Clinical Guideline for Childhood Urinary Tract Infection (Second Revision)

Recommendation 1:

Consider UTI in infants and young children with unexplained fever (>38.0℃). Admit febrile infants younger than three months, infants with toxic symptoms/signs and children with severe pyelonephritis.

1. Urine collection

Diagnosis of UTI should be prompt and accurate by appropriate urine collection, to prevent therapeutic delay and overdiagnosis There are four collection methods, which are different invasiveness and contamination rates. Clean midstream catch (CMC) is an easy and accurate method in toilet-trained (TT) children. The midstream urine is collected (twice) after simple retraction of the prepuce in uncircumcised male infants and simple separation of labia majora in female children. Suprapubic aspiration (SPA) is a gold standard method in non TT children. The success rate in ultrasound guided SPA is very high (90-100%) although it is invasive. Complication is very rare (hematuria 0.5-2%, intestinal puncture 0.2%). After disinfection of suprapubic area, the urine is aspirated by perpendicular midline puncture with 21-gauge needle, 1 cm above the symphisis pubis [14]. Transurethral catheterization (TUC) is less invasive but more contaminated method than SPA. The success rate is very high (99%) except in severe non-retractile physiologic phimosis. But urethral irritation, urethral stenosis, hematuria and catheter induced UTI are rare inevitable complications. After disinfection of periurethral area, catheter is inserted to catch the urine. Sterile-bag collection (SBC) is the easiest method in non-TT children. But the contamination rate is very high. After washing around the prepuce or the perineum with water or saline, attatch a sterile bag. Immediately after voiding, the urine is collected [15]. Because each method has its merit and fitfall, the ideal method should be selected according to the age, the severity of symptoms and the status of toilet training. In TT children, CMC is a satisfactory method for diagnosis. In non-TT children, SBC is a reasonable method for a screening test, but SPA or TUC is mandatory for accurate diagnosis [2,16]. To ensure the accuracy of the tests, the collected urine specimens must be stored adequately to keep fresh (< 1 hour after voiding at room temperature and <4 hours in refrigerator).

2. Urinalysis

An urinalysis, a rapid screening test to make a presumptive diagnosis of UTI, consists of biochemical dipstick (Multistix) and microscopic sediment analysis. Dipstick urinalysis indicates the presence of leukocyte esterase (LE) or nitrite, and sediment urinalysis indicates the presence of WBC, WBC cast and bacteria. Using either the dipstick or sediment analysis, sensitivity improves at the expense of specificity (Table 2) [7,17].

Table 2.

Sensitivity and Specificity of Urinalysis.

The LE test can be false negative (6-33%) in early UTI and false positive (8-36%) in other febrile illness, nonspecific vaginitis or interstitial nephritis. The nitrite test can be also false negative (18-85%) in early UTI and can be false positive (0-10%) by periurethral/perineal normal flora, Gram (+) or contaminated bacteria. The nitrite test has a relatively high specificity but is not a sensitive marker in children, who empty the bladder frequently because Gram (-) bacteria should be present for at least 4 hours in the bladder to convert the dietary nitrate to nitrite [18]. Therefore, the urinalysis cannot substitute for a urine culture, but it can be valuable in selecting children with a presumptive UTI. A positive nitrite with/without LE, give a presumptive diagnosis of UTI to initiate the empirical antibiotic therapy. A negative test for both nitrite and LE suggests no UTI, although it does not rule out a UTI with certainty (Table 3). Urine WBC cast is very significant finding for pyelonephritis but rapidly resolves (<10 minutes) in the alkali urine.

Table 3.

Diagnosis of Presumptive Urinary Tract Infection (UTI) and Empirical Antibiotic Treatment according to Urine Dipstick Test

3. Urine culture

To establish a diagnosis of UTI, a significant number of colony-forming units (CFUs) of a single uropathogen, should be cultured on an appropriately collected urine specimen. The traditional criterion (cut off level) for a positive culture was over 10⁵ CFU/mL although 10⁴-10⁵ CFUs/mL were accepted in symptomatic children, who are on fluid therapy, antibiotics pretreatment or disinfection for urine collection. Recently, America Academy of Pediatrics (AAP) reduced the criterion to 50,000 CFUs/mL in the SPA or the TUC urine [7]. The diagnostic rates of the criterion, over 10⁵ CFU/mL, were different according to the urine collection method [70-90% (once) or 90-95% (twice) in the clean midstream catch urine, 95-99% in the SPA urine, 90-95% in the TUC urine and 14-84% in the sterile bag-collected urine]. A positive culture of the sterile bag-collected urine may suggest asymptomatic bacteriuria (ASB), which is not a true UTI [19]. Therefore, a true UTI must be distinguished from ASB. In symptomatic children with a positive SBC urine culture and abnormal urinalysis, the diagnosis is UTI. In asymptomatic children with a positive SBC urine culture and normal urinalysis, the diagnosis is ASB. In febrile infants who has other viral illness, ASB is frequently confused with a true UTI but should be distinguished because antibiotic treatment may do more harm than good. The positive urine culture of mixed uropathogens or non-pathogenic bacterias (coagulase-negative staphylococcus, corynebacterium etc.) means contamination or the normal flora. The pretreatment of antibiotics should be always considered in children with definite symptoms and a negative culture, where ^99mTc-DMSA renal scan is helpful.

Recommendation 2 : Early and accurate diagnosis

1. The ideal method for urine collection : SPA or TUC in non-TT children who are very ill. SBC first in those who are not so ill and then SPA or TUC if an urinalysis is abnormal.

2. Interpretation of urinalysis : A positive nitrite with/without LE give a presumptive diagnosis of UTI. A positive LE only may or may not suggest UTI. A negative test for both nitrite and LE suggests no UTI.

3. A criterion for a positive urine culture in the SPA and TUC urine, is reduced to 5x10⁴ CFUs/mL. An abnormal urinalysis (pyuria) can distinguish a true UTI from an ASB. When a urine culture is positive (>10⁵ CFU/mL) in the SBC urine, UTI should be diagnosed only in children with both definite symptoms and abnormal urinalysis.

1. Selection of antibiotics

The empirical antibiotic choice should be based on local antimicrobial susceptibility patterns for isolated dominant uropathogen [Escherichia coli (E. coli)] in the community because they are ever changing and have substantial geographic variability [20]. At first, select the sensitive antibiotics empirically and change to the most susceptible one by the susceptibility result if not improved after 48 hours. The reported resistant rates of antibiotics are variable and changing [low (0-20%) in third generation cephalosporins, aminoglycoside and imipenem, intermediate (20-35%) in amoxacillin-clavulanate or ciprofloxacin, and high (30-85%) in ampicillin or trimethoprim/sulfamethoxazole (TMP/SMX). The emergence of extended-spectrum β-lactamase (ESBL) producing uropathogens has increased the resistant rates to third generation cephalosporins. Korean antimicrobial resistance monitoring system regularly gives the sensitivity patterns of antibiotics.

2. Administration of antibiotics

Febrile UTI children, who are younger than three months, toxic or unable to retain oral intake, should receive antibiotics parenterally until clinical improvement and followed by oral treatment. A short course (2-4 days) of parenteral treatment is as effective as a longer course (7-14 days) of parenteral treatment. Moreover oral antibiotics alone are as effective as the combinations of parenteral and oral antibiotics in most febrile UTIs and pyelonephritis. If aminoglycosides is chosen, single daily dosing is safe and effective. The majority of cystitis can be easily treated with oral antibiotics. Parenteral antibiotics include third generation cephalosporins and aminoglycoside and oral antibiotics include third generation cephalosporins, amoxacillin-clavulanate, and trimethprim/sulfamethoxazole (TMP/SMX). Aminiglycoside or imipenem is recommended in UTI by extended-spectrum β-lactamase (ESBL) producing E. coli. (Table 4). For the duration of antibiotics treatment in febrile UTI or pyelonephritis, longer treatment (>7 days) is more effective than shorter treatment (<7 days) in the success and the relapse rates. The minimal duration should be 7 days. A study, comparing 7, 10 and 14 days was not found. In cystitis, shorter treatment (3-5 days) is as effective as longer treatment (5-7 days) [21-23].

Table 4.

Antibiotics for Oral and Parenteral Treatment of UTI

Recommendation 3 : Prompt and adequate antibiotic treatment

Choose the sensitive antibiotics for dominant uropathogen in the community. Oral and parenteral treatment is equally effective in febrile UTI without toxic symptoms. The duration should be 7 to 14 days in febrile UTI and pyelonephritis and 3 to 5 days in afebrile UTI and cystitis.

Recommendation 4 : Targeted restrictive imaging studies.

RBUS is still a basis to detect urinary abnormalities, pyelonephritis, and abscess. VCUG should not be performed routinely after first UTI and is indicated in abnormal RBUS, atypical or complex clinical conditions and recurrent UTI. DMSA is efficacious in diagnosing culture negative pyelonephritis.

1. Antibiotic prophylaxis

Antibiotic prophylaxis has been widely used to prevent recurrent UTIs and subsequent renal scarring in children with primary VUR according to the AUA guideline [1,2]. In the past decade, the beneficial role of antibiotic prophylaxis to prevent renal scar, has been questioned. Moreover, the potential for emergence of antimicrobial resistant bacterias, has been a major concern. Recent randomized controlled trials (RCTs) including the Randomized Intervention for Children with Vesicoureteral reflux (RIVUR) trials do not support the use of antibiotic prophylaxis in children without or with VUR (grade I to IV) [28-30].

2. Physiologic phimosis

Uncircumcised male is listed as an important risk factor for UTI [11]. The tight prepuce in uncircumcised male, designated as physiologic phimosis, had a propensity to be colonized by uropathogens and to develop UTI. Treatment options for physiologic phimosis are neonatal circumcision and topical steroid. AAP policy for neonatal circumcision have turned to positive position because the evidences indicated that potential medical benefits outweigh the risks [31]. However, the Cochrane review (2012) still concluded that more evidences are required for routine neonatal circumcision to prevent UTI [32]. Another option is topical application of steroid. A majority of clinical studies were performed in prepubertal boys, using highly potent steroids with the success rates 68-91% [33]. In infants and younger children with physiologic phimosis, the success rates was much higher (95.1%) even with the least potent hydrocortisone. In infants whose prepuces became completely retractile after topical hydrocortisone, the incidence of recurrent UTI significantly decreased [34].

3. Inadequate urogenital hygiene

Urogenital hygiene (preputial and perineal hygiene) is an another important risk factor for UTI but is frequently ignored. Regular washing can inhibit the adhesion and the growth of uropathogens. The prepuce, the urethra or the perineum is a reservoir for uropathogens. In uncircumcised male infants, simple retraction of prepuce and washing are good preputial hygiene and offer many advantages of neonatal circumcision in eliminating uropathogens. In female infants, simple separation of labia majora and washing are adequate perineal hygiene to eliminate uropathogens. However, there is no clinical study about the effect of urogenital hygiene in preventing ASB or UTI [35].

4. Labial adhesion

Labial adhesion (LA) is defined as complete or partial fusion of the labia minora and is the cause of urethrovaginal reflux and urinary stasis to facilitate the growth of uropathogens. The prevalence was reported as 0.6-5% only in prepubertal girls. Topical steroid or estrogen cream for 2-4 weeks successfully lysed the adhesion without significant side effects in prepubertal girls [36]. LA is listed as a risk factor for childhood UTI in Nelson textbook of Pediatrics [11] but the prevalence in infants and children is unknown and also there is no clinical study in the literature.

5. Dietary factors (breast milk, probiotics, cranberry)

There are some dietary factors to prevent UTI [37]. Breast feeding prevents UTI in infants [38]. Breast milk contains many immunologic factors (sIgA, lactoferrin, oligosaccharides etc) and is a source of lactobacilli. Lactobacilli are acquired at birth as the baby pass through the birth canal and then grow on subsequent breast milk intake. Human colostrum and breast milk are the important natural sources of lactobacilli [39]. Lactobacilli inhibit the growth and the adhesion of uropathogens, and prevent the development of UTI. The beneficial role of lactobacilli are mediated by a number of mechanisms such as production of a biofilm barrier, secretion of antimicrobial compounds and stimulation of innate immunity [40]. A meta-analysis reported that lactobacillus probiotics significantly prevent UTI when a sensitivity analysis was applied [41]. In children, The preventive effect of lactobacillus probiotics was not inferior to antibiotic prophylaxis in children with primary VUR [42,43]. Although the evidence is not definite, considering probiotics mediated activation of the innate immune system, probiotic therapy is a new immunomodulating approach toward UTI in this era of increasing antimicrobial resistance [40]. Cranberry is a traditionally used functional food that contains proanthrocyanidin that inhibit adhesion of p-fimbriated uropathogens to the uroepithelium, prohibit asymptomatic colonization and UTI. RCTs with cranberries showed the effectiveness, significantly more than antibiotics and probiotics in preventing UTIs [44,45]. Breast milk, probiotics and cranberries, the natural diatetary factors, is safe and promising as prophylaxis for UTI [46-49].

6. Voiding dysfunction (VD), constipation and toilet training (TT)

VD, constipation and TT are separately listed as risk factors for UTI but they are interelated [50]. Dysfunctional elimination syndrome (DES) or bladder and bowel dysfunction (BBD) is one form of VD that is associated with constipation. However, voiding dysfunction or constipation should be treated separately and properly. The pathogenesis of VD and constipation is unknown, but maturation delay of neurological bladder and bowel control has been considered, which is related with TT. TT is very important for childhood development, and suggested as the cause of VD and BBD. Regarding the ideal age for TT, the debate has been still ongoing but is defined as 18–24 months in textbooks. Early TT before 18 months was definitely associated with urinary continence and later TT after 24 months was associated with bladder dysfunction [51].

7. Follow–up urine culture

Renal scar increases by the number of recurrent pyelonephritis and is prevented by early treatment. For this reason, children with first UTIs should have the follow-up urine test at the onset of subsequent unexplained febrile illness for early diagnosis. Regular periodic urine culture is not routinely recommended because the detection of ASB is not considered to be useful. ASB is not a cause of further renal damage and has a tendency to disappear spontaneously. Moreover, ASB can progress to symptomatic UTI by more virulent uropathogens, if treated with antibiotics [7]. However, it is unknown whether proper hygiene and probiotics is effective for clearing ASB.

Recommendation 9 : Natural approach for prevention

Antibiotic prophylaxis is not recommended any more in children without or with VUR (grade I to IV). For physiologic phimosis, topical steroid for 2-4 weeks will be a first-line treatment rather than neonatal circumcision. Education for adequate genital hygiene is absolutely required. Labial adhesion should be diagnosed and treated with topical steroid or estrogen for 2-4 weeks. Breast feeding should be encouraged. Probiotics can be a safe, promising agent to prevent UTI in this era of increasing antibiotic resistance. Cranberry is a natural functional food to prevent recurrent UTIs. Early TT at 18-24 month to prevent VD and constipation. Follow-up urine culture should be performed at the onset of subsequent unexplained febrile illness.