen was obtained within 2 weeks [22]. Only 42% of young healthy women had persistent asymptomatic bacteriuria in a second specimen at 1 week [17]. Designating bacteriuria with a single urine specimen identifies a higher prevalence of bacteriuria in women, including misinterpretation of contaminated specimens as bacteriuria and inclusion of women with transient, short-term bacteriuria. A second specimen to confirm bacteriuria identifies women with persistent bacteriuria, who would be of greater interest with respect to potential adverse effects. The number of specimens obtained to designate bacteriuria is an important variable in interpreting reports of the prevalence of bacteriuria in healthy women. Other screening tests for bacteriuria Nonculture urine tests that identify inflammation or bacteria in the urine directly do not have sufficient sensitivity or specificity to replace the urine culture for identification of bacteriuria. Pyuria, determined either by urinalysis or leukocyte esterase dipstick, is not specific for infection, and subjects with asymptomatic bacteriuria do not always have pyuria. The

372 L.E. Nicolle / Infect Dis Clin N Am 17 (2003) 367 394 nitrite dipstick is subject to false-negatives, because 4 to 6 hours is required for bacteria to convert nitrate to nitrite in bladder urine, and some infecting organisms are nitrite negative [36]. In a study of bacteriuria screening in infants, 85% of nitrite tests were false-negatives compared with culture [37]. A 53% false-negative rate was also reported in an obstetric population with dipstick screening of nitrite and leukocyte esterase [38]. When screening for bacteriuria is appropriate, the quantitative urine culture remains the optimal screening test. Healthy, nonelderly populations Children The prevalence of asymptomatic bacteriuria in preschool girls is 1% or less, and subsequently increases slightly with age (Table 2). The prevalence for schoolgirls is less than 2%, although one survey reported a higher prevalence for a group of socioeconomically disadvantaged girls [43]. For boys, bacteriuria is virtually never identified beyond the newborn period (see Table 2). Comprehensive, long-term screening programs for bacteriuria in schoolgirls undertaken in the 1950s and 1960s found no evidence of progression of renal scars or renal failure with untreated asymptomatic bacteriuria [39,40,45 49]. Untreated asymptomatic bacteriuria may persist for many years without evidence of attributable adverse outcomes [50]. A randomized, controlled trial reported no difference in outcomes with antimicrobial treatment or nontreatment over 2 years [51]. A second study randomized girls with normal genitourinary tracts and persistent bacteriuria after 6 months follow-up to therapy or no therapy [52]. In 18 months follow-up following randomization, one episode of pyelonephritis occurred in each group. Girls with asymptomatic bacteriuria do experience more frequent Table 2 Prevalence of bacteriuria in infants and children Population (number screened) (reference) % Female % Male % Both Infants (1617) [39] 1.8 0.5 Infants 3 36 mo (441) [37] 0.4 2.5 Infants (3581) [40] 0.9 2.5 1.4 Preschool children (1711) [39] 0.8 0 Preschool children (1000) [41] 0.5 Children 2 5 y (2197) [42] 1.3 6 13 y (1367) [42] 1.8 Seventh grade, disadvantaged (314) [43] 5.4 0 School-age (6953) [16] 1.1 Adolescents (500) [44] 1.6 Adolescents (1253) [16] 1.8

L.E. Nicolle / Infect Dis Clin N Am 17 (2003) 367 394 373 symptomatic urinary infection compared with those without bacteriuria [44,48]. Antimicrobial therapy given for any indication to bacteriuric girls is also followed by an increased incidence of symptomatic urinary infection in the immediate posttreatment period [53]. These consistent observations are the basis for the current consensus that screening for and treatment of bacteriuria in asymptomatic infants or children does not improve outcomes, and is costly [40,46,54]. Screening for or treatment of asymptomatic bacteriuria in healthy children is not recommended [54]. Premenopausal, nonpregnant women The prevalence of asymptomatic bacteriuria in healthy, premenopausal, nonpregnant women varies from 2% to 5% (Table 3). Bacteriuria increases with age, and sexually active women have a prevalence as much as five times higher than women who are not sexually active [56]. Use of a diaphragm or spermicide for birth control is also associated with bacteriuria [17,68]. Recurrent episodes of transient, short-term, bacteriuria are likely common in young women [17]. Prospective studies evaluating outcomes for young, healthy women with asymptomatic bacteriuria are limited. Bacteriuria was initially identified in 4% of a cohort of over 1000 Swedish women. Those with initial bacteriuria were also more likely to be bacteriuric at subsequent screening 6 and 12 years later [57]. During 24 years follow-up, mortality and progression to kidney disease were similar for women with and without bacteriuria. Other longterm studies also report no association of bacteriuria with hypertension or renal failure [5,69,70]. Women with bacteriuria do experience symptomatic urinary infection and subsequent episodes of bacteriuria more frequently [17,69]. A prospective, randomized, placebo-controlled trial of antimicrobial treatment reported 80% of bacteriuric women were cured with nitrofurantoin therapy at short-term follow-up [71]. At 1 year posttreatment, 55% of treated women remained free of bacteriuria, whereas 36% of placebo recipients had spontaneously cleared. Symptomatic infection during the year of follow-up was identified for 37% and 36% of subjects in the treatment and placebo groups, and in 7% of nonbacteriuric controls. No benefits of treatment were identified. Antimicrobial therapy given to healthy young bacteriuric women for any indication is also associated with an increased frequency of symptomatic infection in the immediate postantimicrobial period [72,73]. Women with asymptomatic bacteriuria are at increased risk for symptomatic urinary infection and recurrent asymptomatic bacteriuria. Treatment of asymptomatic bacteriuria does not decrease the frequency of symptomatic infection, however, and asymptomatic bacteriuria in these women is not associated with any long-term adverse outcomes. Screening for and treatment of asymptomatic bacteriuria are not recommended for healthy young women.

374 L.E. Nicolle / Infect Dis Clin N Am 17 (2003) 367 394 Table 3 Prevalence of asymptomatic bacteriuria in young adult women Population (reference) Number screened % Prevalence Nonpregnant women Japan [55] \20 y 475 0.8 20 29 y 193 1 30 39 y 775 1.8 40 49 y 555 3.1 United States [56] Married women 25 44 y 1340 4.6 Nuns 25 44 y 1252 0.7 Jamaica [12] 15 24 y 611 1.3 25 34 y 532 2.3 35 44 y 389 3.3 United States [13] 16 29 y 2415 1.5 30 49 y 2852 3.1 Sweden [57] 38 y 372 3.5 46 y 431 4.8 50 y 398 5.2 Finland [58] 40 49 y 561 2 Pregnant women England [59] 5000 5.3 United States [60] 691 9.5 England [61] 4470 2.6 Sweden [62] 3254 1.9 2.2 United States [29] 1047 2.3 England, White [63] 6864 6.3 England, Bangladeshi [63] 7470 2 Sweden [64] 865 6.7 Israel [65] 1130 5.9 Nigeria [66] 1000 5.3 Lebanon [67] 888 5.4 Australia [30] 240 4 Pregnant women Screening for and treatment of asymptomatic bacteriuria in pregnant women are beneficial [74]. From 2% to 7% of pregnant women are bacteriuric in the first trimester (see Table 3), a prevalence similar to nonpregnant women of the same age [59,60]. Pregnant women with a prior history of urinary infection or of lower socioeconomic status are more likely to have bacteriuria. If untreated, 20% to 30% of bacteriuric women develop acute pyelonephritis later in pregnancy, usually at the end of the second or early third trimester (Table 4) [30,59,65]. Acute pyelonephritis in late pregnancy is associated with prematurity [80 82], and asymptomatic

L.E. Nicolle / Infect Dis Clin N Am 17 (2003) 367 394 375 Table 4 Impact of antimicrobial treatment of asymptomatic bacteriuria on pyelonephritis in pregnancy Screened and treated Not treated Study design (reference) Number Pyelonephritis a (%) Number Pyelonephritis a (%) Placebo-controlled [59] 124 3.2 141 24.8 Placebo-controlled [30] 72 2.8 73 28.7 Sequential cohort [75] 1652 2.8 3265 28 Randomized [18] 69 4.3 41 19.5 Placebo-controlled [76] 247 NS 179 31 Alternating [77] 90 NS 83 36 Placebo-controlled [78] 133 20 148 19 Placebo-controlled [79] 103 1 100 26 a Percent of subjects with bacteriuria who developed pyelonephritis in pregnancy. Abbreviation: NS, not stated. bacteriuria in pregnancy has also been associated with intrauterine growth retardation and neonatal death [83 85]. Treatment of bacteriuria early in pregnancy decreases the incidence of pyelonephritis to 2% to 3%, about a 90% risk reduction, and also decreases premature delivery (see Table 4). The efficacy of screening and treatment has been questioned by some authors [61], and at least one early study reported no decrease in pyelonephritis with tetracycline therapy for bacteriuria [78]. It has also been argued that the positive effect of antibiotic therapy is mediated by an alternate mechanism, such as modification of vaginal flora, rather than eradication of bacteriuria [83]. Nitrofurantoin, however, which does not alter vaginal flora, is effective in preventing pyelonephritis in pregnancy [76,80]. A more recent prospective, observational study describing introduction of a routine screening program for pregnant women confirms a 90% risk reduction for pyelonephritis in late pregnancy with screening and treatment of bacteriuria earlier in pregnancy [75]. An American cost analysis reported screening was cost-effective if the prevalence of bacteriuria was above 2%, and the risk of pyelonephritis with asymptomatic bacteriuria above 13% [85]. Screening once at the end of the first trimester seems sufficient [62]. The urine culture is the appropriate screening test for bacteriuria in pregnancy. Although one study reported a sensitivity of 94% for urinalysis for identification of bacteriuria [67], others report poor reliability of screening tests for pyuria or nitrite in identifying bacteriuria in pregnant women [59,86]. A sensitivity of 100% but specificity of only 7.7% was observed for urine centrifugation and Gram stain [38]. Urine dipstick for nitrite and leukocyte esterase had sensitivities of 50% [29] and 47% [38], and urinalysis only 25% [86], to identify bacteriuria. Thus, screening for bacteriuria in pregnancy requires a urine culture [87]. Current recommendations are that all pregnant women have at least one urine specimen obtained for culture at the end of the first or early second trimester [74,85,88]. If asymptomatic bacteriuria is identified, a second

376 L.E. Nicolle / Infect Dis Clin N Am 17 (2003) 367 394 specimen for culture should be obtained and treatment initiated. Some practitioners treat following a single positive urine culture, but relative risks, benefits, or costs of treatment following one urine culture compared with a confirmatory culture have not been evaluated. Following treatment, women previously identified with asymptomatic bacteriuria should have periodic urine cultures to identify recurrent bacteriuria throughout the remainder of the pregnancy. The optimal frequency for repeat cultures is not determined, but monthly culture at the routine prenatal visit is one approach. A small proportion (1% to 2%) of women with negative initial screening cultures develop asymptomatic bacteriuria and experience pyelonephritis later in pregnancy [75], but repeated screening of women with initial negative urine cultures is not recommended because the risk of pyelonephritis is low [88]. Young men Asymptomatic bacteriuria is uncommon in healthy, young, adult men [34]. In a Japanese study, the prevalence was 0% in 1234 men under 50 years [5]. Wilson et al [89] reported a prevalence of 1.5% in 405 men aged 20 to 70 years attending a genitourinary outpatient clinic; the prevalence was the same in heterosexual and homosexual men. On careful questioning, however, all bacteriuric men had symptoms of dysuria. Asymptomatic bacteriuria is not a relevant clinical issue in young healthy men, and screening for asymptomatic bacteriuria is not appropriate. Elderly populations Community residents Asymptomatic bacteriuria is common in older populations (Table 5) [23]. The prevalence is 6% to 7% in women 50 to 60 years of age, 8% to 10% at 70 to 80 years, and increases with age irrespective of sexual activity [56]. Bacteriuria in postmenopausal women is more common in women with a prior history of urinary infection [72]. Variables associated with recurrent symptomatic infection in elderly women, including decreased estrogen effect on the genitourinary mucosa, a genetic predisposition as evidenced by association with nonsecretor status, prior urologic events including genitourinary surgery, and urologic abnormalities, such as cystoceles, also likely contribute to the increasing prevalence of asymptomatic bacteriuria with age [97]. Bacteriuria occurs in 4% to 7% of men over 70 years resident in the community, about one half of the prevalence reported for women (see Table 5). Prostatic hypertrophy, leading to obstruction and turbulent urethral urine flow, is likely the major predisposing factor. Prostate stones, which are common in older men, may also serve as a nidus for persistent and recurrent bacteriuria.

L.E. Nicolle / Infect Dis Clin N Am 17 (2003) 367 394 377 Table 5 Prevalence of asymptomatic bacteriuria in elderly populations Women Men Number Prevalence (%) Number Prevalence (%) Community residents Finland [58] 50 59 y 450 4.4 60 64 y 212 6.6 Japan [55] 50 59 y 602 2.8 335 0.6 60 69 y 443 7.4 324 1.5 70+y 148 10.8 112 3.6 United States: married [56] 55 64 y 219 6.3 >65 y 31 6.5 United States: nuns [56] 55 64 y 310 2.7 >65 y 397 5.8 Jamaica [12] 55 64 y 174 8.6 United States [13] 50 59 y 1784 4.4 60 69 y 1286 6.1 Sweden [57] 60 y 81 8.6 United States [90] VA outpatient 65 74 y 111 9 75 84 y 56 15.3 >84 y 68 14.7 Sweden [91] 72 y 259 16 235 6 79 y 297 14 259 6 Scotland [92] 65 74 y 155 16 96 5 >75 y 140 17 75 7 Institutionalized United States [93] 101 29 121 19 Greece [94] 23 27 56 25 United States [95] 158 57 United States [96] 1863 25 Canada [20] 59 37 Canada [19] 100 53 A prospective, randomized study in bacteriuric elderly ambulatory women in a geriatric apartment facility compared 3-days trimethoprim with no treatment [98]. At 6 months, 64% of the nontreated subjects and 35% of the treated group were bacteriuric, and a nonsignificant decrease in symptomatic episodes in treated women was reported. A prospective, observational study in ambulatory male veterans over age 65 years reported an initial prevalence of bacteriuria of 12% [90]. Gram-positive cocci, usually

378 L.E. Nicolle / Infect Dis Clin N Am 17 (2003) 367 394 coagulase-negative staphylococci, were the predominate organisms isolated. Spontaneous resolution of bacteriuria was the outcome for 76% of episodes; only a few patients developed symptomatic infection. Although an association of asymptomatic bacteriuria and increased 5-year mortality was reported for elderly women in an early Finnish study [99], subsequent reports with follow-up of 5 [100,101] and 9 years [101] have not reported an association of bacteriuria and survival for either men or women. There is no evidence to suggest an adverse clinical impact of asymptomatic bacteriuria in the elderly population living in the community, although studies are limited. Currently, screening for or treatment of asymptomatic bacteruria in elderly individuals resident in the community is not recommended. Further study of the determinants of bacteriuria, and impact of management strategies in different sex, age, and functional groups would be of interest. Long-term care facility residents There is an extraordinary prevalence of asymptomatic bacteriuria in elderly institutionalized populations (25% to 50% in women, and 15% to 40% in men) (see Table 5) [23]. Asymptomatic bacteriuria in these residents correlates with impaired functional status, including incontinence of urine or bowel, and dementia [96,102,103]. The major abnormality promoting bacteriuria is assumed to be impaired bladder voiding secondary to chronic degenerative neurologic or cerebrovascular diseases common in this population. For men, prostatic hypertrophy and chronic relapsing prostatic infection likely contribute, and use of an external condom catheter to manage incontinence also increases the prevalence of bacteriuria [104]. Asymptomatic bacteriuria was associated with decreased survival in a Greek population of elderly institutionalized men and women [14]. Subsequent studies in North America have not reported excess mortality for institutionalized men [102] or women [96]. Prospective, randomized comparative trials of antimicrobial therapy or no antimicrobial therapy for management of asymptomatic bacteriuria in these populations have consistently reported no benefits with treatment [19,20,96,105]. Antimicrobial therapy does not decrease symptomatic episodes of urinary infection [19,20], improve survival [19,20,96], or improve chronic genitourinary symptoms [105]. Rapid reinfection following antimicrobial therapy is usual, and persistent bacteriuria remains despite repeated courses of antimicrobials [19,20]. Residents who receive antimicrobials to treat bacteriuria, however, have increased reinfection with resistant organisms and adverse effects from antimicrobial therapy [19]. Treatment of asymptomatic bacteriuria in elderly institutionalized populations is not indicated [87,106]. It follows that screening for asymptomatic bacteriuria, including nonculture screening tests, such as urinalysis for pyuria, are not indicated for asymptomatic patients in longterm care facilities.

L.E. Nicolle / Infect Dis Clin N Am 17 (2003) 367 394 379 Chronic medical conditions Patients with diabetes The prevalence of bacteriuria in diabetic women is 7% to 13% [107 109], about three times higher than reported for nondiabetic women (Table 6) [110]. The reported prevalence varies among studies, likely reflecting differences in the diabetic population screened and the definition of bacteriuria [110,121]. The prevalence of asymptomatic bacteriuria is not increased in diabetic compared with nondiabetic men [110]. The explanation for the increased prevalence of bacteriuria among diabetic women is incomplete. Organism virulence factors [26,109] and parameters of host response [122] are similar for both diabetic and nondiabetic women with bacteriuria. Poor metabolic control, as measured by blood glucose, glycosuria, or hemoglobin A 1 C, is not associated with increased bacteriuria [107 109]. Sexual activity is a risk factor for asymptomatic bacteriuria in diabetic and nondiabetic women [112]. Among diabetic women, duration of diabetes and presence of long-term complications of diabetes including retinopathy, nephropathy, and neuropathy have repeatedly been associated with bacteriuria [107]. Thus, the increased prevalence of bacteriuria in diabetic women may be largely attributable to autonomic neuropathy leading to impaired bladder voiding [123]. Some of the reported bacteriuria in diabetic women may also reflect inappropriate Table 6 Prevalence of asymptomatic bacteriuria in populations with chronic illness or disability Prevalence (%) Population (reference) Female Male Both Diabetes [108] 13 Diabetes [111] 13.9 2.2 Diabetes [112] 17.7 1.5 Diabetes [107] 7.9 Diabetes [113] 9.5 Spinal cord injury Bladder retrained [114] 22 26 Intermittent catheterization [114] 20 43 Intermittent catheterization [115] 65 89 23 74 Sphincterotomy, with condom [116] 98 Children, meningomyeloccle [117] 70 Urologic interventions Intermittent catheterization antibiotics [24] 38 no antibiotics [24] 58 Short-term indwelling catheter [118] 9 23 Chronic indwelling catheter [119] 100 100 Urethral stents permanent [120] 100 temporary [120] 45

380 L.E. Nicolle / Infect Dis Clin N Am 17 (2003) 367 394 selection of controls. In studies with age-matched controls, for instance, there is a less marked difference in prevalence between diabetic and nondiabetic women [110]. Overall, bacteriuria in diabetic women likely reflects the sum of the expected frequency of bacteriuria in women at risk for acute uncomplicated urinary infection who also happen to be diabetic, and bacteriuria in those at increased risk for complicated urinary infection from diabetic cystopathy. Other diabetes specific factors that may contribute remain to be identified. Symptomatic urinary infection may be more severe in diabetic than nondiabetic patients [123]. The severity of symptomatic infection and frequent observation of bacteriuria in diabetic women has led to some recommendations for treatment of asymptomatic bacteriuria [124]. Longterm, prospective studies of the natural history of asymptomatic bacteriuria in diabetic women do not suggest asymptomatic bacteriuria is harmful [111,125]. In 589 diabetic women followed 18 months, 14% with type I diabetes and 23% with type II diabetes developed any symptomatic infection. For type I diabetic women, symptomatic infection was associated with sexual activity, and for type II diabetes, with the presence of asymptomatic bacteriuria at baseline [125]. Accelerated progression to hypertension, renal failure, or other long-term complications was similar for bacteriuric and nonbacteriuric women [111,125]. In 14 years follow-up of 53 diabetic women with and 54 without bacteriuria, there were six and five episodes of pyelonephritis, and 12 and 10 deaths in the two groups, respectively [111]. No differences in creatinine or blood pressure between bacteriuric and nonbacteriuric subjects occurred over this prolonged observation. A prospective, randomized study of 3-monthly screening and therapy or no therapy for asymptomatic bacteriuria in 105 diabetic women reported no decrease in episodes of symptomatic infection or hospitalization for urinary infection in treated subjects, but greater antimicrobial exposure and a higher frequency of adverse drug effects with antimicrobial therapy [126]. A high rate of recurrent asymptomatic bacteriuria was also observed following therapy. These studies suggest that asymptomatic bacteriuria in diabetic women does not impair glucose control or promote development of long-term complications of diabetes. Antimicrobial treatment of bacteriuria does not decrease the frequency or severity of symptomatic urinary infection. Screening for and treatment of asymptomatic bacteriuria should not be recommended for diabetic women. Spinal cord injured patients Patients with spinal cord injury leading to neurologic impairment of bladder emptying have a high prevalence of bacteriuria [114 117]. Current patient care practices with a goal of maintenance of a low pressure bladder have substantially decreased morbidity and mortality from urosepsis and renal failure in these patients [127], but symptomatic urinary infection

L.E. Nicolle / Infect Dis Clin N Am 17 (2003) 367 394 381 remains an important clinical problem [128,129]. When spontaneous voiding is not possible, intermittent catheterization is frequently used for bladder emptying and, for men, sphincterotomy and condom drainage are also common. Whatever voiding method is used, the prevalence of bacteriuria remains high (see Table 6). Organisms colonizing the urethral or periurethral area, or present on the catheter, are repeatedly introduced into the bladder, and some of these persist [115,130,131]. Prospective cohort studies do not report progression to renal failure with bacteriuria if low bladder pressure is maintained [116]. Sotolongo and Koleilat [116] followed 56 male spinal cord injury patients on condom drainage, with sphincterotomy as necessary, for 5 years. Yearly urologic assessment, including measures of bladder pressure, was obtained. All patients had persistent asymptomatic bacteriuria, and none had deterioration in renal function or developed other abnormalities attributable to bacteriuria. In a small placebo-controlled trial Mohler et al [132] reported no decrease in symptomatic infection with antimicrobial therapy of bacteriuria. Screening for or treatment of asymptomatic bacteriuria in spinal cord injury populations is not currently recommended [128,133]. Renal transplant patients Asymptomatic bacteriuria is reported to be common in renal transplant recipients during the early posttransplant period. Ramsey et al [134] identified 65 infections in 35 of 65 transplant recipients during 14.7 months follow-up; 91% were asymptomatic, 57% occurred within 1 month, and 80% by 6 months. Infection correlated with repeated urethral catheterization, age over 40 years, nephrectomy, and splenectomy. Prat et al [135] reported 185 of 299 grafts with at least one episode of infection; 96% of episodes were asymptomatic. The incidence was 0.41 per graft per month in the first month, 0.21 per month in the first 3 months, and 0.0001 per month beyond 3 months. Persistent infection occurred in 11% of grafts and was uniformly associated with urologic complications. This group with persistent infection and urologic complications often experienced sepsis and graft loss. Graft survival is not associated with presence or absence of bacteriuria in patients without urologic complications [134,136]. Early posttransplant management has now evolved to include routine perioperative antibiotics, restriction of duration of urethral catheterization, and use of long-term prophylactic antibiotics to prevent all posttransplant infections. These practices have decreased the frequency of both asymptomatic and symptomatic urinary infection in renal graft recipients [137,138]. Postoperative bacteriuria in renal transplant patients is now less frequent, and recent studies continue to report no association of bacteriuria and graft survival [139,140]. Organ donors should be screened and treated for bacteriuria before the organ is harvested. Periodic urine culture surveillance in the posttransplant

382 L.E. Nicolle / Infect Dis Clin N Am 17 (2003) 367 394 period is recommended [141], but the benefits of this approach with current management of solid organ transplant recipients have not been evaluated [142]. The Immunocompromised Host Society Consensus Conference recommends periodic monitoring for urinary infection posttransplant, but does not recommend a specific frequency of screening, nor make a clear recommendation for therapy if bacteriuria is identified [143]. Whether screening for bacteriuria is useful in identifying renal grafts at risk for urologic complications has not been evaluated. Evidence to support screening recommendations in the postrenal transplant period is incomplete. It may be appropriate to screen for bacteriuria in the early postoperative period and up to 6 months posttransplant. Continued screening for and treatment of asymptomatic bacteriuria in a clinically stable renal transplant recipient beyond 6 months does not seem beneficial given the low frequency of bacteriuria, and lack of impact of bacteriuria on graft survival. Other immunocompromised patients It is not known whether identification and treatment of asymptomatic bacteriuria in patients with solid organ transplants other than the kidney is beneficial. With short periods of urethral catheterization, and widespread use of broad-spectrum antimicrobial prophylaxis, asymptomatic bacteriuria is likely infrequent. Posttransplant urine screening for bacteriuria is not currently recommended [143]. Patients with asymptomatic bacteriuria and chemotherapy-induced granulocytopenia for treatment of hematologic malignancies may be at risk for invasive urinary infection [144], but this observation predates widespread use of prophylactic broad-spectrum antimicrobials. Current guidelines for infection prevention in bone marrow transplant recipients do not recommend screening for asymptomatic bacteriuria [145]. In 222 female prostitutes in Kenya, the prevalence of bacteriuria was 23%. The proportions of HIV-positive and HIV-negative women with bacteriuria were similar, and bacteriuria did not vary with CD4 + count in HIV-infected women [146]. Hoepelman et al [147] reported 30% of HIV-infected men with a CD4 + count less than 200 per milliliter had bacteriuria with 6-monthly screening over 2 years, compared with 11% of HIV-infected men with CD4 + counts of 200 to 500, and no HIV-infected men with CD4 + counts over 500 [147]. De Pinto et al [148] found asymptomatic bacteriuria in 6.6% of men with AIDS at hospital admission; 3.2% of HIV-infected men without AIDS; and 1.8% in outpatient, non HIV-infected men aged 18 to 50 years [148]. The explanation for the increased prevalence with declining CD4 counts is not known, and negative clinical outcomes attributable to bacteriuria have not been reported. Routine screening and treatment of HIV patients is not currently recommended.

L.E. Nicolle / Infect Dis Clin N Am 17 (2003) 367 394 383 Subjects with urologic devices Short-term indwelling catheter From 2% to 7% of patients with a short-term indwelling urethral catheter acquire bacteriuria each day (see Table 6) [149]. The daily incidence is higher in women, and in individuals who do not receive concurrent antimicrobial therapy for the first 4 catheter days [150]. Studies performed early in the antimicrobial era reported no benefits of treatment of asymptomatic bacteriuria in catheterized subjects [151]. Currently, at least 80% of hospitalized patients managed with short-term catheters receive antimicrobial therapy for other indications, so evaluation of any specific benefit with treatment of catheter-acquired bacteriuria is problematic [152,153]. Screening and treatment of bacteriuria for subjects with shortterm indwelling catheters is recommended only for patients in another risk group, such as a pregnant woman or those undergoing an invasive urologic procedure. In a study of management of bacteriuria following catheter removal, women with persistent catheter-acquired bacteriuria 48 hours following catheter removal were randomized to treatment or no treatment with trimethoprim-sulfamethoxazole [154]. By 14 days, 26% of women receiving placebo developed symptomatic urinary infection, whereas 36% had spontaneous resolution. Bacteriuria in nontreated patients resolved spontaneously in 74% of women under 65 years of age and 4% of women over 65 years. Resolution also occurred more frequently in women infected with gram-positive organisms. Bacteriologic cure at 4 weeks for treated subjects was 89% of women less than 65 years, and 62% over 65 years. Antimicrobial treatment of women with persistent bacteriuria at 48 hours post catheter removal may prevent some symptomatic episodes. An alternate approach is treatment only when symptoms develop. Further comparative studies of screening and treatment of asymptomatic bacteriuria to clarify optimal management after catheter removal would be useful. Another controversial issue is whether screening cultures for bacteriuria should be obtained at catheter insertion and removal for surveillance for hospital-acquired urinary infection [155]. Urinary infection is the most frequent hospital-acquired infection, and is usually associated with an indwelling urethral catheter. Routine microbiologic screening for all catheterized patients may be expensive. The appropriate clinical management of patients with positive cultures is also not clear, and positive urine cultures in otherwise asymptomatic patients may promote unnecessary antimicrobial use. On the other hand, surveillance of nosocomial urinary infection facilitates early detection of outbreaks and identifies deficits in patient care practices. There are recommendations both for [156] and against [157] routine screening for nosocomial urinary infection. Currently, a decision about screening for nosocomial urinary infection should be made

384 L.E. Nicolle / Infect Dis Clin N Am 17 (2003) 367 394 at the individual facility level. Screening should be considered on at least a periodic basis, and certainly if potential concerns are identified. Chronic indwelling catheter Urethral catheters remaining in situ for over 30 days are considered chronic indwelling catheters. Indwelling urologic devices become coated with biofilm, a material composed of bacteria and extracellular bacterial substances together with urinary components including Tamm-Horsfall protein, magnesium, and calcium [158]. This same material forms struvite stones, and may result in catheter blockage. Biofilm supports a complex bacterial flora, with two to five distinct bacterial species isolated from the urine of patients with chronic indwelling catheters [119]. Bacteriuria is universal in patients with chronic urethral catheters. A urine specimen obtained through the catheter samples the biofilm as well as bladder urine. There is a greater number of species and higher quantitative count of bacteria isolated in urine collected through a catheter in place for several days than a simultaneous urine specimen collected through a freshly placed catheter [159,160]. Patients with chronic urethral catheters experience greater morbidity from symptomatic urinary infection than bacteriuric subjects without an indwelling catheter [161,162]. One prospective trial randomized elderly chronically catheterized patients with susceptible organisms to cephalexin or no antibiotic [163]. Antimicrobial therapy did not decrease the frequency of fever in treated compared with untreated subjects, and cephalexin-resistant organisms were isolated posttreatment in 47% of treated and 26% of the untreated group. A noncomparative study of intense antimicrobial treatment with sequential antibacterial agents in an elderly population also concluded that antimicrobial therapy seldom eliminates bacteriuria, and usually results in replacement with strains resistant to the antimicrobial given [164]. Treatment of bacteriuria in patients with a chronic indwelling catheter is not beneficial, and may be harmful. Screening for asymptomatic bacteriuria is not appropriate for patients with a chronic indwelling catheter. In selected situations, such as a potential institutional outbreak, screening of bacteriuria may be appropriate to assess the extent of spread of an organism and assist in evaluating interventions for outbreak control, rather than for patient management. Other devices Other urologic devices, such as ureteric stents, are increasingly used in management of patients with complex urologic problems. These devices are also uniformly coated with biofilm, and voided urine does not fully sample the bacteriology of the device [120]. Biofilm formation may contribute to obstruction of stents, but prophylactic antibiotics do not reduce bacterial colonization or prevent obstruction [120]. Pathogenesis and management likely mirror that of the chronic indwelling catheter. Although studies are

L.E. Nicolle / Infect Dis Clin N Am 17 (2003) 367 394 385 limited, screening cultures to identify asymptomatic bacteriuria and treatment are not currently recommended. Further study of the natural history and long-term outcomes of bacteriuria associated with these devices is needed. Surgical interventions Urologic surgery Genitourinary surgery with trauma and bleeding of the mucosa allows organisms in the urinary tract to invade the systemic circulation. If antimicrobial therapy is not given, from 25% to 80% of patients with bacteriuria undergoing a traumatic urologic procedure will have bacteremia [165]. Antimicrobial treatment before the intervention can prevent bacteremia and sepsis [165,166]. Urine cultures obtained before treatment identify the specific infecting organism and allow optimal preintervention antimicrobial selection. Therapy is initiated only immediately before the procedure, because earlier treatment may result in reinfection before the procedure, perhaps with a more resistant organism [165]. Controversy continues with respect to which urologic interventions require preoperative treatment of asymptomatic bacteriuria [166]. In addition, treatment of bacteriuria overlaps with recommendations for routine antimicrobial prophylaxis for all patients for some urologic procedures. Where a high probability of bleeding into the genitourinary tract is anticipated, however, preoperative antimicrobial therapy for bacteriuria is appropriate. Recent recommendations suggest patients with positive urine cultures should be treated before urodynamic studies, stent insertion, transurethral resection of the prostate, and removal of ureteric calculi [166]. Treatment is also recommended for cystoscopy in bacteriuric men, but not women. On the other hand, chronic indwelling catheter replacement does not require antimicrobial pretreatment [106]. Other surgical procedures Any concurrent infection at a site other than the surgical site, including bacteriuria, is associated with an increased risk of surgical wound infection [167], although this has not always been a consistent observation [168]. Asymptomatic bacteriuria may be a reservoir for bacterial contamination of the wound, or may simply identify a patient at increased risk of infection at any site, without having a causal relationship. Current recommendations suggest any infection remote to the surgical site should be identified and treated before an elective operation, and one assumes this includes asymptomatic bacteriuria [169]. Screening of urine specimens for bacteriuria before any surgical procedure, however, has not been recommended. In practice, perioperative prophylactic antibiotics, such as the cephalosporins,

386 L.E. Nicolle / Infect Dis Clin N Am 17 (2003) 367 394 used to prevent postoperative infection in clean-contaminated and selected clean procedures, suppress or eradicate bacteriuria in most patients. Summary Asymptomatic bacteriuria is common. Populations with structural or functional abnormalities of the genitourinary tract may have an exceedingly high prevalence of bacteriuria, but even healthy individuals frequently have positive urine cultures. Asymptomatic bacteriuria is seldom associated with adverse outcomes. Pregnant women and individuals who are to undergo traumatic genitourinary interventions are at risk for complications of bacteriuria and benefit from screening and treatment programs. Although screening is recommended for renal transplant recipients, the benefits for these patients are less clear. For other populations, including most bacteriuric individuals, negative outcomes attributable to asymptomatic bacteriuria have not been described. Treatment of asymptomatic bacteriuria in these patients is not beneficial and, in fact, may be associated with harmful outcomes, such as increased short-term frequency of symptomatic infection, adverse drug effects, and reinfection with organisms of increased antimicrobial resistance. Screening for asymptomatic bacteriuria and treatment is recommended for only selected groups where benefit has been shown. Many research questions still need to be addressed. Different populations have unique risk factors, and the benefits and risks of different management approaches for asymptomatic bacteriuria must continue to be addressed systematically in appropriate clinical trials. References [1] Rubin RH, Shapiro ED, Andriole VT, Davis RJ, Stamm WE. Evaluation of new anti-infective drugs for the treatment of urinary tract infection. Clin Infect Dis 1992; 15(suppl 1):S216 27. [2] Kass EH. Asymptomatic infections of the urinary tract. Trans Assoc Am Physicians 1956;69:56 63. [3] Kass EH. Bacteriuria and the diagnosis of infections of the urinary tract. Arch Intern Med 1957;100:709 14. [4] Marple CD. The frequency and character of urinary tract infections in an unselected group of women. Ann Intern Med 1941;14:2220 30. [5] Freedman LR. Natural history of urinary infection in adults. Kidney Int 1975;8: S96 S100. [6] Kunin CM. Asymptomatic bacteriuria. Annu Rev Med 1966;17:383 406. [7] Meares EM Jr. Asymptomatic bacteriuria. Postgrad Med 1977;62:106 11. [8] Kass EH. Pyelonephritis and bacteriuria: a major problem in preventive medicine. Ann Intern Med 1962;56:46 53. [9] Kantor AF, Hartge P, Hoover RN, Narayana AS, Sullivan JW, Fraumeni JF. Urinary tract infection and risk of bladder cancer. Am J Epidemiol 1984;119:510 5. [10] Asscher AW, Chick S, Radford N, Waters WE, Sussman S, Evans JS, et al. Natural history of asymptomatic bacteriuria in non-pregnant women. In: Brumfitt W, Asscher AW, editors. Urinary tract infection. London: Oxford University Press; 1973. p. 51 60.