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UTI in children
- 1. Urinary Tract Infection inChildren, revisited DR GABY FALAKHA PEDIATRICIAN-NEONATOLOGIST CHN- ZGHARTA FEBRUARY 25TH, 2019
- 2. Outline 1. Epidemiology 2. Terminology 3.Pathogenesis 4. Diagnosis 5. Management 6. Resistance
- 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 InfectionTerminology 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 UTIcan 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 UTIcan 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 UTIis 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 UrinaryTract 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 UrinaryTract 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 UrinaryTract 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 UrinaryTract 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 AmericanAcademy 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 UrinaryTract 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 UrinaryTract 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 Intoilet 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 Presenceof 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 Viralcystitis 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 Theclinical 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 ofantibiotic 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 ofurinary 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 patternsof uropathogens among children with urinary tract infection in Shiraz. Pouladfar G et al. Medicine (Baltimore). 2017 Sep;96(37):e7834.
- 24. Antimicrobial Susceptibility (%)for E. Coli at AUBMC 1/7/2017-30/6/2018 E Coli Ampicillin Amoxy-Clav Aztreonam Cefepime Cefixime Cefoxitine Cefuroxime Cefotaxime Ceftazidime Pipera/Tazo Imipenem Ciproflox Amikacin Gentamicine Trimeth/Sulfa Nitrofurantoin 22 61 66 67 56 83 52 56 68 88 95 53 99 79 50 97
- 25. Workup After FirstFebrile 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 degreeof 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 ishighly 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 TractInfection 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 Physicalexam 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 orUrofacial 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 TheRIVUR 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
- 35.
- 36. Antibiotic Resistance Acorrect 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 asa 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 wasmore 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 asa 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 theFuture 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 theFuture 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
- 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
- #23 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)