This document provides an overview of urinary tract infections in children. Some key points include:
- UTIs are common in young children, especially girls under age 7 and uncircumcised boys under 1.
- Symptoms range from cystitis to more severe pyelonephritis. Proper diagnosis requires urinalysis and urine culture.
- Risk factors for UTIs and recurrent UTIs include anatomical abnormalities, functional issues, prior antibiotic use, and young age.
- Treatment involves antibiotics chosen based on local resistance patterns. Follow up includes imaging to identify issues like reflux.
- Antibiotic resistance is a growing problem, with varying resistance levels in different geographic regions.
3. Epidemiology of UTI
Urinary tract infection (UTI) is the second most common bacterial infection in
children
8% of girls and up to 2% of boys within the first 7 years of life
Of those who develop a UTI in childhood, up to 30% will develop a second UTI
The highest prevalence of UTI include neonates, young infants, toddler girls,
and uncircumcised boys less than 1 year of age
4. Urinary Tract Infection Terminology
Bacteriuria is defined as the presence of bacteria in the urine. This can be associated
with infection or urinary tract colonization
Infection is defined by the presence of pathogenic microorganisms in the urinary tract,
resulting in a symptomatic inflammatory response
Colonization or asymptomatic bacteriuria (ABU) is the asymptomatic presence of
bacteria in the urine without significant pyuria
Cystitis, the most common form of UTI, refers to the presence of inflammation isolated
to the bladder.
Pyelonephritis occurs when microbes ascend to the upper urinary tract and infect the
renal parenchyma
5. UTI classification
UTI can be classified as simple or complicated based on the absence or presence
of risk factors, respectively, including structural or functional urinary tract
abnormalities, indwelling devices, immunosuppression, or renal transplantation
6. UTI classification
UTI can be classified as simple or complicated based on the absence or presence
of risk factors, respectively, including structural or functional urinary tract
abnormalities, indwelling devices, immunosuppression, or renal transplantation
Structural
VUR
Posterior urethral valves
Prune belly syndrome
Ureteropelvic or ureterovesical junction obstruction
Megaureter
Polycystic kidney disease
Functional
Neurogenic bladder
7. Clinical Impact
UTI is responsible for 500,000 pediatric emergency department visits and more
than 1 million clinic visits each year in the United States.
UTI carries an acute risk of morbidity and mortality due to urosepsis, renal abscess
formation, and acute kidney injury.
There is also a chronic risk of morbidity due to acquired renal scars, leading to
chronic renal insufficiency, proteinuria, and hypertension.
8. Pathogenesis of Urinary Tract Infection
The urinary tract has multiple mechanisms to prevent invasion by uropathogenic
bacteria, including:
Unidirectional flow of urine
Complete bladder emptying
Secretion of antimicrobial proteins and peptides into the urine stream
Urine ionic composition.
The urothelium serves as the first line of defense against bacterial infection by
preventing bacterial adherence and producing antibacterial peptides and mucous
9. Pathogenesis of Urinary Tract Infection
Uropathogenic Escherichia coli (UPEC) is the most common pathogen implicated in
UTI, accounting for 85% to 90% of episodes.
Other enteric gram-negative bacteria can cause UTI, including Klebsiella,
Pseudomonas, Proteus, Enterobacter, and Citrobacter spp
Most uropathogens originate from fecal flora that crosses the perineum to ascend
the urethra and infect the bladder.
10. Pathogenesis of Urinary Tract Infection
UPEC triggers the host innate immune response, with production of inflammatory
cytokines, complement activation, antimicrobial peptide secretion, and recruitment
of phagocytes.
Although innate immunity functions effectively to eradicate bacteria, the resulting
inflammation also leads to urothelial injury and clinical symptoms of cystitis.
In the pathogenesis of acute pyelonephritis, most of the cases occur as a
consequence of bacterial ascension from the bladder.
11. Pathogenesis of Urinary Tract Infection
The presence of vesicoureteral reflux confers increased susceptibility to APN.
UPEC triggers phagocyte recruitment and activation, leading to acute tubulo-
interstitial nephritis.
The collateral damage triggered by the host immune response is self-limited
and reversible in most instances but a subset of children experience renal
scarring
12. DIAGNOSIS
The American Academy of Pediatrics (AAP) clinical practice guidelines define UTI
based on urine culture and presence of pyuria.
Pyuria is identified by urinalysis: ≥10 white blood count (WBC)/mm3 or ≥ 5 WBC per
high-powered field (HPF), or by the presence of leukocyte esterase (LE) on a
dipstick.
A positive urine culture is defined by isolation of a single uro-pathogen at a density
of:
≥ 50,000 colony-forming units (CFUs)/mL for urine specimens collected by
catheterization or suprapubic aspiration(SPA)
≥ 100,000 CFU/mL for a midstream, clean-catch urine specimen
13. Screening for Urinary Tract Infection
in Febrile Infants and Young Children (2–24 Months)
Infant girls
Presence of more than 2 of the
following risk factors increases
probability of UTI to greater than 2%
1. White race
2. Age less than 12 months
3. Fever greater than 48 hours
4. No other apparent fever source
5. Fever greater than or equal to 39°C.
Circumcised infant boys
Presence of more than 3 of the
following risk factors increases
probability of UTI to greater than 2%
1. Non-black race
2. Fever greater than 24 hours
3. No other apparent fever source
4. Or fever greater than or equal to
39°C.
In uncircumcised infant boys, the probability of UTI is greater than 2% in the presence
of fever greater than 39°C, without additional risk factors
14. Screening for Urinary Tract Infection
in Older Children and Specific Populations
Verbal children and adolescents should be screened for UTI if they have symptoms
of dysuria, urgency, frequency, cloudy urine, or abdominal or flank pain, with or
without fever.
Screening should also be done in children of any age with fever without a source if
they have known urinary tract abnormalities, such as hydronephrosis, VUR,
multicystic dysplastic kidney, neurogenic bladder, and voiding dysfunction
Nonverbal children with cognitive disabilities
15. Urine collection
In toilet trained children and adolescents, urine should be collected via
midstream, clean catch.
In children who have not achieved urinary continence, urine should be collected
by transurethral catheterization or SPA.
Urine collected via urinary bag placed on the perineum should only be used to
rule out a UTI based on UA but should never be used to diagnose a UTI.
There is a high likelihood of contamination and false-positive results from
bagged urine specimens.
16. Urine Nitrites
Presence of LE and nitrites on urine dipstick has a combined sensitivity of 93% and
specificity 72% for UTI.
Urine nitrites are very specific for UTI but are not always present in the setting of
UTI. Nitrites are the conversion of dietary nitrates by enteric gram-negative,
enteric organisms.
It can take up to 4 hours for organisms to reduce nitrates to nitrites, and this can
be missed on initial screening UA.
Furthermore, not all uropathogenic bacteria produce nitrites, giving nitrates a
poor sensitivity for ruling out UTI
17. Atypical Uropathogens
Viral cystitis can occur in both immunocompetent and immunocompromised
patients.
In immunocompetent children, certain adenovirus strains cause a viral cystitis
characterized by gross hematuria, dysuria, and abdominal discomfort.
In immunocompromised children, polyomaviruses such as BK virus can cause
hemorrhagic cystitis
Children with urinary schistosomiasis may present with cystitis and terminal
hematuria
Fungal cystitis is rare but can occur in children on chronic antibiotics, with
indwelling catheters, or children who are immunocompromised
18. Asymptomatic Bacteriuria
The clinical significance of ABU in healthy children is controversial. Various
studies have shown 0% to 10% of children with ABU will develop a symptomatic
UTI.
One randomized, prospective study of young girls with ABU showed no
difference in renal function or renal size between girls treated for ABU and
those left untreated
Screening for ABU is not recommended in any population and bacteriuria
should only be treated if there is clinical suspicion for symptomatic infection.
19. CLINICAL MANAGEMENT
Antimicrobial Treatment
Prompt empiric antibiotics should be prescribed based on local sensitivity and
resistance patterns.
Antimicrobial therapy should be tailored to the results of urine culture and
sensitivities.
Antibiotics should be continued for a total of 7 to 14 days
Inpatient parenteral therapy should be considered for the first 2 to 4 days in acutely ill
children, children who cannot tolerate oral therapy
20. Susceptibility and resistance
In 2013, Edlin et al. described resistance patterns in pediatric urinary isolates from 192 hospitals
throughout the United States
24% of E coli cultured were resistant to trimethoprim-sulfamethoxazole
45% resistant to ampicillin
10% of E coli were resistant to cephalosporins, amoxicillin-clavulanate, ciprofloxacin,
and nitrofurantoin.
Nitrofurantoin is excreted primarily in the urine and can be a good antibiotic choice for isolated, afebrile cystitis.
However, it does not achieve adequate concentrations within the blood stream, making it a poor therapy for
febrile infants or young children with UTI
Empiric antibiotics should be discontinued immediately if the urine culture is sterile by 48 hours.
Edlin RS et al. Antibiotic resistance patterns of outpatient pediatric urinary tract infections. J Urol 2013;190(1):222–7.
21. Global prevalence of antibiotic resistance in pediatric urinary tract
infections caused by Escherichia coli and association with routine use of
antibiotics in primary care: systematic review and meta-analysis
Results 58 observational studies investigated 77 783 E coli isolates in urine.
In studies from OECD countries, the pooled prevalence of resistance was 53.4% for ampicillin,
23.6% for trimethoprim, 8.2% for co-amoxiclav, and 2.1% for ciprofloxacin; nitrofurantoin was
the lowest at 1.3%
Resistance in studies in countries outside the OECD was significantly higher: 79.8% for
ampicillin, 60.3% for co-amoxiclav, 26.8% for ciprofloxacin, and 17.0% for nitrofurantoin.
There was evidence that bacterial isolates from the urinary tract from individual children who
had received previous prescriptions for antibiotics in primary care were more likely to be
resistant to antibiotics, and this increased risk could persist for up to six months
22. Geographical distribution of urinary E coli resistance prevalence to ampicillin (%) by OECD and
non-OECD countries,15 with number of included studies per country in parentheses).
Ashley Bryce et al. BMJ 2016;352:bmj.i939OECD (Organisation for Economic Co-operation and Development)
23. The antibiotic susceptibility
patterns of uropathogens
among children with urinary
tract infection in Shiraz.
Pouladfar G et al.
Medicine (Baltimore). 2017
Sep;96(37):e7834.
25. Workup After First Febrile Urinary Tract Infection
Renal and bladder ultrasound (RBUS) is recommended after the first febrile UTI in
children 2 to 24 months old to evaluate renal parenchyma, renal size, and urinary
tract abnormalities that require further evaluation
RBUS can and should be obtained after treatment of UTI because acute infection
can alter the size and echogenicity of the renal parenchyma and cause transient
hydronephrosis
However, to rule out abscess or pyonephrosis that would require parenteral
antibiotics, RBUS should be considered in the first 48 hours of treatment if illness
is more severe than expected or if there is failure to improve with appropriate
therapy
26. VUR
Some degree of VUR is found in up to 40% of children after a first febrile UTI.
Based on 2008 data from the North American Pediatric Renal Trials and
Collaborative Studies (NAPRTCS), reflux nephropathy is the reported cause of
chronic kidney disease in up to 8.4% of children.
Current guidelines recommend obtaining voiding cystourethrogram (VCUG) only
if RBUS is abnormal or after a second febrile UTI.
RBUS abnormalities include hydronephrosis, scarring, or other findings
suggestive of high grade VUR or obstructive uropathy (ie, abnormal bladder
thickening, uroepithelial thickening in the renal pelvis, or hydroureter
Roberts KB et al. Pediatrics 2011;128(3):595–610.
27. DMSA
DMSA is highly sensitive for identifying APN.
Up to 57% of children with a febrile UTI have findings of APN on DMSA.
According to the Randomized Intervention for Children with Vesicoureteral
Reflux (RIVUR) study data, DMSA done 4 to 6 months following treatment of a
UTI revealed renal scarring in up to 15% of children who had radiologic
evidence of pyelonephritis
Mattoo TK et al. Clin J Am Soc Nephrol 2016;11(1):54–61.
28. Recurrent Urinary Tract Infection
Defined as 2 or more episodes
Risk factors:
Female
VUR grade 3 to 4
Toilet training age
Bowel and Bladder Dysfunction
Sexually active adolescents
Examination for neurologic deficits, sacral dimples, tufts of hair, or genitourinary abnormalities is
required.
29. History and Physical exam in rUTI
History should focus on evaluation of baseline voiding and stooling behaviors.
The child or parent should be questioned about stooling habits to assess for
constipation or stool withholding and history of urinary accidents during the day
or night.
Patients and families should be asked about gait disturbances and alterations in
lower extremity sensation or movement to assess for underlying spinal cord
abnormalities.
30. Imaging after rUTI
Imaging should start with an RBUS to assess for hydronephrosis, hydroureter, or
bladder abnormalities.
VCUG should be obtained in children with recurrent febrile UTIs to assess for VUR
and other bladder defects.
Special attention should be paid to bladder capacity, postvoid residual, and
bladder wall thickening that may suggest bladder dysfunction
31. Ochoa syndrome or Urofacial syndrome (UFS) is
characterized by urinary bladder or/and bowel
dysfunction along with a characteristic facial
expression that is most obvious during smiling or
laughing wherein one gets an appearance of a
‘grimace’ despite an attempt at smiling (resulting
from abnormal co-contraction of the corners of the
mouth and eyes).
It is inherited as autosomal recessive disorder with
abnormalities in either of two genes – HPSE2
localized on chromosome 10q23-10q24 or LRIG
localized on chromosome 1p13
32. Prophylactic Antibiotics
The RIVUR trial demonstrated a 50% reduction in rUTI among patients on CAP
between the ages of 2 to 71 months with grade I to IV VUR.
The benefit of CAP was particularly evident in girls, patients with febrile index UTI,
and those with BBD.
However, CAP was associated with a 3-fold increase in antibiotic resistance among
stool E coli isolates.
There was no significant impact of CAP on new renal scarring in the RIVUR study,
which was relatively infrequent (8.3%) over the 24-month study period
The Swedish Reflux Trial concluded that girls with high-grade VUR experienced
reduced rates of rUTI and renal scarring compared with placebo controls over a 2-
year period
Brandstrom P et al. The Swedish reflux trial in children: J Urol 2010;184(1):286–91.
Hoberman A, Antimicrobial prophylaxis for children with vesicoureteral reflux. N Engl J Med 2014;370(25):2367–76
33. Other Prophylactic Measures
Cranberry juice and supplements may provide benefit as prophylactic agents by
acidifying the urine due to increased excretion of hippuric acid and/or by
preventing adhesion of UPEC to urothelial cells.
Studies using cranberry products in children have led to conflicting results, and
they differ widely in cranberry dosing and frequency.
Durham SH, Cranberry products for the prophylaxis of urinary UTI in pediatric patients. Ann Pharmacother 2015;49(12): 1349–56
36. Antibiotic Resistance
A correct Dx is the first step to reduce resistance
It takes on average 3 years to develop resistance to an antibiotic after its
introduction
Antibiotic resistance can be reversed if the Antibiotic is removed from the
environment
Prior use of Antibiotics is the most important cause of resistance
37. Mechanisms of resistance
Active removal of the drug by effluence pumps, which lower the intracellular concentration
Inactivation or degradation of the antibiotic
Modification of the bacterial cell wall, which prevents the antibiotic from recognizing its
target site
Biofilm formation
Genetic factors, such as changes in the bacterial genome, which can result from mutations to
chromosomal target genes and acquisition of foreign resistance genes.
Plasmid material that can produce (ESBLs), which allow intrinsic resistance to antibiotics like
trimethoprim, fluoroquinolones, cephalosporins, and aminoglycosides
38. Intestinal microbiome as a risk factor for
urinary tract infections in children
Their prospective case-control study compared the intestinal microbiomes of 37
children with a febrile UTI with those of 69 healthy children.
They sequenced the regions of the bacterial 16S rRNA gene and used the LefSe
algorithm to calculate the size of the linear discriminant analysis (LDA) effect.
They measured fecal lactoferrin, iron concentrations and quantitative PCR for
Escherichia coli
Niko Paalanne et al. European Journal of Clinical Microbiology & Infectious Diseases (2018) 37:1881–1891
39. Enterobacter was more abundant in UTI patients with an LDA score > 3 , while
Peptostreptococcaceae were more abundant in healthy subjects with an LDA score > 3.
In total, 20 OTUs with significantly different abundances were observed.
Previous use of antimicrobials did not associate with intestinal microbiome.
The relative abundance of E. coli was 1.9% in UTI patients and 0.5% in controls
The mean concentration of E.coli in quantitative PCR was 0.14 ng/μl in the patients and
0.08 ng/μl in the controls
Niko Paalanne et al. European Journal of Clinical Microbiology & Infectious Diseases (2018) 37:1881–1891
LEfSe scores linear discriminant analysis (LDA) effect size (LEfSe)
can be interpreted as the degree of consistent difference in relative abundance
between features in the two classes of analyzed microbial communities
40. Intestinal microbiome as a risk factor for
urinary tract infections in children
Enterobacter was more abundant in UTI patients with an LDA score > 3 , while
Peptostreptococcaceae were more abundant in healthy subjects with an LDA score > 3.
In total, 20 OTUs with significantly different abundances were observed.
Previous use of antimicrobials did not associate with intestinal microbiome.
The relative abundance of E. coli was 1.9% in UTI patients and 0.5% in controls
The mean concentration of E.coli in quantitative PCR was 0.14 ng/μl in the patients and
0.08 ng/μl in the controls
Histogram of the LDA scores computed for features differentially abundant between mucosal and non-
mucosal body sites. LEfSe scores can be interpreted as the degree of consistent difference in relative
abundance between features in the two classes of analyzed microbial communities
Niko Paalanne et al. European Journal of Clinical Microbiology & Infectious Diseases (2018) 37:1881–1891
41. Perspectives for the Future Management of
Pediatric Urinary Tract Infection
Role of mass spectrometry and nucleic acid
testing in improving the speed and
accuracy of UTI diagnosis
Mannosides are a novel class of antibiotics
that disrupts high-affinity binding
interactions between type I piliated E coli
and mannosylated receptors on the
bladder mucosal surface
The potential value of rapidly evolving
genomics approaches including analysis of
gene copy number variation and whole
genome sequencing as prognostic tools to
identify patients at risk for UTI recurrence
Urinary tract infections revisited G Godal et al. Kidney International (2007) 71, 721–723
42. Perspectives for the Future Management of
Pediatric Urinary Tract Infection
Role of mass spectrometry and nucleic acid testing in improving the speed and
accuracy of UTI diagnosis
Mannosides are a novel class of antibiotics that disrupts high-affinity binding
interactions between type I piliated E coli and mannosylated receptors on the
bladder mucosal surface
The potential value of rapidly evolving genomics approaches including analysis of
gene copy number variation and whole genome sequencing as prognostic tools
to identify patients at risk for UTI recurrence
43.
44.
45. Take Home messages
1. Think of UTI in any febrile child with no focal signs
2. Urine should be collected by transurethral catheterization or SPA.
3. Start treatment promptly if APN
4. Investigate if recurrent UTI or complicated UTI
5. Value of Prophylactic ATB and Cranberry is controversial
Editor's Notes
Fig 2 Geographical distribution of urinary E coli resistance prevalence to ampicillin (%) by OECD and non-OECD countries,15 with number of included studies per country in parentheses)
