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Essentials in Pediatric Urology, 2012: 95-106 ISBN: 978-81-308-0511-5 Editor: George Sakellaris

10. Urinary tract infections in children Nikolaos M. Baltogiannis

Consultant Pediatric Surgeon, 2nd Department of Paediatric Surgery, “St. Sophia” Children’s Hospital, Athens, Greece

Urinary tract infection (UTI) is a common pediatric problem with the potential to produce long-term morbidity (1, 2). The incidence of UTI in the pediatric population varies based on age and gender. Overall, UTIs are estimated to affect 2.4-2.8% of all children every year in the United States. The international incidence of UTI is difficult to accurately assess, especially in developing countries, but is assumed to be similar to that in the United States. Only during the first year of life do males have a higher incidence of UTI when compared to females. Furthermore, during the first 6 months of life, uncircumcised males have a 10- to 12-fold increased risk compared to circumcised males for development of UTI. With advancing age, the incidence decreases to less than 1% in school-age boys but rises to 1% to 3% in schoolage girls (3). The diagnosis is difficult to establish in early childhood due to the lack of specific urinary symptoms, difficulty in urine collection, and contamination of samples (4). Over recent decades, the importance of UTI has been increasingly recognized, in particular the role of UTI as an occult cause of febrile illness in young children. Studies from developing countries show that the around 10% of children with febrile illnesses have UTI (5). Correspondence/Reprint request: Dr. Nikolaos M. Baltogiannis, Consultant Pediatric Surgeon, 2nd Department of Paediatric Surgery, “St. Sophia” Children’s Hospital, Athens, Greece.

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Urinary tract infection is defined by the presence of organisms in the urinary tract, which is usually sterile. However, since asymptomatic colonization of the urinary tract can occur, other features such as the presence of inflammatory markers or follow-up cultures may be needed to definitively diagnose a UTI. Urinary tract infection can be further subdivided into infection localized to the bladder and urethra (cystitis and urethritis) versus upper tract infection of the ureter, collecting system, and renal parenchyma (pyelonephritis). Urinary tract infections in children may be symptomatic or asymptomatic. Age, gender, race, circumcision status, the method of detection, and presentation all influence the prevalence of symptomatic versus asymptomatic urinary infection. During preschool and school age, the male-to female ratio observed in neonates is reversed, making screening bacteriuria more prevalent in girls (6-8). Once treated, infants with symptomatic urinary infections are at risk for recurrent infection (26%), usually in the first 3 months of follow-up. In older girls the risk for recurrence following symptomatic urinary infection is as high as 40–60% within 18 months (9). The clinical significance of UTI has been controversial. In the preantibiotic era, UTI had a mortality rate as high as 20% although acute complications in healthy children are now uncommon except in young infants, who may progress to systemic infection (10,11) Long-term complications of UTI have been associated with renal scarring and include hypertension, chronic renal failure, and toxemia in pregnancy (12). Bacteria infect the urinary tract by ascending from the urethra, although hematogenous infection may occur in rare instances among young infants. Unfortunately, many of the organisms responsible for UTI in developing and industrialized countries have become resistant to first-line antimicrobials. It is thus necessary to establish the type of pathogen and antimicrobial sensitivities in the local environment in order to treat the UTI with the appropriate antibiotic. A large family of Gram-negative (aerobic bacilli known as Enterobacteriaciae) such as Escherichia coli, Klebsiella, Proteus, Enterobacter, Pseudomonas, Salmonella and Serratia spp., cause the majority of uncomplicated UTIs. Of these, E. coli is by far the most frequently isolated organism, being responsible for approximately 80% of UTIs. (9) The most common Gram-positive organisms including group B streptococci, Enterococcus sp., and Staphylococcus aureus. Studies have shown that there is a high frequency of Proteus sp. infections in older boys and greater variability in infecting organisms in boys than in girls, a greater likelihood of staphylococcal infection in adolescence, especially in girls, a greater frequency of E. coli urinary infection in neonatal boys than in girls of that age and a decreased frequency of Klebsiella urinary infection in older children (9).

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Ascending infection of the urinary tract is a complex process that has been associated with virulence, bacterial adhesion, and motility properties as well as host anatomic, humoral, and genetic factors. The term virulence simply refers to the ability of microorganisms to cause disease. The concept of uropathogenic bacteria refers to certain strains presenting specific factors that enhance colonization of the uroepithelium. Bacterial adherence or attachment is an essential initiating step in all infections. Tissue invasion, inflammation, and cell damage are secondary events (3,9). Establishing an accurate diagnosis includes determining the causative bacteria of the infection, its antibiotic sensitivity profile, and determining whether any anatomical or functional risk factors are present that might predispose the child to the current infection. Such information is crucial to establish the individual's risk for recurrent urinary tract infections, which can predispose to scarring of the kidney. It is therefore important note the need for well-collected and rapidly transported urine. Collection of an appropriate urine sample is an important component of the accurate diagnosis of urinary tract infection in children. If collection of a urine specimen is carried out badly, the future management of the child may be compromised. It could result in the giving of unnecessary antibiotics or the instigation of unnecessary imaging investigations if a contaminated sample is mistakenly considered to indicate the presence of a UTI. At least one well-collected, uncontaminated sample should be taken before antibiotics are started. Methods currently available for urine collection, from most to least invasive, are: supra-pubic aspiration, catheter-specimen urine, bagspecimen urine and clean-catch urine or mid-stream urine. Mid-stream urine was defined as a urine sample obtained from a child able to void on command, whereas a clean catch sample was defined as a urine sample obtained from a child unable to void on command. Supra-pubic aspiration is considered the “gold standard” method of urine collection. This can be performed safely in children and even in premature infants with a full bladder by cleansing the skin and percutaneously introducing a 21- or 22-gauge needle 1 to 2 cm above the pubic symphysis until urine is obtained by aspiration into a sterile syringe. In older children and infants who do not require immediate antibiotic treatment, cleancatch urine or mid-stream urine are the methods of choice for obtaining a urine sample (14). The gold standard for diagnosis of UTI is growth of pathogenic bacteria in a urine culture. The NICE (UK National Institute for Health and Clinical Excellence) guidance emphasizes that results from urine culture should be interpreted in relation to the clinical symptoms and findings. The presence of specific symptoms for UTI, including dysuria, frequency, urgency, suprapubic discomfort, and flank pain, should lead to screening. However, young children

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with UTI may present with nonspecific symptoms, such as poor feeding, vomiting, irritability, jaundice (in newborns), or fever alone, and a broader approach to screening may be appropriate. Symptoms of dysuria, urgency, frequency, and enuresis are non-specific and may be the result of vulvitis, urethritis, dysfunctional voiding, or non-specific causes, such as dehydration associated with febrile illness (12). However, according NICE, must be considering a diagnosis of urinary tract infection in all infants and children with: I. II. – – –

unexplained fever of 38°C or higher after 24 hours at the latest symptoms and signs suggestive of urinary tract infection, including: fever non- specific symptoms, such as lethargy, irritability, malaise, failure to thrive, vomiting, poor feeding, abdominal pain, jaundice (in infants) specific symptoms, such as frequency, dysuria, loin tenderness, dysfunctional voiding, changes to continence, hematuria, and offensive or cloudy urine (4).

Yet, controversy exists regarding the interpretation of urinalysis and culture results. Four determinations from the urinalysis may be useful in supporting a diagnosis of UTI (3): I. II. III. IV.

microscopic urinary examination for “pyuria”; microscopic urinary examination for bacteria; urinary leukocyte esterase; and urinary nitrite

The finding of significant pyuria on routine urinalysis varies with the volume of urine centrifuged and examined, the force and duration of centrifugation, and the volume in which cells are resuspended (15). Urine microscopy for bacteria significantly improves the reliability of urinalysis for the detection of urinary infection, particularly when one combines this with examination of urinary sediment for pyuria (16). The data obtained demonstrated that UTI is best defined by more than 10 leukocytes/mm3 on urinalysis combined with urine cultures yielding more than 50000 cfu/ml (17). In a recent study of febrile children, Hoberman et al. noted that a high proportion (65%) of cultures with colony counts between 10,000 and 49,000 grew mixed or gram-positive organisms suggestive of

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contamination (18). The NICE guidance mentions the cut-off value of 105 cfu/mL of a single organism as being the usually accepted laboratory indicator of UTI, but it also recognizes that lower amounts of growth, as well as the very occasional mixed culture, may be significant in some children. Especially in small male infants, the urine may not always remain in the bladder long enough to reach 105 cfu per mL. In paediatric practice, the level at which a growth is considered significant can vary according to the collection method used (7, 13, 32, 33). Usually >105 cfu/mL of a single organism is considered significant for clean-catch urines. For in/out catheter urines this figure is >104 cfu/mL (26) and for supra-pubic aspirates any growth should be reported, as this specimen should be sterile if taken correctly in the absence of a UTI. Although urine culture is the gold standard for diagnosis of UTI, results are not available for 24 to 48 h. In assessing the recommendations in the NICE guidance for urine screening tests pediatricians need to be aware that there is no rapid screening test that will detect all pediatric UTIs. The two main screening methods in use are dipstick testing for leukocyte esterase and nitrites and conventional microscopy, but false-positive and false-negative results may occur with both of them (12). These studies are inexpensive, rapid, and easy to perform. The NICE guidelines recommend the use of dipstick testing only in the case of children over the age of three years. The diagnostic accuracy of leukocyte esterase and nitrite dipsticks is much lower in younger children (22). The leukocyte esterase dipstick test demonstrates the presence of pyuria by histochemical methods that specifically detect esterases in the neutrophils. The nitrite method employs reagent paper that change color when in contact with nitrite (bacteria convert urine nitrate to nitrite). These methods had good overall performance and may be the most practical approach in an outpatient setting. However, back-up urine culture should be sent to detect the approximately 12% of UTIs that will be missed by the dipstick test (12). For decisions on urine testing strategies the NICE guidance on paediatric UTI has divided children into three groups: those < 3 months; those >3 months but 3 years of age. The reasons for division at this age are that acceptable urine samples are more easily obtained from the older age group, their symptoms tend to be more specific and they are more able to verbalize them. In contrast, uncontaminated specimens are less easily obtained from the two younger age groups. These children are more likely to have nonspecific symptoms, such as malaise, irritability, poor feeding, jaundice, failure to thrive and vomiting. Many will not be toilet trained and this increases the difficulty of obtaining satisfactory samples. The NICE guidance recommends that infants < 3 months of age should have urgent urine microscopy carried out.

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For children >3 months but 3 years old with a possible first time lower UTI, the NICE guidance recommends dipstick testing. If leukocyte esterase and nitrite are positive it is imperative to start antibiotic treatment for urinary tract infection and if child has high or intermediate risk of serious illness or a history of infection send urine sample for culture. If leukocyte esterase is negative and nitrite is positive start antibiotic treatment if fresh sample was tested and send urine sample for culture. If leukocyte esterase is positive and nitrite is negative send urine sample for microscopy and culture. Only start antibiotic treatment for urinary tract infection if there is good clinical evidence of such infection. Result may indicate infection elsewhere. Treat depending on results of culture. If leukocyte esterase and nitrite are negative do not send urine sample for culture unless the patient has a high to intermediate risk of serious illness, has recurrent UTI or is in one of the other indication groups for culture listed in the guidance (including an infection that does not respond to treatment within 2448 h). Do not start treatment for urinary tract infection and explore other causes of illness (4, 23). However, controversy continues to exist in literature regarding when and how a child with documented UTI should be evaluated. A recent systematic overview of the literature to assess the evidence on which current recommendations for routine diagnostic imaging are based found that there were no controlled trials or analytic studies which evaluated the need for routine diagnostic imaging (24). Generally, we would agree that all children under 5 years of age, boys of any age, and all with febrile UTI or documented acute pyelonephritis should be evaluated when infection is first recognized. Imaging evaluation is important to the diagnosis and management of UTI with the goal of altering or preventing further morbidity. Radiologic imaging can be used to (3): I. II. III. IV.

evaluate and localize the acute urinary infection, detect renal damage from the acute infection, identify genitourinary anatomy that increases the risk of future renal damage from infection, and Evaluate changes in the urinary tract over time.

Recommended imaging studies for a child with a history of a culturedocumented UTI are based on the experience of the radiologist and the availability of imaging modalities. Age, gender, race, and the type and

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frequency of UTIs must also be taken into consideration. Infants and young children presenting with urinary tract infections have traditionally been investigated extensively due to a concern that developing kidneys are more susceptible to damage from pyelonephritis and that the risk of identifying associated urinary tract abnormalities is statistically higher in this group. Children of all ages with atypical urinary tract infection must be performing ultrasonography of the urinary tract during the acute infection to identify structural abnormalities of the urinary tract. The American Academy of Pediatrics guidelines focus on children under the age of 2 years, stating that those over 2 years old are less likely to have factors predisposing them to renal damage and are at lower risk (12). Thus, the initial evaluation in children older than 2 years should be of the kidney, including sonography to exclude surgical conditions which predispose to infection and DMSA scintigraphy to detect acute pyelonephritic inflammation. With this approach, cystography is reserved for infants under 1–2 years and older children with abnormal DMSA scan findings or recurrent UTIs. Also, a cystogram can detect the presence of VUR, ureteroceles, posterior urethral valves in boys, or bladder wall thickening and a sonogram to look for obstruction, hydronephrosis, or other congenital malformations (25, 26). Cystogram is generally accepted that it can be performed whenever the child is afebrile and when the urine is sterile (27). Both direct and indirect cystography techniques are used. Direct cystography involves filling the bladder by urethral catheterization or percutaneous suprapubic infusion. Indirect radionuclide cystography uses 99mTc DTPA which is excreted by glomerular filtration. The presence of reflux can be assumed when radioisotope counts increase in the renal areas after voiding. Indirect cystography is less reliable for the detection of VUR than direct radionuclide cystography, with false-negative rates ranging from 22 to 51% (28, 29). Routine antibiotic prophylaxis following a first-time UTI is no longer recommended, although it may be considered for certain infants and children with recurrent UTI (23). Prophylactic antibiotics reduced bacteriuria, but there was no high-level evidence that they were effective in preventing further symptomatic UTIs and renal scarring, the most important outcomes for the patient (30, 31). Further problems relating to the use of prophylactic antibiotics for pediatric UTIs are that they are inconvenient for the patient and compliance is not always good. In addition, the increased risk of development of resistant organisms following prophylactic antibiotics and the cost of the drugs has to be taken into account as well as the risks that can be associated with any medication (30). Long-term, continuous antibiotic prophylaxis is recommended in children with VUR (particularly under 8 years of age) and those with frequent symptomatic recurrences. Antibiotic prophylaxis should

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also be considered in young children (under age 1) with no reflux acute pyelonephritis when acute or chronic renal damage is documented by cortical scintigraphy. Children with recurrent pyelonephritis and those with frequent recurrent symptomatic lower UTIs (three in 6 months, four in a year) should also be considered for prophylaxis for a minimum of 6–12 months, even in the absence of VUR. Without timely treatment, renal scarring can occur (32), which is likely to affect approximately 5–15% of young children with a UTI (33-36). Renal scarring is associated with serious health problems in later life, such as hypertension, complications during pregnancy, and renal failure (32). Amoxicillin/clavulanic acid or co-trimoxazole are the medications of choice in an attempt to reach effective tissue levels and to maximize the chance of the most effective medicine until test results are available. The American Academy of Pediatrics committee reviewing this topic recommended oral or parenteral antibiotics unless the child appeared “toxic, dehydrated or unable to take oral intake,” in which case parenteral therapy is indicated (37). The appropriate treatment for UTI has been a subject of recent research. Amoxicillin/clavulanic acid is the antibiotic most commonly prescribed, by pediatrician for the ‘blind’ treatment of UTI in children. This is consistent with the results of three randomized control trials which compared the effectiveness of different oral antibiotics in lower UTI in children reported no significant difference between treatments (38-41). NICE do not recommend a specific antibiotic for ‘blind’ treatment, but instead suggest that the choice should be based upon locally developed multidisciplinary guidance. It is suggested that an antibiotic with low resistance patterns, such as a cephalosporin, should be used when treating an upper urinary tract infection with oral antibiotics. It is also suggested that trimethoprim, nitrofurantoin, cephalosporin or amoxicillin may be suitable for the treatment of lower urinary tract infection (cystitis) (42). The WHO Pocketbook of Hospital Care for Children recommends for antibiotic therapy: I.

II.

Give oral cotrimoxazole for 5 days. Alternatives include ampicillin, amoxicillin and cephalexin, depending on local sensitivity patterns of Escherichia coli and other Gram-negative bacilli that cause UTI, and on antibiotic availability. However, increased rates of Escherichia coli resistance have made amoxicillin a less acceptable choice, and studies have found higher cure rates for trimethoprim-sulfamethoxazole (37). If there is a poor response to the first-line antibiotic or the child’s condition deteriorates, give gentamicin plus ampicillin or a parenteral cephalosporin. Consider complications such as pyelonephritis (tenderness in the costo-vertebral angle and high fever) or septicaemia.

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Treat young infants aged